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Issue 38, September 20, 2022

CDC Science Clips: Volume 14, Issue 38, September 20, 2022

This week, Science Clips is pleased to feature articles related to the new CDC Vital Signs on Preventing Sickle Cell Anemia Complications in Children

Sickle cell anemia, which primarily affects Black or African American people, is associated with a shorter life span and life-threatening complications that can affect all parts of the body. These complications cause pain and suffering. Sickle cell anemia is a common cause of childhood stroke.

Two recommended healthcare measures to prevent complications in children with sickle cell anemia are:

  • Transcranial doppler (TCD) ultrasound screening, which identifies children with increased risk for stroke.
  • Hydroxyurea therapy, which reduces the occurrence of several complications, including severe acute pain episodes and acute chest syndrome.
Managing sickle cell anemia in children is complex. These children face discrimination and multiple barriers to care. Racism and prejudice contribute to and worsen these barriers to care, making it harder to receive quality care. This leads to immense physical, emotional, and mental distress for children and their families.

Everyone can help improve care for people with sickle cell anemia by taking steps to address racism and prejudice. The healthcare system can promote tailored strategies to reduce barriers and increase TCD screening and hydroxyurea use among children with sickle cell anemia.


  1. CDC Vital Signs
    • Preventing Sickle Cell Anemia Complications in Children
      1. Hydroxyurea (hydroxycarbamide) is approved for treating both children and adults with sickle cell anaemia (SCA). Fetal haemoglobin (HbF) induction is the primary treatment response, along with improved anaemia, reduced haemolysis, myelosuppression and decreased endothelial inflammation. Hydroxyurea has proven clinical efficacy for SCA - treatment significantly reduces disease manifestations and prolongs survival. Despite these recognised benefits, long-standing concerns regarding the risks of mutagenic and potentially carcinogenic drug exposure have hampered efforts for broad hydroxyurea use in SCA, although these are based largely on outdated experimental models and treatment experiences with myeloproliferative neoplasms. Consequently, many patients with SCA are not receiving this highly effective disease-modifying therapy. In this review, we describe the concept of genotoxicity and its laboratory measurements, summarise hydroxyurea-associated data from both preclinical and clinical studies, and discuss carcinogenic potential. The genotoxicity results clearly demonstrate that hydroxyurea does not directly bind DNA and is not mutagenic. Rather, its genotoxic effects are limited to indirect clastogenicity occurring in select cell types, and only when high dose and time thresholds are exceeded. This absence of mutagenic activity is consistent with the observed lack of any compelling carcinogenic potential. Since hydroxyurea therapy for SCA carries minimal carcinogenic risks, the current drug labelling should be modified accordingly, and prescribing practices should be broadened to allow better access and increased utilisation of this highly effective drug.

      2. This review describes current considerations in the use of hydroxyurea for the management of sickle cell disease in the context of clinical severity. Randomized trials of hydroxyurea have generally enrolled subjects with increased severity based on frequent vaso-occlusive events. An exception was the BABY HUG study in infants which documented substantial benefit even for asymptomatic subjects. Increasing data indicate that hydroxyurea has a substantial effect on reducing mortality in both adults and children-perhaps the most compelling reason for advocating the drug's widespread use. Although the efficacy of hydroxyurea is mediated primarily through increased erythrocyte fetal hemoglobin and much has been learned about the genomic influences on fetal hemoglobin levels in sickle cell disease, our ability to predict the fetal hemoglobin response to hydroxyurea remains limited; much more work in this area is indicated. The review is concluded with the recommendations of the 2014 NIH Evidence-Based Management of Sickle Cell Disease Expert Panel Report.

      3. Barriers to pediatric sickle cell disease guideline recommendations
        Cabana MD, Kanter J, Marsh AM, Treadwell MJ, Rowland M, Stemmler P, Bardach NS.
        Glob Pediatr Health. 2019 ;6:2333794x19847026.
        National guidelines recommend that providers counsel all patients with sickle cell anemia about hydroxyurea (HU) therapy and screen children with sickle cell anemia annually for the risk of stroke with transcranial Doppler (TCD). We surveyed a national convenience sample of sickle cell disease clinicians to assess factors associated with low adherence. Adherence was 46% for TCD screening. Low adherence was associated with a lack of outcome expectancy (eg, a belief that there would be poor patient follow-up to TCD testing; P < .05). Adherence was 72% for HU counseling. Practice barriers (eg, lack of support staff or time) and a lack of agreement with HU recommendations were associated with low adherence (P < .05). This study demonstrates that different types of strategies are needed to improve TCD screening (to address follow-up and access to testing) versus HU counseling (to address physician agreement and practice barriers).

      4. Advances in the diagnosis and treatment of sickle cell disease
        Brandow AM, Liem RI.
        J Hematol Oncol. 2022 Mar 3;15(1):20.
        Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of L-glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.

      5. Transcranial doppler screening in a current cohort of children with sickle cell anemia: Results from the DISPLACE Study
        Kanter J, Phillips S, Schlenz AM, Mueller M, Dooley M, Sirline L, Nickel R, Brown RC, Hilliard L, Melvin CL, Adams RJ.
        J Pediatr Hematol Oncol. 2021 Nov 1;43(8):e1062-e1068.
        Stroke prevention guidelines for sickle cell anemia (SCA) recommend transcranial Doppler (TCD) screening to identify children at stroke risk; however, TCD screening implementation remains poor. This report describes results from Part 1 of the 28-site DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) study, a baseline assessment of TCD implementation rates. This report describes TCD implementation by consortium site characteristics; characteristics of TCDs completed; and TCD results based on age. The cohort included 5247 children with SCA, of whom 5116 were eligible for TCD implementation assessment for at least 1 study year. The majority of children were African American or Black, non-Hispanic and received Medicaid. Mean age at first recorded TCD was 5.9 and 10.5 years at study end. Observed TCD screening rates were unsatisfactory across geographic regions (mean 49.9%; range: 30.9% to 74.7%) independent of size, institution type, or previous stroke prevention trial participation. The abnormal TCD rate was 2.9%, with a median age of 6.3 years for first abnormal TCD result. Findings highlight real-world TCD screening practices and results from the largest SCA cohort to date. Data informed the part 3 implementation study for improving stroke screening and findings may inform clinical practice improvements.

      6. Sickle cell disease: A review
        Kavanagh PL, Fasipe TA, Wun T.
        Jama. 2022 Jul 5;328(1):57-68.
        IMPORTANCE: Sickle cell disease (SCD) is an inherited disorder of hemoglobin, characterized by formation of long chains of hemoglobin when deoxygenated within capillary beds, resulting in sickle-shaped red blood cells, progressive multiorgan damage, and increased mortality. An estimated 30 000 infants are born annually worldwide with SCD. Most individuals with SCD live in sub-Saharan Africa, India, the Mediterranean, and Middle East; approximately 100 000 individuals with SCD live in the US. OBSERVATIONS: SCD is diagnosed through newborn screening programs, where available, or when patients present with unexplained severe atraumatic pain or normocytic anemia. In SCD, sickling and hemolysis of red blood cells result in vaso-occlusion with associated ischemia. SCD is characterized by repeated episodes of severe acute pain and acute chest syndrome, and by other complications including stroke, chronic pain, nephropathy, retinopathy, avascular necrosis, priapism, and leg ulcers. In the US, nearly all children with SCD survive to adulthood, but average life expectancy remains 20 years less than the general population, with higher mortality as individuals transition from pediatric to adult-focused health care systems. Until 2017, hydroxyurea, which increases fetal hemoglobin and reduces red blood cell sickling, was the only disease-modifying therapy available for SCD and remains first-line therapy for most individuals with SCD. Three additional therapies, L-glutamine, crizanlizumab, and voxelotor, have been approved as adjunctive or second-line agents. In clinical trials, L-glutamine reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo. Crizanlizumab reduced pain crises from 2.98 to 1.63 per year compared with placebo. Voxelotor increased hemoglobin by at least 1 g/dL, significantly more than placebo (51% vs 7%). Hematopoietic stem cell transplant is the only curative therapy, but it is limited by donor availability, with best results seen in children with a matched sibling donor. While SCD is characterized by acute and chronic pain, patients are not more likely to develop addiction to pain medications than the general population. CONCLUSIONS AND RELEVANCE: In the US, approximately 100 000 people have SCD, which is characterized by hemolytic anemia, acute and chronic pain, acute chest syndrome; increased incidence of stroke, nephropathy, and retinopathy; and a life span that is 20 years shorter than the general population. While hydroxyurea is first-line therapy for SCD, L-glutamine, crizanlizumab, and voxelotor have been approved in the US since 2017 as adjunctive or second-line treatments, and hematopoietic stem cell transplant with a matched sibling donor is now standard care for severe disease.

      7. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members
        Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J.
        Jama. 2014 Sep 10;312(10):1033-48.
        IMPORTANCE: Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100,000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused. OBJECTIVE: To support and expand the number of health professionals able and willing to provide care for persons with SCD. EVIDENCE REVIEW: Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists. FINDINGS: Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (≥200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated. CONCLUSIONS AND RELEVANCE: Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.

      8. Estimated life expectancy and income of patients with sickle cell disease compared with those without sickle cell disease
        Lubeck D, Agodoa I, Bhakta N, Danese M, Pappu K, Howard R, Gleeson M, Halperin M, Lanzkron S.
        JAMA Netw Open. 2019 Nov 1;2(11):e1915374.
        IMPORTANCE: Individuals with sickle cell disease (SCD) have reduced life expectancy; however, there are limited data available on lifetime income in patients with SCD. OBJECTIVE: To estimate life expectancy, quality-adjusted life expectancy, and income differences between a US cohort of patients with SCD and an age-, sex-, and race/ethnicity-matched cohort without SCD. DESIGN, SETTING, AND PARTICIPANTS: Cohort simulation modeling was used to (1) build a prevalent SCD cohort and a matched non-SCD cohort, (2) identify utility weights for quality-adjusted life expectancy, (3) calculate average expected annual personal income, and (4) model life expectancy, quality-adjusted life expectancy, and lifetime incomes for SCD and matched non-SCD cohorts. Data sources included the Centers for Disease Control and Prevention, National Newborn Screening Information System, and published literature. The target population was individuals with SCD, the time horizon was lifetime, and the perspective was societal. Model data were collected from November 29, 2017, to March 21, 2018, and the analysis was performed from April 28 to December 3, 2018. MAIN OUTCOMES AND MEASURES: Life expectancy, quality-adjusted life expectancy, and projected lifetime income. RESULTS: The estimated prevalent population for the SCD cohort was 87 328 (95% uncertainty interval, 79 344-101 398); 998 were male and 952 were female. Projected life expectancy for the SCD cohort was 54 years vs 76 years for the matched non-SCD cohort; quality-adjusted life expectancy was 33 years vs 67 years, respectively. Projected lifetime income was $ 227 000 for an individual with SCD and $1 922 000 for a matched individual without SCD, reflecting a lost income of $695 000 owing to the 22-year difference in life expectancy. One study limitation is that the higher estimates of life expectancy yielded conservative estimates of lost life-years and income. The analysis only considered the value of lost personal income owing to premature mortality and did not consider direct medical costs or other societal costs associated with excess morbidity (eg, lost workdays for disability, time spent in the hospital). The model was most sensitive to changes in income levels and mortality rates. CONCLUSIONS AND RELEVANCE: In this simulated cohort modeling study, SCD had societal consequences beyond medical costs in terms of reduced life expectancy, quality-adjusted life expectancy, and lifetime earnings. These results underscore the need for disease-modifying therapies to improve the underlying morbidity and mortality associated with SCD.

      9. When actions speak louder than words - racism and sickle cell disease
        Power-Hays A, McGann PT.
        N Engl J Med. 2020 Nov 12;383(20):1902-1903.

      10. Recommendation to reality: Closing the transcranial Doppler screening gap for children with sickle cell anemia
        Singh A, Danda V, Van Swol L, Scott JP, Brandow AM, Panepinto JA.
        Pediatr Blood Cancer. 2021 Feb;68(2):e28831.
        BACKGROUND: Although annual transcranial Doppler (TCD) screening is recommended for children with sickle cell anemia (SCA), compliance is low and variable. Our objective was to utilize an electronic health record (EHR)-based registry to improve TCD adherence among children with SCA, 2-16 years of age, at our institution. METHODS: We developed an in-EPIC real time registry for children with sickle cell disease in year 2016. Since end of year 2016, we have been extracting data quarterly to examine TCD rates and share the list of children who have not received a TCD screen in the past 18 months with the clinical team. The registry also includes a TCD risk score to enhance point of care. We also added Child Life support to increase TCD compliance among children <7 years. Control charts are used to examine TCD rates. RESULTS: At baseline, prior to and start of quarterly data audit and feedback, 63% of children received the recommended annual TCD screen. TCD rates steadily increased to 80% by the third quarter of 2017. We observed a dip in TCD rates, driven by failure of screening young children. Since the initiation of Child Life support for children <7 years, we have sustained TCD screen rates >70%. Overall, our data meet criteria for special cause variation, indicating improvement in TCD rates since 2015. CONCLUSIONS: Regular tracking and identification of patients overdue for a TCD screen using an EHR-based registry resulted in sustained improvement in TCD screening rates. Involvement of Child Life support further improved TCD rates.

  2. CDC Authored Publications
    The names of CDC authors are indicated in bold text.
    Articles published in the past 6-8 weeks authored by CDC or ATSDR staff.
    • Antimicrobial Resistance and Antibiotic Stewardship
      1. Whole-genome sequencing reveals diversity of carbapenem-resistant pseudomonas aeruginosa collected through CDC's Emerging Infections Program, United States, 2016-2018
        Stanton RA, Campbell D, McAllister GA, Breaker E, Adamczyk M, Daniels JB, Lutgring JD, Karlsson M, Schutz K, Jacob JT, Wilson LE, Vaeth E, Li L, Lynfield R, Snippes Vagnone PM, Phipps EC, Hancock EB, Dumyati G, Tsay R, Cassidy PM, Mounsey J, Grass JE, Bulens SN, Walters MS, Halpin AL.
        Antimicrob Agents Chemother. 2022 Sep 6:e0049622.
        The CDC's Emerging Infections Program (EIP) conducted population- and laboratory-based surveillance of US carbapenem-resistant Pseudomonas aeruginosa (CRPA) from 2016 through 2018. To characterize the pathotype, 1,019 isolates collected through this project underwent antimicrobial susceptibility testing and whole-genome sequencing. Sequenced genomes were classified using the seven-gene multilocus sequence typing (MLST) scheme and a core genome (cg)MLST scheme was used to determine phylogeny. Both chromosomal and horizontally transmitted mechanisms of carbapenem resistance were assessed. There were 336 sequence types (STs) among the 1,019 sequenced genomes, and the genomes varied by an average of 84.7% of the cgMLST alleles used. Mutations associated with dysfunction of the porin OprD were found in 888 (87.1%) of the genomes and were correlated with carbapenem resistance, and a machine learning model incorporating hundreds of genetic variations among the chromosomal mechanisms of resistance was able to classify resistant genomes. While only 7 (0.1%) isolates harbored carbapenemase genes, 66 (6.5%) had acquired non-carbapenemase β-lactamase genes, and these were more likely to have OprD dysfunction and be resistant to all carbapenems tested. The genetic diversity demonstrates that the pathotype includes a variety of strains, and clones previously identified as high-risk make up only a minority of CRPA strains in the United States. The increased carbapenem resistance in isolates with acquired non-carbapenemase β-lactamase genes suggests that horizontally transmitted mechanisms aside from carbapenemases themselves may be important drivers of the spread of carbapenem resistance in P. aeruginosa.

    • Chronic Diseases and Conditions
      1. Blood pressure cuff sizes for adults in the United States: National Health and Nutrition Examination Survey, 2015-2020
        Jackson SL, Gillespie C, Shimbo D, Rakotz M, Wall HK.
        Am J Hypertens. 2022 Sep 6.
        BACKGROUND: Hypertension, defined as blood pressure (BP) ≥130/80 mm Hg or antihypertensive medication use, affects approximately half of US adults, and appropriately-sized BP cuffs are important for accurate BP measurement and hypertension management. METHODS: This cross-sectional study analyzed 13,038 US adults (≥18y) in the National Health and Nutrition Examination Survey 2015-March 2020 cycles. Recommended BP cuff sizes were categorized based on mid-arm circumference: small adult (≤26 cm), adult (>26 to ≤34 cm), large adult (>34 to ≤44 cm), and extra-large adult (>44 cm). Analyses were weighted and proportions were extrapolated to the US population. RESULTS: Among US adults (246 million), recommended cuff sizes were: 6% (16 million) small adult, 51% adult (125 million), 40% large adult (98 million), and 3% extra-large adult (8 million). Among adults with hypertension (116 million), large or extra-large cuffs were needed by over half (51%) overall, including 65% of those aged 18-34 and 84% of those with obesity (BMI ≥30 kg/m 2). By race/ethnicity, the proportion needing a large or extra-large cuff was 57% of non-Hispanic Black adults, 54% of Hispanic adults, 51% of non-Hispanic White adults, and 23% of non-Hispanic Asian adults. Approximately 40% of adults with hypertension in Medicare needed a large or extra-large cuff, compared to 54% for private insurance and 53% for Medicaid. CONCLUSIONS: Over half of US adults with hypertension need a large or extra-large BP cuff.

      2. Utilization of preventive services in a systemic lupus erythematosus population-based cohort: a Lupus Midwest Network (LUMEN) study
        Chevet B, Figueroa-Parra G, Yang JX, Hocaoglu M, Osei-Onomah SA, Hulshizer CA, Gunderson TM, Cornec D, Barbour KE, Greenlund KJ, Crowson CS, Duarte-García A.
        Arthritis Res Ther. 2022 Sep 1;24(1):211.
        BACKGROUND: Systemic lupus erythematosus (SLE) is a disease that can lead to damage of multiple organs and, along with certain treatments, increase the risk of developing cancer, cardiovascular disease, diabetes, osteoporosis, and infections. Preventive services are particularly important in patients with SLE to mitigate the aforementioned risks. We aimed to evaluate the trends of preventive services utilization in patients with systemic lupus erythematosus, compared with non-SLE population. METHODS: All ≥19-year-old patients in the Lupus Midwest Network (LUMEN) registry, a population-based cohort, with SLE on January 1, 2015, were included and matched (1:1) by sex, age, race, and county to non-SLE comparators. Among both groups, we compared the rates of screenings for breast and cervical cancer, hypertension, hyperlipidemia, diabetes mellitus, and osteoporosis as well as immunizations. RESULTS: We included 440 SLE patients and 430 non-SLE comparators. The probability of breast cancer screening among women with SLE was similar to comparators (hazard ratio [HR] 1.09, 95% CI 0.85-1.39), while cervical cancer screening was lower (HR 0.75, 95% CI 0.58-0.96). Hypertension screening was higher among patients with SLE (HR 1.35, 95% CI 1.13-1.62); however, hyperlipidemia screening was similar to comparators (HR 1.16, 95% CI 0.96-1.41). Diabetes and osteoporosis screenings were more likely to be performed for SLE patients than for comparators (HR 2.46, 95% CI 2.11-2.87; and HR 3.19, 95% CI 2.31-4.41; respectively). Influenza and pneumococcal immunizations were higher among SLE patients (HR 1.31, 95% CI 1.12-1.54; and HR 2.06, 95% CI 1.38-3.09; respectively), while zoster vaccination was similar (HR 1.17, 95% CI 0.81-1.69). CONCLUSIONS: The trends of utilization of preventive services by SLE patients vary according to screening or vaccine compared with the general population. Considering these differences, we demonstrate an opportunity for improvement, particularly in cervical cancer, hyperlipidemia, and osteoporosis screenings and vaccinations.

      3. Pediatric rhabdomyosarcoma incidence and survival in the United States: An assessment of 5656 cases, 2001-2017
        McEvoy MT, Siegel DA, Dai S, Okcu MF, Zobeck M, Venkatramani R, Lupo PJ.
        Cancer Med. 2022 Sep 7.
        BACKGROUND: While rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents, past epidemiology studies of this malignancy used data that covered <30% of the US population. Therefore, we evaluated RMS incidence using data from U.S. Cancer Statistics (USCS) and survival trends using the National Program of Cancer Registries (NPCR), which covers 100% and 94% of the U.S. population, respectively. METHODS: Incidence and survival were assessed for pediatric patients diagnosed with RMS during 2003-2017 and 2001-2016, respectively. Both demographic and clinical variables were evaluated. Age-adjusted incidence rates, average annual percent change (AAPC), and 5-year relative survival (RS) were calculated, all with corresponding 95% confidence intervals (CIs). Cox regression models were used to evaluate the impact of demographic and clinical variables on survival. RESULTS: We identified 5656 primary RMS cases in USCS during 2003-2017. The age-adjusted incidence rate was 4.58 per 1 million (95% CI: 4.46-4.70) with an AAPC of 0.3% (95% CI: -0.7 to 1.2%). In NPCR, 5-year RS for all cases was 68.0% (95% CI: 66.6-69.3%). In multivariable analyses, non-Hispanic (NH) Black cases had worse survival compared with NH White cases (hazard ratio [HR] = 1.16, 95% CI: 1.01-1.33). CONCLUSION: The incidence and survival rates were stable in the largest and most comprehensive population-based analysis for pediatric RMS cases in the U.S. Additionally, we observed a survival disparity among NH Black cases. Findings from this study could inform interventions to address disparities, risk stratification strategies, and clinical trial design.

      4. Cost-effectiveness of pharmacologic treatment options for women with endocrine-refractory or triple-negative metastatic breast cancer
        Wheeler SB, Rotter J, Gogate A, Reeder-Hayes KE, Drier SW, Ekwueme DU, Fairley TL, Rocque GB, Trogdon JG.
        J Clin Oncol. 2022 Sep 2:Jco2102473.
        PURPOSE: Treatments for endocrine-refractory or triple-negative metastatic breast cancer (mBC) are modestly effective at prolonging life and improving quality of life but can be extremely expensive. Given these tradeoffs in quality of life and cost, the optimal choice of treatment sequencing is unclear. Cost-effectiveness analysis can explicitly quantify such tradeoffs, enabling more informed decision making. Our objective was to estimate the societal cost-effectiveness of different therapeutic alternatives in the first- to third-line sequences of single-agent chemotherapy regimens among patients with endocrine-refractory or triple-negative mBC. METHODS: Using three dynamic microsimulation models of 10,000 patients each, three cohorts were simulated, based upon prior chemotherapy exposure: (1) unexposed to either taxane or anthracycline, (2) taxane- and anthracycline-exposed, and (3) taxane-exposed/anthracycline-naive. We focused on the following single-agent chemotherapy regimens as reasonable and commonly used options in the first three lines of therapy for each cohort, based upon feedback from oncologists treating endocrine-refractory or triple-negative mBC: (1) for taxane- and anthracycline-unexposed patients, paclitaxel, capecitabine (CAPE), or pegylated liposomal doxorubicin; (2) for taxane- and anthracycline-exposed patients, Eribulin, CAPE, or carboplatin; and (3) for taxane-exposed/anthracycline-naive patients, pegylated liposomal doxorubicin, CAPE, or Eribulin. RESULTS: In each cohort, accumulated quality-adjusted life-years were similar between regimens, but total societal costs varied considerably. Sequences beginning first-line treatment with paclitaxel, carboplatin, and CAPE, respectively, for cohorts 1, 2, and 3, had lower costs and similar or slightly better outcomes compared with alternative options. CONCLUSION: In this setting where multiple single-agent chemotherapy options are recommended by clinical guidelines and share similar survival and adverse event trajectories, treatment sequencing approaches that minimize costs early may improve the value of care.

      5. A longitudinal assessment of diabetes autoantibodies in the SEARCH for diabetes in youth study
        Merjaneh L, Dolan LM, Suerken CK, D'Agostino R, Imperatore G, Saydah S, Roberts A, Marcovina S, Mayer-Davis EJ, Dabelea D, Lawrence JM, Pihoker C.
        Pediatr Diabetes. 2022 Aug 17.
        To assess changes in diabetes autoantibodies (DAs) over time in children and young adults with diabetes and determine whether observed changes were associated with demographic characteristics, clinical parameters and diabetes complications. Participants had DAs measured at baseline (10.3 ± 7.1 months after diabetes diagnosis) and at 12, 24 months and ≥5 years after the baseline measurement. At the ≥5-year follow-up, the presence of diabetes complications was assessed. We examined the associations between change in number of positive DAs and changes in individual DA status with the participants' characteristics and clinical parameters over time. Out of 4179 participants, 62% had longitudinal DA data and 51% had complications and longitudinal DA data. In participants with ≥1 baseline positive DA (n = 1699), 83.4% remained positive after 7.3 ± 2.3 years duration of diabetes. Decrease in number of positive DAs was associated with longer diabetes duration (p = 0.003 for 1 baseline positive DA; p < 0.001 for 2 baseline positive DAs) and younger age at diagnosis (p < 0.001 for 2 baseline positive DAs). No associations were found between change in number of positive DAs in participants with ≥1 baseline positive DA (n = 1391) and HbA1c, insulin dose, acute, or chronic complications after 7.7 ± 1.9 years duration of diabetes. DA status likely remains stable in the first 7 years after diabetes diagnosis. Younger age at diabetes diagnosis and longer duration were associated with less persistence of DAs. Measuring DAs after initial presentation may aid in diabetes classification but not likely in predicting the clinical course.

    • Communicable Diseases
      1. An assessment of household knowledge and practices during a cholera epidemic-dar es Salaam, Tanzania, 2016
        Chae SR, Lukupulo H, Kim S, Walker T, Hardy C, Abade A, Urio LJ, Mghamba J, Quick R.
        Am J Trop Med Hyg. 2022 Sep 6.
        From August 15, 2015 to March 5, 2016, Tanzania reported 16,521 cholera cases and 251 deaths, with 4,596 cases and 44 deaths in its largest city, Dar es Salaam. To evaluate outbreak response efforts, we conducted a household survey with drinking water testing in the five most affected wards in Dar es Salaam. We interviewed 641 households 6 months after the beginning of the outbreak. Although most respondents knew that cholera causes diarrhea (90%) and would seek care if suspecting cholera (95%), only 45% were aware of the current outbreak in the area and only 5% would use oral rehydration salts (ORS) if ill. Of 200 (31%) respondents reporting no regular water treatment, 46% believed treatment was unnecessary and 18% believed treatment was too expensive. Fecal contamination was found in 45% of water samples and was associated with water availability (P = 0.047). Only 11% of samples had detectable free chlorine residual, which was associated with water availability (P = 0.025), reported current water treatment (P = 0.006), and observed free chlorine product in the household (P = 0.015). The provision of accessible, adequately chlorinated water supply, and implementation of social mobilization campaigns advocating household water treatment and use of ORS should be prioritized to address gaps in cholera prevention and treatment activities.

      2. Sexual and reproductive health needs and practices of female sex workers in Papua New Guinea: findings from a biobehavioral survey Kauntim mi tu ('Count me too')
        Weikum D, Kelly-Hanku A, Neo-Boli R, Aeno H, Badman SG, Vallely LM, Willie B, Kupul M, Hou P, Amos A, Narokobi R, Pekon S, Coy K, Wapling J, Gare J, Kaldor JM, Vallely AJ, Hakim AJ.
        Arch Public Health. 2022 Sep 5;80(1):202.
        BACKGROUND: Little research has explored the sexual and reproductive health (SRH) experience of female sex workers (FSW), including girls aged < 18 years who are commercially sexually exploited (CSE), in Papua New Guinea (PNG). This paper describes the SRH history of FSW and CSE girls and factors associated with their use of moderately or highly effective contraceptive methods in three settings in PNG. METHODS: From 2016 to 2017, respondent-driven sampling (RDS) surveys were conducted among FSW and CSE girls in Port Moresby, Lae, and Mt. Hagen. FSW and CSE girls who were born female, aged ≥12 years, sold or exchanged vaginal sex in the past 6 months, spoke English or Tok Pisin, and had a valid RDS study coupon were eligible to participate. Interviews were conducted face-to-face and participants were offered rapid routine HIV and syphilis testing. Survey logistic regression procedures were used to identify factors associated with the use of moderately or highly effective contraceptive methods. Weighted data analysis was conducted. RESULTS: A total of 2901 FSW and CSE girls (Port Moresby, 673; Lae, 709; and Mt. Hagen, 709) were enrolled. The proportion using moderately or highly effective contraceptive methods was 37.7% in Port Moresby, 30.9% in Lae, and 26.5% in Mt. Hagen. After adjusting for covariates, factors significantly associated with the use of moderately or highly effective contraceptive methods in Port Moresby were being age 20-24, being married, being divorced or separated, having one or more dependent children, being away from home for more than 1 month in the last 6 months, and having tested HIV negative. No factors were significantly associated in Lae or Mt. Hagen. ANC attendance amongst FSW and CSE girls who gave birth in last 3 years was highest in Port Moresby at 91.2%. HIV testing was inconsistently and inadequately offered at ANC across the three cities. CONCLUSIONS: Kauntim mi tu provides much-needed insight into the SRH experiences of FSW and CSE girls in PNG, where their use of moderately or highly effective contraceptive methods is low. We hope to shed light on the complicated reality they face due to illegality of sex work and multitude of complex healthcare experiences.

      3. Pregnancy and infant outcomes by trimester of SARS-CoV-2 infection in pregnancy-SET-NET, 22 jurisdictions, January 25, 2020-December 31, 2020
        Neelam V, Reeves EL, Woodworth KR, O'Malley Olsen E, Reynolds MR, Rende J, Wingate H, Manning SE, Romitti P, Ojo KD, Silcox K, Barton J, Mobley E, Longcore ND, Sokale A, Lush M, Delgado-Lopez C, Diedhiou A, Mbotha D, Simon W, Reynolds B, Hamdan TS, Beauregard S, Ellis EM, Seo JY, Bennett A, Ellington S, Hall AJ, Azziz-Baumgartner E, Tong VT, Gilboa SM.
        Birth Defects Res. 2022 Sep 6.
        OBJECTIVES: We describe clinical characteristics, pregnancy, and infant outcomes in pregnant people with laboratory-confirmed SARS-CoV-2 infection by trimester of infection. STUDY DESIGN: We analyzed data from the Surveillance for Emerging Threats to Mothers and Babies Network and included people with infection in 2020, with known timing of infection and pregnancy outcome. Outcomes are described by trimester of infection. Pregnancy outcomes included live birth and pregnancy loss (<20 weeks and ≥20 weeks gestation). Infant outcomes included preterm birth (<37 weeks gestation), small for gestational age, birth defects, and neonatal intensive care unit admission. Adjusted prevalence ratios (aPR) were calculated for pregnancy and selected infant outcomes by trimester of infection, controlling for demographics. RESULTS: Of 35,200 people included in this analysis, 50.8% of pregnant people had infection in the third trimester, 30.8% in the second, and 18.3% in the first. Third trimester infection was associated with a higher frequency of preterm birth compared to first or second trimester infection combined (17.8% vs. 11.8%; aPR 1.44 95% CI: 1.35-1.54). Prevalence of birth defects was 553.4/10,000 live births, with no difference by trimester of infection. CONCLUSIONS: There were no signals for increased birth defects among infants in this population relative to national baseline estimates, regardless of timing of infection. However, the prevalence of preterm birth in people with SARS-CoV-2 infection in pregnancy in our analysis was higher relative to national baseline data (10.0-10.2%), particularly among people with third trimester infection. Consequences of COVID-19 during pregnancy support recommended COVID-19 prevention strategies, including vaccination.

      4. We analyzed a national pharmacy database to estimate the annual number of persons who abandoned preexposure prophylaxis (PrEP) prescriptions and assessed associated factors. About 9% of persons prescribed PrEP abandoned prescriptions in 2019; abandonment was associated with sex, age, insurance type, black race/ethnicity, and drug copayment amount.

      5. Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at high viral loads among hospitalized immunocompromised persons living with human immunodeficiency virus (HIV), South Africa
        Meiring S, Tempia S, Bhiman JN, Buys A, Kleynhans J, Makhasi M, McMorrow M, Moyes J, Quan V, Walaza S, Plessis Md, Wolter N, Gottberg Av, Cohen C.
        Clin Infect Dis. 2022 ;75(1):e144-e156.
        Background: We assessed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding duration and magnitude among persons living with human immunodeficiency virus (HIV, PLHIV).

      6. Background: A better understanding of the risk for coronavirus disease 2019 (COVID-19) that people experiencing homelessness (PEH) face in congregate shelters versus unsheltered encampments is critical for an effective pandemic response.

      7. 'They can stigmatize you': a qualitative assessment of the influence of school factors on engagement in care and medication adherence among adolescents with HIV in Western Kenya
        Wiggins L, O'Malley G, Wagner AD, Mutisya I, Wilson KS, Lawrence S, Moraa H, Kinuthia J, Itindi J, Muhenje O, Chen TH, Singa B, McGrath CJ, Ngugi E, Katana A, Ng Ang AL, John-Stewart G, Kholer P, Beima-Sofie K.
        Health Educ Res. 2022 Sep 2.
        School-related factors may influence retention in care and adherence to antiretroviral therapy (ART) among adolescents with human immunodeficiency virus (HIV). We analyzed data from in-depth interviews with 40 adolescents with HIV (aged 14 -19 years), 40 caregivers of adolescents with HIV, and 4 focus group discussions with healthcare workers to evaluate contextual factors affecting adherence to ART and clinic attendance among adolescents, with a focus on the school environment. Informed by Anderson's Model of Health Services Utilization, transcripts were systematically coded and synthesized to identify school-related themes. All groups identified the school environment as a critical barrier to engagement in HIV care and medication adherence for adolescents with HIV. Adolescent participants reported inflexible school schedules and disclosure to school staff as the biggest challenges adhering to clinic appointments and ART. Adolescents described experiencing stigma and discrimination by peers and school staff and would adjust when, where and how often they took ART to avoid inadvertent disclosure. Boarding school students faced challenges because they had limited private space or time. Caregivers were often instrumental in navigating school permissions, including identifying a treatment supporter among school staff. Additional research engaging school staff may guide interventions for schools to reduce stigma and improve adherence and retention.

      8. The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis
        Rajasingham R, Govender NP, Jordan A, Loyse A, Shroufi A, Denning DW, Meya DB, Chiller TM, Boulware DR.
        Lancet Infect Dis. 2022 Aug 29.
        BACKGROUND: Cryptococcal meningitis is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. The estimates of national, regional, and global burden of cryptococcal meningitis are essential to guide prevention strategies and determine needs for diagnostic tests and treatments. We present a 2020 estimate of the global burden of HIV-associated cryptococcal infection (antigenaemia), cryptococcal meningitis, and cryptococcal-associated deaths. METHODS: We defined advanced HIV disease as adults with a CD4 count of less than 200 cells/μL, as this group is at highest risk for cryptococcosis. We used UNAIDS estimates (2019-20) and population-based HIV impact assessment surveys (2016-18) to estimate the number of adults with CD4 counts of less than 200 cells/μL at risk for cryptococcosis, by country and region. Secondly, we summarised cryptococcal antigenaemia prevalence in those with a CD4 count of less than 200 cells/μL by reviewing published literature. Thereafter, we calculated the number of cryptococcal antigen (CrAg)-positive people in each country and region by multiplying the number with advanced HIV disease at risk for cryptococcal infection by the cryptococcal antigenaemia prevalence of the respective country or region. We estimated progression from cryptococcal antigenaemia to meningitis or death based on estimates from the published literature. FINDINGS: We estimated that there were 4·3 million (IQR 3·0-4·8) adults with HIV and CD4 counts of less than 200 cells/μL globally in 2020. We calculated a mean global cryptococcal antigenaemia prevalence of 4·4% (95% CI 1·6-7·4) among HIV-positive people with CD4 counts of less than 200 cells/μL, corresponding to 179 000 cases (IQR 133 000-219 000) of cryptococcal antigenaemia globally in 2020. Annually, we estimated that there are 152 000 cases (111 000-185 000) of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deaths (79 000-134 000). Globally, cryptococcal disease accounts for 19% (13-24) of AIDS-related mortality. INTERPRETATION: Despite a reduction in the estimated absolute global burden of HIV-associated cryptococcal meningitis compared with 2014, likely to be due to antiretroviral therapy expansion, cryptococcal disease still accounts for 19% of AIDS-related deaths, similar to 2014 estimates. To end cryptococcal meningitis deaths by 2030, cryptococcal diagnostics, meningitis treatments, and implementation of preventive screening are urgently needed. FUNDING: None.

      9. Strategies adopted by gay, bisexual, and other men who have sex with men to prevent Monkeypox virus transmission - United States, August 2022
        Delaney KP, Sanchez T, Hannah M, Edwards OW, Carpino T, Agnew-Brune C, Renfro K, Kachur R, Carnes N, DiNenno EA, Lansky A, Ethier K, Sullivan P, Baral S, Oster AM.
        MMWR Morb Mortal Wkly Rep. 2022 Sep 2;71(35).

      10. Modeling the impact of sexual networks in the transmission of monkeypox virus among gay, bisexual, and other men who have sex with men - United States, 2022
        Spicknall IH, Pollock ED, Clay PA, Oster AM, Charniga K, Masters N, Nakazawa YJ, Rainisch G, Gundlapalli AV, Gift TL.
        MMWR Morb Mortal Wkly Rep. 2022 Sep 2;71(35):1131-1135.

      11. Pretomanid in the treatment of patients with tuberculosis in the United States
        Goswami ND, Ashkin D, Haley CA.
        N Engl J Med. 2022 Sep 1;387(9):850-852.

      12. Seroprevalence of SARS-CoV-2 in four states of Nigeria in October 2020: a population-based household survey
        Audu RA, Stafford KA, Steinhardt L, Musa ZA, Iriemenam N, Ilori E, Blanco N, Mitchell A, Hamada Y, Moloney M, Iwara E, Abimiku A, Ige FA, William NE, Igumbor E, Ochu C, Omoare AA, Okunoye O, Greby SM, Rangaka MX, Copas A, Dalhatu I, Abubakar I, McCracken S, Alagi M, Mba N, Anthony A, Okoye M, Okoi C, Ezechi OC, Salako BL, Ihekweazu C.
        PLoS Glob Public Health. 2022 ;2(6).
        The observed epidemiology of SARS-CoV-2 in sub-Saharan Africa has varied greatly from that in Europe and the United States, with much lower reported incidence. Population-based studies are needed to estimate true cumulative incidence of SARS-CoV-2 to inform public health interventions. This study estimated SARS-CoV-2 seroprevalence in four selected states in Nigeria in October 2020. We implemented a two-stage cluster sample household survey in four Nigerian states (Enugu, Gombe, Lagos, and Nasarawa) to estimate age-stratified prevalence of SARS-CoV-2 antibodies. All individuals in sampled households were eligible for interview, blood draw, and nasal/oropharyngeal swab collection. We additionally tested participants for current/recent malaria infection. Seroprevalence estimates were calculated accounting for the complex survey design. Across all four states, 10,629 (96.5%) of 11,015 interviewed individuals provided blood samples. The seroprevalence of SARS-CoV- 2 antibodies was 25.2% (95% CI 21.8-28.6) in Enugu State, 9.3% (95% CI 7.0-11.5) in Gombe State, 23.3% (95% CI 20.5-26.4) in Lagos State, and 18.0% (95% CI 14.4-21.6) in Nasarawa State. Prevalence of current/recent malaria infection ranged from 2.8% in Lagos to 45.8% in Gombe and was not significantly related to SARS-CoV-2 seroprevalence. The prevalence of active SARS-CoV-2 infection in the four states during the survey period was 0.2% (95% CI 0.1-0.4). Approximately eight months after the first reported COVID-19 case in Nigeria, seroprevalence indicated infection levels 194 times higher than the 24,198 officially reported COVID-19 cases across the four states; however, most of the population remained susceptible to COVID-19 in October 2020.

      13. Spatial analysis of genetic clusters and epidemiologic factors related to wild Poliovirus type 1 persistence in Afghanistan and Pakistan
        Mendesid A, Whiteman A, Bullard K, Sharif S, Khurshidid A, Alam MM, Salman M, Fordid V, Blairid T, Burns CC, Ehrhardt D, Jorba J, Hsuid CH.
        PLoS Glob Public Health. 2022 ;2(6).
        Following the certification of the World Health Organization Region of Africa as free of serotype 1 wild poliovirus (WPV1) in 2020, Afghanistan and Pakistan represent the last remaining WPV1 reservoirs. As efforts continue in these countries to progress to eradication, there is an opportunity for a deeper understanding of the spatiotemporal characteristics and epidemiological risk factors associated with continual WPV1 circulation in the region. Using poliovirus surveillance data from 2017-2019, we used pairwise comparisons of VP1 nucleotide sequences to illustrate the spatiotemporal WPV1 dispersal to identify key sources and destinations of potentially infected, highly mobile populations. We then predicted the odds of WPV1 detection at the district level using a generalized linear model with structural indicators of health, security, environment, and population demographics. We identified evidence of widespread population mobility based on WPV1 dispersal within and between the countries, and evidence indicating five districts in Afghanistan (Arghandab, Batikot, Bermel, Muhamandara and Nawzad) and four districts in Pakistan (Charsada, Dera Ismail Khan, Killa Abdullah and Khyber) act as cross-border WPV1 circulation reservoirs. We found that the probability of detecting WPV1 in a district increases with each armed conflict event (OR = 1.024, +- 0.008), level of food insecurity (OR = 1.531, +-0.179), and mean degrees Celsius during the months of greatest precipitation (OR = 1.079, +- 0.019). Our results highlight the multidisciplinary complexities contributing to the continued transmission of WPV1 in Afghanistan and Pakistan. We discuss the implications of our results, stressing the value of coordination during this final chapter of the wild polio virus eradication initiative.

      14. Diagnostics to support the eradication of yaws-Development of two target product profiles
        Fongwen N, Handley BL, Martin DL, Beiras C, Dyson L, Frimpong M, Mitja O, Asiedu K, Marks M.
        PLoS Negl Trop Dis. 2022 Sep 1;16(9):e0010554.
        BACKGROUND: Yaws is targeted for eradication by 2030, using a strategy based on mass drug administration (MDA) with azithromycin. New diagnostics are needed to aid eradication. Serology is currently the mainstay for yaws diagnosis; however, inaccuracies associated with current serological tests makes it difficult to fully assess the need for and impact of eradication campaigns using these tools. Under the recommendation of the WHO Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases(NTDs), a working group was assembled and tasked with agreeing on priority use cases for developing target product profiles (TPPs) for new diagnostics tools. METHODOLOGY AND PRINCIPAL FINDINGS: The working group convened three times and established two use cases: identifying a single case of yaws and detecting azithromycin resistance. One subgroup assessed the current diagnostic landscape for yaws and a second subgroup determined the test requirements for both use cases. Draft TPPs were sent out for input from stakeholders and experts. Both TPPs considered the following parameters: product use, design, performance, configuration, cost, access and equity. To identify a single case of yaws, the test should be able to detect an analyte which confirms an active infection with at least 95% sensitivity and 99.9% specificity. The high specificity was deemed important to avoid a high false positive rate which could result in unnecessary continuation or initiation of MDA campaigns. If used in settings where the number of suspected cases is low, further testing could be considered to compensate for imperfect sensitivity and to improve specificity. The test to detect azithromycin resistance should be able to detect known genetic resistance mutations with a minimum sensitivity and specificity of 95%, with the caveat that all patients with suspected treatment failure should be treated as having resistant yaws and offered alternative treatment. CONCLUSIONS: The TPPs developed will provide test developers with guidance to ensure that novel diagnostic tests meet identified public health needs.

      15. Acute febrile illness among outpatients seeking health care in Bangladeshi hospitals prior to the COVID-19 pandemic
        Das P, Rahman MZ, Banu S, Rahman M, Chisti MJ, Chowdhury F, Akhtar Z, Palit A, Martin DW, Anwar MU, Namwase AS, Angra P, Kato CY, Ramos CJ, Singleton J, Stewart-Juba J, Patel N, Condit M, Chung IH, Galloway R, Friedman M, Cohen AL.
        PLoS One. 2022 ;17(9):e0273902.
        Understanding the distribution of pathogens causing acute febrile illness (AFI) is important for clinical management of patients in resource-poor settings. We evaluated the proportion of AFI caused by specific pathogens among outpatients in Bangladesh. During May 2019-March 2020, physicians screened patients aged ≥2 years in outpatient departments of four tertiary level public hospitals. We randomly enrolled patients having measured fever (≥100.4°F) during assessment with onset within the past 14 days. Blood and urine samples were tested at icddr,b through rapid diagnostic tests, bacterial culture, and polymerase chain reaction (PCR). Acute and convalescent samples were sent to the Centers for Disease Control and Prevention (USA) for Rickettsia and Orientia (R/O) and Leptospira tests. Among 690 patients, 69 (10%) had enteric fever (Salmonella enterica serotype Typhi orSalmonella enterica serotype Paratyphi), 51 (7.4%) Escherichia coli, and 28 (4.1%) dengue detected. Of the 441 patients tested for R/O, 39 (8.8%) had rickettsioses. We found 7 (2%) Leptospira cases among the 403 AFI patients tested. Nine patients (1%) were hospitalized, and none died. The highest proportion of enteric fever (15%, 36/231) and rickettsioses (14%, 25/182) was in Rajshahi. Dhaka had the most dengue cases (68%, 19/28). R/O affected older children and young adults (IQR 8-23 years) and was detected more frequently in the 21-25 years age-group (17%, 12/70). R/O was more likely to be found in patients in Rajshahi region than in Sylhet (aOR 2.49, 95% CI 0.85-7.32) between July and December (aOR 2.01, 1.01-5.23), and who had a history of recent animal entry inside their house than not (aOR 2.0, 0.93-4.3). Gram-negative Enterobacteriaceae were the most common bacterial infections, and dengue was the most common viral infection among AFI patients in Bangladeshi hospitals, though there was geographic variability. These results can help guide empiric outpatient AFI management.

      16. Toward elimination of mother-to-child transmission of HIV in Malawi: Findings from the Malawi Population-based HIV Impact Assessment (2015-2016)
        Kim E, Jonnalagadda S, Cuervo-Rojas J, Jahn A, Payne D, West C, Ogollah F, Maida A, Kayira D, Nyirenda R, Dobbs T, Patel H, Radin E, Voetsch A, Auld A.
        PLoS One. 2022 ;17(9):e0273639.
        BACKGROUND: Malawi spearheaded the development and implementation of Option B+ for prevention of mother-to-child transmission of HIV (PMTCT), providing life-long ART for all HIV-positive pregnant and breastfeeding women. We used data from the 2015-2016 Malawi Population-based HIV Impact Assessment (MPHIA) to estimate progress toward 90-90-90 targets (90% of those with HIV know their HIV-positive status; of these, 90% are receiving ART; and of these, 90% have viral load suppression [VLS]) for HIV-positive women reporting a live birth in the previous 3 years. METHODS: MPHIA was a nationally representative household survey; consenting eligible women aged 15-64 years were interviewed on pregnancies and outcomes, including HIV status during their most recent pregnancy, PMTCT uptake, and early infant diagnosis (EID) testing. Descriptive analyses were weighted to account for the complex survey design. Viral load (VL) results were categorized by VLS (<1,000 copies/mL) and undetectable VL (target not detected/below the limit of detection). RESULTS: Of the 3,153 women included in our analysis, 371 (10.1%, 95% confidence interval [CI]: 8.8%-11.3%) tested HIV positive in the survey. Most HIV-positive women (84.2%, 95% CI: 79.9%-88.6%) reported knowing their HIV-positive status; of these, 94.9% (95% CI: 91.7%-98.2%) were receiving ART; and of these, 91.2% (95% CI: 87.4%-95.0%) had VLS. Among the 371 HIV-positive women, 76.0% (95% CI: 70.4%-81.7%) had VLS and 66.5% (95% CI: 59.8%-73.2%) had undetectable VL. Among 262 HIV-exposed children, 50.8% (95% CI: 42.8%-58.8%) received EID testing within 2 months of birth, whereas 17.9% (95% CI: 11.9%-23.8%) did not receive EID testing. Of 190 HIV-exposed children with a reported HIV test result, 2.1% (95% CI: 0.0%-4.6%) had positive results. CONCLUSIONS: MPHIA data demonstrate high PMTCT uptake at a population level. However, our results identify some gaps in VLS in postpartum women and EID testing.

      17. Low quality antibody responses in critically ill patients hospitalized with pandemic influenza A(H1N1)pdm09 virus infection
        Lu X, Guo Z, Li ZN, Holiday C, Liu F, Jefferson S, Gross FL, Tzeng WP, Kumar A, York IA, Uyeki TM, Tumpey T, Stevens J, Levine MZ.
        Sci Rep. 2022 Sep 2;12(1):14971.
        Although some adults infected with influenza 2009 A(H1N1)pdm09 viruses mounted high hemagglutination inhibition (HAI) antibody response, they still suffered from severe disease, or even death. Here, we analyzed antibody profiles in patients (n = 31, 17-65 years) admitted to intensive care units (ICUs) with lung failure and invasive mechanical ventilation use due to infection with A(H1N1)pdm09 viruses during 2009-2011. We performed a comprehensive analysis of the quality and quantity of antibody responses using HAI, virus neutralization, biolayer interferometry, enzyme-linked-lectin and enzyme-linked immunosorbent assays. At time of the ICU admission, 45% (14/31) of the patients had HAI antibody titers ≥ 80 in the first serum (S1), most (13/14) exhibited narrowly-focused HAI and/or anti-HA-head binding antibodies targeting single epitopes in or around the receptor binding site. In contrast, 42% (13/31) of the patients with HAI titers ≤ 10 in S1 had non-neutralizing anti-HA-stem antibodies against A(H1N1)pdm09 viruses. Only 19% (6/31) of the patients showed HA-specific IgG1-dominant antibody responses. Three of 5 fatal patients possessed highly focused cross-type HAI antibodies targeting the (K130 + Q223)-epitopes with extremely low avidity. Our findings suggest that narrowly-focused low-quality antibody responses targeting specific HA-epitopes may have contributed to severe infection of the lower respiratory tract.

      18. Epidemiology and pre-vaccine burden of rotavirus diarrhea in Democratic Republic of Congo (DRC): Results of sentinel surveillance, 2009-2019
        Luhata Lungayo C, Burke RM, Cikomola A, Mukamba E, Burnett E, Tate JE, Samuel Otomba J, Albert MK, Nimpa MM, Dommergues MA, Pukuta E, Mwenda JM, Shaba K, Paluku GK, N'Diaye A, Ditekemena J, Launay O, Jouffroy R.
        Vaccine. 2022 Sep 3.
        INTRODUCTION: Since August 2009, the Democratic Republic of Congo (DRC) has implemented sentinel site surveillance for rotavirus gastroenteritis. Limited hospital studies have been carried out, in DRC, describing the epidemiology of rotavirus diarrhea before rotavirus vaccine introduction in October 2019. This analysis describes the epidemiology of rotavirus gastroenteritis and characteristics of circulating viral strains from 2009 to 2019. MATERIALS AND METHODS: We analyzed demographic and clinic data collected from children < 5 years old enrolled at three rotavirus sentinel surveillance sites in DRC during 2009-2019, prior to rotavirus vaccine introduction in 2019. Data have been described and presented as mean ± standard deviation for quantitative variables with normal distribution, or as median with an interquartile range [Q1-Q3] for quantitative variables with non-normal distribution, or as absolute value with percentage for qualitative variables. RESULTS: Between August 2009 and December 2019, 4,928 children < 5 years old were admitted to sentinel surveillance sites for gastroenteritis in the DRC; the rotavirus positivity rate was 60 %. There was a slight male gender predominance (56 %), and the majority of children (79 %) were 0-11 months of age. Every year, the incidence was highest between May and September corresponding to the dry and cool season. Genotyping was performed for 50 % of confirmed rotavirus cases. The most common G genotypes were G1 (39 %) and G2 (24 %) and most common P genotypes were P[6] (49 %) and P[8] (37 %). The most common G-P genotype combinations were G1P[8] (22 %), G2P[6] (16 %) and G1P[6] (14 %). Genotype distribution varied by site, age group, and year. CONCLUSION: From 2009 to 2019, rotavirus-associated gastroenteritis represented a significant burden among DRC children under 5 who were admitted to sentinel sites. G1P[8] was the most commonly identified genotype. Continued monitoring after the introduction of rotavirus vaccine will be essential to monitor any changes in epidemiology.

    • Disease Reservoirs and Vectors
      1. Strategies for conducting Anopheles stephensi surveys in non-endemic areas
        Ahmed A, Irish SR, Zohdy S, Yoshimizu M, Tadesse FG.
        Acta Trop. 2022 Sep 1:106671.
        Anopheles stephensi, a malaria vector species previously only known from Asia, was first detected in Africa in Djibouti in 2012, has been subsequently collected in Ethiopia, Sudan, and Somalia, and may be spreading further. Countries may wish to implement mosquito surveys to determine if An. stephensi is present, or to determine the extent of its distribution, if present. Furthermore, mosquito surveys can provide data on the bionomics of An. stephensi and its adaptation to the local environment that can help plan and implement control activities. The present strategies provide suggestions on surveillance approaches for monitoring An. stephensi. The first step is to determine the aim of the study, as this will determine the specific activities conducted in each location. Challenges related to identification and detection of resistance and sporozoites are also discussed. Results should be communicated to relevant stakeholders in a timely manner, both in country and internationally, to help understand the introduction, distribution, and bionomics of An. stephensi in a given country and work towards cross-border and coordinated international response.

      2. An experimental hut study evaluating the impact of pyrethroid-only and PBO nets alone and in combination with pirimiphos-methyl-based IRS in Ethiopia
        Yewhalaw D, Balkew M, Zemene E, Chibsa S, Mumba P, Flatley C, Seyoum A, Yoshimizu M, Zohdy S, Dengela D, Irish S.
        Malar J. 2022 Aug 20;21(1):238.
        BACKGROUND: Pyrethroid resistance observed in populations of malaria vectors is widespread in Ethiopia and could potentially compromise the effectiveness of insecticide-based malaria vector control interventions. In this study, the impact of combining indoor residual spraying (IRS) and insecticide-treated nets (ITNs) on mosquito behaviour and mortality was evaluated using experimental huts. METHODS: A Latin Square Design was employed using six experimental huts to collect entomological data. Human volunteers slept in huts with different types of nets (pyrethroid-only net, PBO net, and untreated net) either with or without IRS (Actellic 300CS). The hut with no IRS and an untreated net served as a negative control. The study was conducted for a total of 54 nights. Both alive and dead mosquitoes were collected from inside nets, in the central rooms and verandah the following morning. Data were analysed using Stata/SE 14.0 software package (College Station, TX, USA). RESULTS: The personal protection rate of huts with PermaNet® 2.0 alone and PermaNet® 3.0 alone was 33.3% and 50%, respectively. The mean killing effect of huts with PermaNet® 2.0 alone and PermaNet® 3.0 alone was 2% and 49%, respectively. Huts with PermaNet® 2.0 alone and PermaNet® 3.0 alone demonstrated significantly higher excito-repellency than the control hut. However, mosquito mortality in the hut with IRS + untreated net, hut with IRS + PermaNet® 2.0 and hut with IRS + PermaNet® 3.0 were not significantly different from each other (p > 0.05). Additionally, pre-exposure of both the susceptible Anopheles arabiensis laboratory strain and wild Anopheles gambiae sensu lato to PBO in the cone bioassay tests of Actellic 300CS sprayed surfaces did not reduce mosquito mortality when compared to mortality without pre-exposure to PBO. CONCLUSION: Mosquito mortality rates from the huts with IRS alone were similar to mosquito mortality rates from the huts with the combination of vector control intervention tools (IRS + ITNs) and mosquito mortality rates from huts with PBO nets alone were significantly higher than huts with pyrethroid-only nets. The findings of this study help inform studies to be conducted under field condition for decision-making for future selection of cost-effective vector control intervention tools.

    • Environmental Health
      1. The epidemiology of lung cancer following radiation exposure
        Zablotska LB, Richardson DB, Golden A, Pasqual E, Smith B, Rage E, Demers PA, Do M, Fenske N, Deffner V, Kreuzer M, Samet J, Bertke S, Kelly-Reif K, Schubauer-Berigan MK, Tomasek L, Wiggins C, Laurier D, Apostoaei I, Thomas BA, Simon SL, Hoffman FO, Boice JD, Dauer LT, Howard SC, Cohen SS, Mumma MT, Ellis ED, Eckerman KF, Leggett RW, Pawel DJ.
        Int J Radiat Biol. 2022 Aug 22:1-12.

    • Genetics and Genomics
      1. Enhancing meningococcal genomic surveillance in the meningitis belt using high-resolution culture-free whole-genome sequencing
        Itsko M, Topaz N, Ousmane-Traoré S, Popoola M, Ouedraogo R, Gamougam K, Sadji AY, Abdul-Karim A, Lascols C, Wang X.
        J Infect Dis. 2022 Sep 4;226(4):729-737.
        Rollout of meningococcal serogroup A conjugate vaccine in Africa started in 2010, aiming to eliminate meningitis outbreaks, in meningitis belt countries. Since then, studies have been conducted, primarily using isolates, to assess the vaccine impact on the distribution of meningococcal strains in the region. Here, we implemented an innovative, culture-free whole-genome sequencing approach on almost 400 clinical specimens collected between 2017 and 2019 from meningococcal meningitis cases in 6 African countries. About 50% of specimens provided high-quality whole-genome sequence data for comprehensive molecular profiling of the meningococcal pathogen. Three major clonal complexes were identified: CC11 associated with serogroup W, CC181 associated with serogroup X, and CC10217 associated with serogroup C, which continues to rise as a predominant clonal complex in the region. Genomic surveillance for meningococcal meningitis can be significantly improved using culture-free methods to increase data representativeness and monitor changes in epidemiological landscape, especially for countries with low culture rate.

    • Health Economics
      1. Costs and cost-effectiveness of HIV counselling and testing modalities in Southern Mozambique
        Choo JH, Lopez-Varela E, Fuente-Soro L, Augusto O, Sacoor C, Nhacolo A, Wei S, Naniche D, Thomas R, Sicuri E.
        Cost Eff Resour Alloc. 2022 Sep 6;20(1):49.
        OBJECTIVE: Despite the high HIV associated burden, Mozambique lacks data on HIV counselling and testing (HCT) costs. To help guide national HIV/AIDS programs, we estimated the cost per test for voluntary counselling and testing (VCT) from the patient's perspective and the costs per person tested and per HIV-positive individual linked to care to the healthcare provider for VCT, provider-initiated counselling and testing (PICT) and home-based testing (HBT). We also assessed the cost-effectiveness of these strategies for linking patients to care. METHODS: Data from a cohort study conducted in the Manhiça District were used to derive costs and linkage-to-care outcomes of the three HCT strategies. A decision tree was used to model HCT costs according to the likelihood of HCT linking individuals to care and to obtain the incremental cost-effectiveness ratios (ICERs) of PICT and HBT with VCT as the comparator. Sensitivity analyses were performed to assess robustness of base-case findings. FINDINGS: Based on costs and valuations in 2015, average and median VCT costs to the patient per individual tested were US$1.34 and US$1.08, respectively. Costs per individual tested were greatest for HBT (US$11.07), followed by VCT (US$7.79), and PICT (US$7.14). The costs per HIV-positive individual linked to care followed a similar trend. PICT was not cost-effective in comparison with VCT at a willingness-to-accept threshold of US$4.53, but only marginally given a corresponding base-case ICER of US$4.15, while HBT was dominated, with higher costs and lower impact than VCT. Base-case results for the comparison between PICT and VCT presented great uncertainty, whereas findings for HBT were robust. CONCLUSION: PICT and VCT are likely equally cost-effective in Manhiça. We recommend that VCT be offered as the predominant HCT strategy in Mozambique, but expansion of PICT could be considered in limited-resource areas. HBT without facilitated linkage or reduced costs is unlikely to be cost-effective.

    • Health Equity and Health Disparities
      1. Exploring residents' perceptions of neighborhood development and revitalization for active living opportunities
        Dsouza N, Serrano N, Watson KB, McMahon J, Devlin HM, Lemon SC, Eyler AA, Gustat J, Hirsch JA.
        Prev Chronic Dis. 2022 Sep 1;19:E56.
        INTRODUCTION: Community fears of gentrification have created concerns about building active living infrastructure in neighborhoods with low-income populations. However, little empirical research exists related to these concerns. This work describes characteristics of residents who reported 1) concerns about increased cost of living caused by neighborhood development and 2) support for infrastructural improvements even if the changes lead to a higher cost of living. METHODS: Data on concerns about or support for transportation-related and land use-related improvements and sociodemographic characteristics were obtained from the 2018 SummerStyles survey, an online panel survey conducted on a nationwide sample of US adults (n = 3,782). Descriptive statistics characterized the sample, and χ(2) tests examined associations among variables. RESULTS: Overall, 19.1% of study respondents agreed that development had caused concerns about higher cost of living. Approximately half (50.7%) supported neighborhood changes for active living opportunities even if they lead to higher costs of living. Prevalences of both concern and support were higher among respondents who were younger and who had higher levels of education than their counterparts. Support did not differ between racial or ethnic groups, but concern was reported more often by Hispanic/Latino (28.9%) and other non-Hispanic (including multiracial) respondents (25.5%) than by non-Hispanic White respondents (15.6%). Respondents who reported concerns were more likely to express support (65.3%) than respondents who did not report concerns (47.3%). CONCLUSION: The study showed that that low-income, racial, or ethnic minority populations support environmental changes to improve active living despite cost of living concerns associated with community revitalization.

    • Immunity and Immunization
      1. Evaluating risk factors associated with COVID-19 infections among vaccinated people early in the U.S. vaccination campaign: an observational study of five states, January-March 2021
        Sadigh KS, Kugeler KJ, Bressler S, Massay SC, Schmoll E, Milroy L, Cavanaugh AM, Sierocki A, Fischer M, Nolen LD.
        BMC Infect Dis. 2022 Sep 1;22(1):718.
        BACKGROUND: COVID-19 vaccines are an effective tool to prevent illness due to SARS-CoV-2 infection. However, infection after vaccination still occurs. We evaluated all infections identified among recipients of either the Pfizer-BioNTech or Moderna COVID-19 vaccine in five U.S. states during January-March 2021. METHODS: Using observational data reported to CDC, we compared the incidence of SARS-CoV-2 infection among vaccinated and unvaccinated persons, and the sex, age, and vaccine product received for individuals with vaccine breakthrough infections to those of the vaccinated population using Poisson regression models. We also compared the proportion of vaccine breakthrough cases due to a SARS-CoV-2 variant of concern to data reported to CDC's national genomic surveillance program. RESULTS: The age-adjusted incidence of reported SARS-CoV-2 infection was 97% lower among vaccinated as compared to unvaccinated persons aged ≥ 16 years (68 vs 2252 cases per 100,000 people). Vaccinated adults aged ≥ 85 years were 1.6 times (95% CI 1.3-1.9) as likely to become infected with SARS-CoV-2 than vaccinated adults aged < 65 years. Pfizer-BioNTech COVID-19 vaccine recipients were 1.4 times (95% CI 1.3-1.6) as likely to experience infection compared to Moderna COVID-19 recipients. The proportion of infections among vaccinated persons caused by SARS-CoV-2 variants of concern was similar to the proportion of circulating viruses identified as variants of concern in the five states during the same time. CONCLUSIONS: Vaccinated persons had a substantially lower incidence of SARS-CoV-2 infection compared to unvaccinated persons. Adults aged ≥ 85 years and Pfizer-BioNTech vaccine recipients had a higher risk of infection following vaccination. We provide an analytic framework for ongoing evaluation of patterns associated with SARS-CoV-2 infection among vaccinated persons using observational surveillance and immunization data. Our findings reinforce the effectiveness of COVID-19 vaccines in preventing infection in real-world settings.

      2. Rotavirus vaccine impact within an integrated healthcare delivery system in the United States
        Burke RM, Tate JE, Groom H, Parashar UD, Mattison CP, Donald J, Salas SB, Naleway AL, Lee MH, Dickerson JF, Biggs C, Tsaknaridis L, Bowen MD, Schmidt M, Hall AJ.
        J Pediatric Infect Dis Soc. 2022 Sep 7.
        We assessed rotavirus vaccine impact using data on acute gastroenteritis (AGE) encounters within an integrated healthcare delivery system during 2000 - 2018. Following rotavirus vaccine introduction, all-cause AGE rates among children <5 years declined by 36% (95% CI: 32-40%) for outpatient and 54% (95% CI: 46-60%) for inpatient encounters.

      3. Booster COVID-19 vaccinations among persons aged ≥5 years and second booster COVID-19 vaccinations among persons aged ≥50 years - United States, August 13, 2021-August 5, 2022
        Fast HE, Murthy BP, Zell E, Meng L, Murthy N, Saelee R, Lu PJ, Kang Y, Shaw L, Gibbs-Scharf L, Harris L.
        MMWR Morb Mortal Wkly Rep. 2022 Sep 2;71(35):1121-1125.

      4. COVID-19 mRNA Vaccine Safety Among Children Aged 6 Months-5 Years - United States, June 18, 2022-August 21, 2022
        Hause AM, Marquez P, Zhang B, Myers TR, Gee J, Su JR, Parker C, Thompson D, Panchanathan SS, Shimabukuro TT, Shay DK.
        MMWR Morb Mortal Wkly Rep. 2022 Sep 2;71(35):1115-1120.

      5. Parental intentions and perceptions toward COVID-19 vaccination among children aged 4 months to 4 years - protect cohort, four states, July 2021-May 2022
        Lutrick K, Fowlkes A, Rivers P, Herder K, Santibanez TA, LeClair L, Groover K, Lamberte JM, Grant L, Odame-Bamfo L, Ferraris MV, Phillips AL, Sokol B, Lowe AA, Mathenge C, Pubillones FA, Cottam B, McLeland-Wieser H, Jovel KS, Ochoa JS, McKell J, Berry M, Khan S, Solle NS, Rai RP, Nakayima FM, Newes-Adeyi G, Porter C, Baccam Z, Ellingson KD, Burgess JL, Gaglani M, Gwynn L, Caban-Martinez A, Yoon S.
        MMWR Morb Mortal Wkly Rep. 2022 Sep 2;71(35):1109-1114.

      6. National vaccination coverage among adolescents aged 13-17 Years - National Immunization Survey-Teen, United States, 2021
        Pingali C, Yankey D, Elam-Evans LD, Markowitz LE, Valier MR, Fredua B, Crowe SJ, Stokley S, Singleton JA.
        MMWR Morb Mortal Wkly Rep. 2022 Sep 2;71(35):1101-1108.

      7. Travelers and travel vaccines at six health care systems in the Vaccine Safety Datalink
        Lewin B, Qian L, Huang R, Sy LS, Goddard K, Naleway AL, DeSilva M, Daley MF, McNeil MM, Jackson LA, Jacobsen SJ.
        Vaccine. 2022 Sep 2.
        BACKGROUND: Studying the safety of travel vaccines poses challenges since recipients may be traveling during the risk window for adverse events and the identification of a suitable comparison group can also be difficult. The examination of traveler characteristics, travel vaccination patterns, and health care utilization using electronic health record (EHR) data can inform the feasibility of future travel vaccine safety studies. METHODS: A retrospective cohort study of health plan members in the Vaccine Safety Datalink Project aged 9 months and older who had a travel-related encounter or received a travel vaccine from 2009 to 2018 was performed. Travel regions visited, travel duration, type of travel vaccine received (typhoid, yellow fever, Japanese encephalitis, rabies, and cholera), and timing of vaccination date before departure date were described. Sociodemographic information, clinical characteristics, and health care utilization were compared between travelers who received travel vaccines and travelers who did not. RESULTS: A total of 1,026,822 unique travelers departing from the United States were identified; 612,795 travelers received 898,196 doses of travel vaccines. The most commonly administered travel vaccine was typhoid vaccine and 77% of all travel vaccines were given more than one week prior to departure. Compared with travelers without travel vaccines, travelers with travel vaccines were overall similar but as a group were slightly younger, healthier, and had lower Hispanic representation. Health care utilization dramatically decreased during travel. Outpatient visits decreased from 294.8 visits per 10,000 person-days before travel to 24.2 visits per 10,000 person-days during reported travel dates. CONCLUSIONS: Through the EHR information from almost a million travelers, a departure date and duration of travel were successfully captured for the majority of travelers with corresponding health care utilization data. Time after vaccination and prior to departure can potentially be used in the future to compare travelers who receive travel vaccines with travelers who do not receive travel vaccines when looking at adverse events of interest after vaccination.

    • Laboratory Sciences
      1. The use of readily available laboratory tests for the identification of the emerging yeast Candida auris in Mexico
        González-Durán E, Contreras-Pérez CU, Caceres DH, Ríos-Rosas C, Piñón-Ortega JJ, Téllez-Saucedo MD, Marín-Suro ES, Wong-Arámbula CE, Moreno-Escobar EA, Ramírez-González JE, Ramírez-Barrios JG, Montes-Colima NA, Lockhart SR, Martínez-Montiel N, Martínez-Contreras RD, García-Ruíz P, Salazar-Sánchez MI, Hernández-Rivas L, López-Martínez I.
        Arch Microbiol. 2022 Sep 2;204(9):592.
        Identification of the emerging multidrug-resistant yeast Candida auris is challenging. Here, we describe the role of the Mexico national reference laboratory Instituto de Diagnóstico y Referencia Epidemiológicos Dr. Manuel Martínez Báez (InDRE) and the Mexican national laboratory network in the identification of C. auris. Reference identification of six suspected isolates was done based on phenotypic and molecular laboratory methods, including growth in special media, evaluation of isolate micromorphology, and species-specific PCR and pan-fungal PCR and sequencing. The four C. auris isolates identified were able to grow on modified Sabouraud agar with 10% NaCl incubated at 42 °C. With one exception, isolates of C. auris were spherical to ovoid yeast-like cells and blastoconidia, with no hyphae or pseudohyphae on cornmeal agar. C. auris isolates were resistant to fluconazole. Species-specific and pan-fungal PCR confirmed isolates as C. auris. Sequence analysis revealed the presence of two different C. auris clades in Mexico, clade I (South Asia) and clade IV (South America).

      2. Dried blood spot is the feasible matrix for detection of some but not all hepatitis B virus markers of infection
        Kikuchi M, Lindstrom P, Tejada-Strop A, Mixson-Hayden T, Kamili S, Sawabe M.
        BMC Res Notes. 2022 Sep 5;15(1):287.
        OBJECTIVE: Use of dried blood spots (DBS) for detection of hepatitis B virus (HBV) markers of infection has the potential to facilitate diagnosis of HBV infection especially in resource-limited countries. The aim of this study was to evaluate the feasibility of DBS for detection of various markers of HBV infections. RESULTS: Fifty-four DBS samples were engineered from well-characterized plasma samples. All DBS samples were tested for HBsAg, total anti-HBc and HBV DNA, 20 of 54 samples were also tested for HBeAg using commercially available assays. HBsAg was detected in 24 of 25 (96%), HBV DNA in 22 of 25 (88%), total anti-HBc in all 9 (100%), and HBeAg in all 7 (100%) DBS samples. The average difference in HBV DNA levels between DBS eluates and corresponding plasma samples was 2.7 log(10) IU/mL. Fifteen DBS eluates positive for HBV DNA were sequenced and all of them belonged to HBV genotype A. Thirteen samples which were negative for all HBV markers showed HBeAg false positivity. Therefore, DBS is a reliable sample matrix for detection of HBsAg, total anti-HBc and HBV DNA, but not HBeAg. Further feasibility studies of DBS for diagnostic purposes and epidemiologic studies are warranted.

      3. Ferrets as a model for tuberculosis transmission
        Gupta T, Somanna N, Rowe T, LaGatta M, Helms S, Owino SO, Jelesijevic T, Harvey S, Jacobs W, Voss T, Sakamoto K, Day C, Whalen C, Karls R, He B, Tompkins SM, Bakre A, Ross T, Quinn FD.
        Front Cell Infect Microbiol. 2022 ;12:873416.
        Even with the COVID-19 pandemic, tuberculosis remains a leading cause of human death due to a single infectious agent. Until successfully treated, infected individuals may continue to transmit Mycobacterium tuberculosis bacilli to contacts. As with other respiratory pathogens, such as SARS-CoV-2, modeling the process of person-to-person transmission will inform efforts to develop vaccines and therapies that specifically impede disease transmission. The ferret (Mustela furo), a relatively inexpensive, small animal has been successfully employed to model transmissibility, pathogenicity, and tropism of influenza and other respiratory disease agents. Ferrets can become naturally infected with Mycobacterium bovis and are closely related to badgers, well known in Great Britain and elsewhere as a natural transmission vehicle for bovine tuberculosis. Herein, we report results of a study demonstrating that within 7 weeks of intratracheal infection with a high dose (>5 x 10(3) CFU) of M. tuberculosis bacilli, ferrets develop clinical signs and pathological features similar to acute disease reported in larger animals, and ferrets infected with very-high doses (>5 x 10(4) CFU) develop severe signs within two to four weeks, with loss of body weight as high as 30%. Natural transmission of this pathogen was also examined. Acutely-infected ferrets transmitted M. tuberculosis bacilli to co-housed naïve sentinels; most of the sentinels tested positive for M. tuberculosis in nasal washes, while several developed variable disease symptomologies similar to those reported for humans exposed to an active tuberculosis patient in a closed setting. Transmission was more efficient when the transmitting animal had a well-established acute infection. The findings support further assessment of this model system for tuberculosis transmission including the testing of prevention measures and vaccine efficacy.

      4. Robustness of the ferret model for influenza risk assessment studies: A cross-laboratory exercise
        Belser JA, Lau EH, Barclay W, Barr IG, Chen H, Fouchier RA, Hatta M, Herfst S, Kawaoka Y, Lakdawala SS, Lee LY, Neumann G, Peiris M, Perez DR, Russell C, Subbarao K, Sutton TC, Webby RJ, Yang H, Yen HL.
        mBio. 2022 Aug 30;13(4):e0117422.
        Past pandemic influenza viruses with sustained human-to-human transmissibility have emerged from animal influenza viruses. Employment of experimental models to assess the pandemic risk of emerging zoonotic influenza viruses provides critical information supporting public health efforts. Ferret transmission experiments have been utilized to predict the human-to-human transmission potential of novel influenza viruses. However, small sample sizes and a lack of standardized protocols can introduce interlaboratory variability, complicating interpretation of transmission experimental data. To assess the range of variation in ferret transmission experiments, a global exercise was conducted by 11 laboratories using two common stock H1N1 influenza viruses with different transmission characteristics in ferrets. Parameters known to affect transmission were standardized, including the inoculation route, dose, and volume, as well as a strict 1:1 donor/contact ratio for respiratory droplet transmission. Additional host and environmental parameters likely to affect influenza transmission kinetics were monitored and analyzed. The overall transmission outcomes for both viruses across 11 laboratories were concordant, suggesting the robustness of the ferret model for zoonotic influenza risk assessment. Among environmental parameters that varied across laboratories, donor-to-contact airflow directionality was associated with increased transmissibility. To attain high confidence in identifying viruses with moderate to high transmissibility or low transmissibility under a smaller number of participating laboratories, our analyses support the notion that as few as three but as many as five laboratories, respectively, would need to independently perform viral transmission experiments with concordant results. This exercise facilitates the development of a more homogenous protocol for ferret transmission experiments that are employed for the purposes of risk assessment. IMPORTANCE Following detection of a novel virus, rapid characterization efforts (both in vitro and in vivo) are undertaken at numerous laboratories worldwide to evaluate the relative risk posed to human health. Aggregation of these data are critical, but the use of nonstandardized protocols can make interpretation of divergent results a challenge. For evaluation of virus transmissibility, a multifactorial trait which can only be evaluated in vivo, identifying intrinsic levels of variability between groups can improve the utility of these data, as well as ensure that experiments are performed with sufficient replication to ensure high confidence in compiled results. Using the ferret transmission model and two influenza A viruses, we conducted a multicenter standardization exercise to improve the interpretation of transmission data generated during risk assessment activities; this exercise serves as a model for future efforts employing both in vitro and in vivo models against possible pandemic pathogens.

    • Maternal and Child Health
      1. Assessment of congenital cytomegalovirus prevalence among newborns in Minnesota during the COVID-19 pandemic
        Schleiss MR, Rosendahl S, McCann M, Dollard SC, Lanzieri TM.
        JAMA Netw Open. 2022 Sep 1;5(9):e2230020.

      2. Orphanhood and caregiver loss among children based on new global excess COVID-19 death estimates
        Hillis S, N'Konzi J N, Msemburi W, Cluver L, Villaveces A, Flaxman S, Unwin HJ.
        JAMA Pediatr. 2022 Sep 6.

    • Occupational Safety and Health

      1. We conducted laboratory experiments to investigate a suspected effect of tetrahydrofuran (THF) on quantifying crystalline silica in samples collected from working with engineered stone when THF is used to process samples prior to the X-ray diffraction (XRD) analysis. Two groups of samples from grinding either engineered stone or granite were simultaneously taken from a laboratory testing system, with one group of samples using THF for processing and another group using muffle furnace for ashing. For each stone type, we also tested four levels of respirable dust loading on the samples by varying the grinding time from 1 to 8 min. Statistical analysis of the experimental results on crystalline silica contents of the two groups of samples showed that the difference between the two methods was not significant (P ≥ 0.05) for the granite at all four levels of respirable dust loading and for the engineered stone at the two levels of respirable dust loading greater than 0.5 mg. However, the crystalline silica content from using THF processing was significantly lower (P = 0.001) than that from using muffle furnace ashing for engineered stone when the respirable dust loading levels were less than 0.5 mg. For the engineered stone dust samples with grinding times of 1 and 2 min, the average respirable dust loading was about 0.19 and 0.34 mg, respectively; while the crystalline silica content from using THF processing was 30.9 and 21.5% lower than that from using muffle furnace ashing, respectively. Since most full-shift samples from field assessments in this industry are expected to have respirable dust loading less than 0.5 mg, muffle furnace or radio frequency plasma ashing should be specified as the preferred sample processing method instead of the THF processing method for quantification of crystalline silica when engineered stone is expected to present to avoid artificially reduced silica content values, which are likely caused by the reactions between THF and the resins in engineered stone.

      2. Encounter patterns and worker absenteeism/presenteeism among healthcare providers in Thailand
        Piyaraj P, Kittikraisak W, Buathong S, Sinthuwattanawibool C, Nivesvivat T, Yoocharoen P, Nuchtean T, Klungthong C, Lyman M, Mott JA, Chottanapund S.
        Curr Res in Behav Sci. 2022 ;3.
        Background: We examined the characteristics of healthcare providers’ (HCPs) encounters, and the frequency of worker absenteeism/presenteeism, among HCPs in inpatient wards at a tertiary-level public hospital in Bangkok, Thailand. The wards were stratified by risk of respiratory virus transmission: low-risk (Surgery, Rehabilitation, Orthopedic, and Obstetrics and Gynecology) and high-risk (Medicine, Pediatric, Emergency, and Ear, Nose, and Throat). Methods: Observers followed HCPs throughout one self-selected 8-hour work shift to record their interaction with others. An encounter was defined as a 2-way conversation with ≥3 words in the physical presence of ≥1 person at <3 feet distance; or a physical skin-to-skin touch. We administered structured questionnaires to document demographics, health and work history, past practice while ill, and recent and current acute muscle pain and/or respiratory symptoms. We collected data from time and attendance records of participants reporting illness within the past seven days. Results: From July to August 2019, 240 HCPs were enrolled and observed during 395 work shifts; 15,878 total encounters were made with a median duration of two minutes (interquartile range, 1–3). Number of contacts ranged from 25 to 49 encounters/8 h in the low-risk wards and 40 to 66 encounters/8 h in the high-risk wards. Physicians working during the 8-hour evening shift in high-risk wards had the highest estimated number of contacts (66 encounters; 95% confidence interval [CI], 43–89) while nurses working during the 8-hour night shift in the low-risk wards had the lowest number of contacts (25 encounters; 95% CI, 22–28). Forty-two (11%) shifts were staffed by HCPs with acute muscle pain and/or respiratory symptom(s) at the time of interview, and 89 (23%) by HCPs who reported symptom(s) during the past seven days, for which none were absent from work. Conclusion: We observed difference in encounter patterns by ward type. About one in five work shifts were staffed by HCPs with acute muscle pain and/or respiratory symptoms who continued to work while ill. These findings have implications for preventing infectious disease transmission and the policy around sick leave in healthcare settings. © 2022

      3. Case studies of robots and automation as health/safety interventions in small manufacturing enterprises
        Lowe BD, Hayden M, Albers J, Naber S.
        Hum Factors Ergonomics Manufacturing. 2022 .
        This article reviews the experiences of 63 case studies of small businesses (<250 employees) with manufacturing automation equipment acquired through a health/safety intervention grant program. The review scope included equipment technologies classified as industrial robots (n = 17), computer numerical control (CNC) machining (n = 29), or other programmable automation systems (n = 17). Descriptions of workers' compensation (WC) claim injuries and identified risk factors that motivated the acquisition of the equipment were extracted from grant applications. Other aspects of the employer experiences, including qualitative and quantitative assessment of effects on risk factors for musculoskeletal disorders (MSD), effects on productivity, and employee acceptance of the intervention were summarized from the case study reports. Case studies associated with a combination of large reduction in risk factors, lower cost per affected employee, and reported increases in productivity were CNC stone cutting system, CNC/vertical machining system, automated system for bottling, CNC/routing system for plastics products manufacturing, and a CNC/Cutting system for vinyl/carpet. Six case studies of industrial robots reported quantitative reductions in MSD risk factors in these diverse manufacturing industries: snack foods; photographic film, paper, plate, and chemical; machine shops; leather goods and allied products; plastic products; and iron and steel forging. This review of health/safety intervention case studies indicates that advanced (programmable) manufacturing automation, including industrial robots, reduced workplace musculoskeletal risk factors, and improved process productivity in most cases. © 2022 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

    • Occupational Safety and Health - Mining
      1. Hot surface ignition of liquid fuels under ventilation
        Tang W, Bahrami D, Yuan L, Thomas R, Soles J.
        Min Metall Explor. 2022 May 4;39(3):961-968.
        Mine equipment fires remain as one of the most concerning safety issues in the mining industry, and most equipment fires were caused by hot surface ignitions. Detailed experimental investigations were conducted at the NIOSH Pittsburgh Mining Research Division on hot surface ignition of liquid fuels under ventilation in a mining environment. Three types of metal surface materials (stainless steel, cast iron, carbon steel), three types of liquids (diesel fuel, hydraulic fluid, engine oil), four air ventilation speeds (0, 0.5, 1.5, 3 m/s) were used to study the hot surface ignition probability under these conditions. Visual observation and thermocouples attached on the metal surface were used to indicate the hot surface ignition from the measured temperatures. Results show that the type of metal has a noticeable effect on the hot surface ignition, while ventilation speed has a mixed influence on ignition. Different types of liquid fuels also show different ranges of ignition temperatures. Results from this work can be used to help understand equipment mine fires and develop mitigation strategies.

    • Parasitic Diseases
      1. BACKGROUND: Studies have demonstrated the safety and efficacy of intravenous artesunate (IVAS) for treatment of severe malaria in endemic and non-endemic countries. However, post-artesunate delayed hemolysis (PADH) is an increasingly recognized phenomenon after its administration. This study describes the prevalence and outcomes of PADH events among severe malaria cases treated with IVAS in the United States. METHODS: Patients diagnosed with severe malaria and treated with IVAS April 2019-July2021 were included. Demographic, clinical, laboratory, therapeutic, and outcome measures were described using proportions, medians, and interquartile range (IQR). Patients reported to experience PADH were compared to those not reported to have PADH and tests of significance were performed. RESULTS: Of 332 patients included in our analysis, 9 (2.7%) experienced PADH. The majority of infections in both groups were in non-Hispanic Black individuals. Parasite density (11.0% vs 8.0%), admission hemoglobin (11.0 g/dL vs 11.8 g/dL), were similar in the two groups. Total bilirubin at admission (4.7 mg/dL vs 2.2 mg/dL) and within eight hours after completion of IVAS (2.6 mg/dL vs 1.2 mg/dL) were notably higher in PADH patients. Cumulative IVAS dose of >9.5 mg/kg and >3 doses of IVAS were risk factors for PADH. The majority (7 of 9) of PADH cases were diagnosed within two weeks after initiation of IVAS. Five patients (56%) required blood transfusions, all recovered without sequelae. CONCLUSIONS: PADH is an uncommon and self-limiting adverse event in many cases; weekly monitoring of hemoglobin and hemolytic markers may identify cases requiring intervention in a timely manner.

      2. Diagnostic performance of loop-mediated isothermal amplification and ultrasensitive rapid diagnostic tests for malaria screening among pregnant women in Kenya
        Samuels AM, Towett O, Seda B, Wiegand RE, Otieno K, Chomba M, Lucchi N, Ljolje D, Schneider K, Walker PG, Kwambai TK, Slutsker L, Ter Kuile FO, Kariuki SK.
        J Infect Dis. 2022 Sep 4;226(4):696-707.
        BACKGROUND: Screen-and-treat strategies with sensitive diagnostic tests may reduce malaria-associated adverse pregnancy outcomes. We conducted a diagnostic accuracy study to evaluate new point-of-care tests to screen pregnant women for malaria at their first antenatal visit in western Kenya. METHODS: Consecutively women were tested for Plasmodium infection by expert microscopy, conventional rapid diagnostic test (cRDT), ultra sensitive RDT (usRDT), and loop-mediated isothermal amplification (LAMP). Photoinduced electron-transfer polymerase chain reaction (PET-PCR) served as the reference standard. Diagnostic performance was calculated and modelled at low parasite densities. RESULTS: Between May and September 2018, 172 of 482 screened participants (35.7%) were PET-PCR positive. Relative to PET-PCR, expert microscopy was least sensitive (40.1%; 95% confidence interval [CI], 32.7%-47.9%), followed by cRDT (49.4%; 95% CI, 41.7%-57.1), usRDT (54.7%; 95% CI, 46.9%-62.2%), and LAMP (68.6%; 95% CI, 61.1%-75.5%). Test sensitivities were comparable in febrile women (n = 90). Among afebrile women (n = 392), the geometric-mean parasite density was 29 parasites/µL and LAMP (sensitivity = 61.9%) and usRDT (43.2%) detected 1.74 (95% CI, 1.31-2.30) and 1.21 (95% CI, 88-2.21) more infections than cRDT (35.6%). Per our model, tests performed similarly at densities >200 parasites/µL. At 50 parasites/µL, the sensitivities were 45%, 56%, 62%, and 74% with expert microscopy, cRDT, usRDT, and LAMP, respectively. CONCLUSIONS: This first-generation usRDT provided moderate improvement in detecting low-density infections in afebrile pregnant women compared to cRDTs.

      3. Malaria surveillance - United States, 2018
        Mace KE, Lucchi NW, Tan KR.
        MMWR Surveill Summ. 2022 Sep 2;71(8):1-35.
        PROBLEM/CONDITION: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. Most malaria infections in the United States and its territories occur among persons who have traveled to regions with ongoing malaria transmission. However, among persons who have not traveled out of the country, malaria is occasionally acquired through exposure to infected blood or tissues, congenital transmission, nosocomial exposure, or local mosquitoborne transmission. Malaria surveillance in the United States and its territories provides information on its occurrence (e.g., temporal, geographic, and demographic), guides prevention and treatment recommendations for travelers and patients, and facilitates rapid transmission control measures if locally acquired cases are identified. PERIOD COVERED: This report summarizes confirmed malaria cases in persons with onset of illness in 2018 and trends in previous years. DESCRIPTION OF SYSTEM: Malaria cases diagnosed by blood smear microscopy, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments through electronic laboratory reports or by health care providers or laboratory staff members directly reporting to CDC or health departments. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), the National Notifiable Diseases Surveillance System (NNDSS), or direct CDC clinical consultations. CDC reference laboratories provide diagnostic assistance and conduct antimalarial drug resistance marker testing on blood specimens submitted by health care providers or local or state health departments. This report summarizes data from the integration of all cases from NMSS and NNDSS, CDC clinical consultations, and CDC reference laboratory reports. RESULTS: CDC received reports of 1,823 confirmed malaria cases with onset of symptoms in 2018, including one cryptic case and one case acquired through a bone marrow transplant. The number of cases reported in 2018 is 15.6% fewer than in 2017. The number of cases diagnosed in the United States and its territories has been increasing since the mid-1970s; the number of cases reported in 2017 was the highest since 1972. Of the cases in 2018, a total of 1,519 (85.0%) were imported cases that originated from Africa; 1,061 (69.9%) of the cases from Africa were from West Africa, a similar proportion to what was observed in 2017. Among all cases, P. falciparum accounted for most infections (1,273 [69.8%]), followed by P. vivax (173 [9.5%]), P. ovale (95 [5.2%]), and P. malariae (48 [2.6%]). For the first time since 2008, an imported case of P. knowlesi was identified in the United States and its territories. Infections by two or more species accounted for 17 cases (<1.0%). The infecting species was not reported or was undetermined in 216 cases (11.9%). Most patients (92.6%) had symptom onset <90 days after returning to the United States or its territories from a country with malaria transmission. Of the U.S. civilian patients who reported reason for travel, 77.0% were visiting friends and relatives. Chemoprophylaxis with antimalarial medications are recommended for U.S. residents to prevent malaria while traveling in countries where it is endemic. Fewer U.S. residents with imported malaria reported taking any malaria chemoprophylaxis in 2018 (24.5%) than in 2017 (28.4%), and adherence was poor among those who took chemoprophylaxis. Among the 864 U.S. residents with malaria for whom information on chemoprophylaxis use and travel region were known, 95.0% did not adhere to or did not take a CDC-recommended chemoprophylaxis regimen. Among 683 women with malaria, 19 reported being pregnant. Of these, 11 pregnant women were U.S. residents, and one of whom reported taking chemoprophylaxis to prevent malaria but her adherence to chemoprophylaxis was not reported. Thirty-eight (2.1%) malaria cases occurred among U.S. military personnel in 2018, more than in 2017 (26 [1.2%]). Among all reported malaria cases in 2018, a total of 251 (13.8%) were classified as severe malaria illness, and seven persons died from malaria. In 2018, CDC analyzed 106 P. falciparum-positive and four P. falciparum mixed species specimens for antimalarial resistance markers (although certain loci were untestable in some specimens); identification of genetic polymorphisms associated with resistance to pyrimethamine were found in 99 (98.0%), to sulfadoxine in 49 (49.6%), to chloroquine in 50 (45.5%), and to mefloquine in two (2.0%); no specimens tested contained a marker for atovaquone or artemisinin resistance. INTERPRETATION: The importation of malaria reflects the overall trends in global travel to and from areas where malaria is endemic, and 15.6% fewer cases were imported in 2018 compared with 2017. Of imported cases, 59.3% were among persons who had traveled from West Africa. Among U.S. civilians, visiting friends and relatives was the most common reason for travel (77.1%). PUBLIC HEALTH ACTIONS: The best way for U.S. residents to prevent malaria is to take chemoprophylaxis medication before, during, and after travel to a country where malaria is endemic. Adherence to recommended malaria prevention strategies among U.S. travelers would reduce the number of imported cases. Reported reasons for nonadherence include prematurely stopping after leaving the area where malaria was endemic, forgetting to take the medication, and experiencing a side effect. Health care providers can make travelers aware of the risks posed by malaria and incorporate education to motivate them to be adherent to chemoprophylaxis. Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient's age, pregnancy status, medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Antimalarial use for chemoprophylaxis and treatment should be determined by the CDC guidelines, which are frequently updated. In April 2019, intravenous (IV) artesunate became the first-line medication for treatment of severe malaria in the United States and its territories. Artesunate was approved by the Food and Drug Administration (FDA) in 2020 and is commercially available (Artesunate for Injection) from major U.S. drug distributors (https://amivas.com). Stocking IV artesunate locally allows for immediate treatment of severe malaria once diagnosed and provides patients with the best chance of a complete recovery and no sequelae. With commercial IV artesunate now available, CDC will discontinue distribution of non-FDA-approved IV artesunate under an investigational new drug protocol on September 30, 2022. Detailed recommendations for preventing malaria are online at https://www.cdc.gov/malaria/travelers/drugs.html. Malaria diagnosis and treatment recommendations are also available online at https://www.cdc.gov/malaria/diagnosis_treatment. Health care providers who have sought urgent infectious disease consultation and require additional assistance on diagnosis and treatment of malaria can call the Malaria Hotline 9:00 a.m.-5:00 p.m. Eastern Time, Monday-Friday, at 770-488-7788 or 855-856-4713 or after hours for urgent inquiries at 770-488-7100. Persons submitting malaria case reports (care providers, laboratories, and state and local public health officials) should provide complete information because incomplete reporting compromises case investigations and public health efforts to prevent future infections and examine trends in malaria cases. Molecular surveillance of antimalarial drug resistance markers enables CDC to track, guide treatment, and manage drug resistance in malaria parasites both domestically and globally. A greater proportion of specimens from domestic malaria cases are needed to improve the completeness of antimalarial drug resistance analysis; therefore, CDC requests that blood specimens be submitted for any case of malaria diagnosed in the United States and its territories.

      4. Burden of malaria in pregnancy among adolescent girls compared to adult women in 5 sub-Saharan African countries: A secondary individual participant data meta-analysis of 2 clinical trials
        Pons-Duran C, Mombo-Ngoma G, Macete E, Desai M, Kakolwa MA, Zoleko-Manego R, Ouédragou S, Briand V, Valá A, Kabanywanyi AM, Ouma P, Massougbodji A, Sevene E, Cot M, Aponte JJ, Mayor A, Slutsker L, Ramharter M, Menéndez C, González R.
        PLoS Med. 2022 Sep;19(9):e1004084.
        BACKGROUND: Malaria is among the top causes of death in adolescent girls (10 to 19 years) globally. Adolescent motherhood is associated with increased risk of adverse maternal and neonatal outcomes. The interaction of malaria, adolescence, and pregnancy is especially relevant in malaria endemic areas, where rates of adolescent pregnancy are high. However, data on burden of malaria among adolescent girls are limited. This study aimed at investigating whether adolescent girls were at a greater risk of experiencing malaria-related outcomes in pregnancy-parasitaemia and clinical disease-than adult women. METHODS AND FINDINGS: An individual secondary participant-level meta-analysis was conducted using data from 5,804 pregnant women participating in 2 malaria prevention clinical trials in Benin, Gabon, Kenya, Mozambique, and Tanzania between 2009 and 2014. Of the sample, 1,201 participants were adolescent girls with a mean age of 17.5 years (standard deviation (SD) 1.3) and 886 (73.8%) of them primigravidae. Among the 4,603 adult women with mean age of 27.0 years (SD 5.4), 595 (12.9%) were primigravidae. Mean gestational age at enrolment was 20.2 weeks (SD 5.2) and 1,069 (18.4%) participants were HIV-infected. Women were followed monthly until the postpartum visit (1 month to 6 weeks after delivery). This study considered outcomes including clinical episodes during pregnancy, peripheral parasitaemia at delivery, and placental malaria. A 2-stage meta-analysis approach was followed by pooling single multivariable regression results into standard DerSimonian-Laird random-effects models. Adolescent girls were more likely than adult women to present with clinical malaria during pregnancy (incidence risk ratio (IRR) 1.70, 95% confidence interval (CI) 1.20; 2.39, p-value = 0.003, I2 = 0.0%, N = 4,092), peripheral parasitaemia at delivery (odds ratio (OR) 2.28, 95% CI 1.46; 3.55, p-value < 0.001, I2 = 0.0%, N = 3,977), and placental infection (OR 1.97, 95% CI 1.31; 2.98, p-value = 0.001, I2 = 1.4%, N = 4,797). Similar associations were observed among the subgroup of HIV-uninfected participants: IRR 1.72 (95% CI 1.22; 2.45, p-value = 0.002, I2 = 0.0%, N = 3,531) for clinical malaria episodes, OR 2.39 (95% CI 1.49; 3.86, p-value < 0.001, I2 = 0.0%, N = 3,053) for peripheral parasitaemia, and OR 1.88 (95% CI 1.06 to 3.33, p-value = 0.03, I2 = 34.9%, N = 3,847) for placental malaria. Among HIV-infected subgroups statistically significant associations were not observed. Similar associations were found in the subgroup analysis by gravidity. The small sample size and outcome prevalence in specific countries limited the inclusion of some countries in the meta-analysis. Furthermore, peripheral parasitaemia and placental malaria presented a considerable level of missing data-12.6% and 18.2% of participants had missing data on those outcomes, respectively. Given the original scope of the clinical trials, asymptomatic malaria infection was only assessed at the end of pregnancy through peripheral and placental parasitaemia. CONCLUSIONS: In this study, we observed that adolescent girls in sub-Saharan Africa (SSA) are more prone to experience clinical malaria episodes during pregnancy and have peripheral malaria and placental infection at delivery than adult women. Moreover, to the best of our knowledge, for the first time this study disaggregates figures and stratifies analyses by HIV infection. Similar associations were found for both HIV-infected and uninfected women, although those for HIV-infected participants were not statistically significant. Our finding suggests that adolescent girls may benefit from targeted malaria prevention strategies even before they become pregnant.

    • Physical Activity
      1. Evaluation of practice-based programs to increase use of trails among youth from under-resourced communities
        Brown D, Berrigan D, Do V, Hill M, Reed J.
        Med Sci Sports Exerc. 2022 :233-234.

      2. Awareness and knowledge of the 2018 physical activity guidelines among US adults
        Chen T, Whitfield G, Ussery E, Watson K, Hyde E, Fulton J, Rose K.
        Med Sci Sports Exerc. 2022 :56-57.

      3. Delivery of yoga properties across in-person and remote formats in a weight loss maintenance intervention
        Sherman S, Quinn T, Braun T, Unick J.
        Med Sci Sports Exerc. 2022 :216-216.

      4. Examining the use of wearable activity monitors and goal setting toward a step goal
        Soto G, Omura J, Fulton J, Whitfield G.
        Med Sci Sports Exerc. 2022 :170-170.

      5. Physical activity level of the military age- and BMI-eligible population of the United States, 2015-2020
        Webber B, Omura J, Bornstein D, Deuster P, O'Connor F, Park S, Whitfield G.
        Med Sci Sports Exerc. 2022 :54-55.

    • Substance Use and Abuse
      1. Supporting syringe services programs in the initiation and scale-up of vaccine administration: findings from in-depth interviews
        Carry M, Bixler D, Weng MK, Doshani M, Roberts E, Montgomery MP.
        Harm Reduct J. 2022 Sep 1;19(1):100.
        BACKGROUND: Vaccine-hesitant persons who inject drugs are at increased risk for several vaccine-preventable diseases. However, vaccination rates among this population remain low. While syringe services programs (SSPs) are places where persons who inject drugs feel comfortable accessing services, few offer vaccination services. This study describes facilitators and barriers to vaccination at SSPs. METHODS: We used convenience sampling to conduct semi-structured, qualitative in-depth interviews with 21 SSPs in the USA from June to August 2021. Interview questions asked SSPs about their perceptions, priorities, barriers, facilitators, and the effects of partnerships and policies on vaccine administration. We used deductive thematic analysis to identify the main themes. RESULTS: Eight (n = 8) SSPs offered vaccinations, and thirteen (n = 13) did not offer vaccinations. Most SSPs believed offering vaccination services was important, although addressing SSP participants' immediate needs often took precedence. Staffing, physical space, and logistical issues were the most common barriers to vaccine administration reported by SSPs, followed by SSP participant-related barriers. Facilitators of vaccine administration included access to a tracking system, partnering with agencies or other organizations providing vaccines, and having a licensed vaccination provider on-site. Partnerships provided SSPs opportunities to expand capacity but could also restrict how SSPs operate. Recommended policy changes to facilitate vaccine administration included subsidizing the cost of vaccinations and addressing restrictions around who could administer vaccinations. CONCLUSIONS: Increasing the availability of vaccination services at SSPs requires addressing the varying capacity needs of SSPs, such as tracking systems, licensed vaccinators, and free or low-cost vaccination supplies. While these needs can be met through partnerships and supportive policies, both must consider and reflect cultural competence around the lived experiences of persons who inject drugs.

      2. Psychological distress and the risk of drug overdose death
        Aram JW, Spencer MR, Garnett MF, Hedegaard HB.
        J Affect Disord. 2022 Aug 31;318:16-21.
        BACKGROUND: Previous research has shown an association between psychological distress and overdose death among specific populations. However, few studies have examined this relationship in a large US population-based cohort. METHODS: Data from the 2010-2018 NHIS were linked to mortality data from the National Death Index through 2019. Psychological distress was measured using the Kessler 6 scale. Drug overdose deaths were examined, and deaths from all other causes were included as a comparison group. Cox proportional hazards regression was used to estimate mortality risk by psychological distress level. RESULTS: The study population included 272,561 adults. Adjusting for demographic covariates and using no psychological distress as the reference, distress level was positively associated with the risk of overdose death: low (HR = 1.8, 95 % CI = 1.1-2.8), moderate (HR = 4.1, 95 % CI = 2.5-6.7), high (HR = 10.3, 95 % CI = 6.5-16.1). A similar pattern was observed for deaths from all other causes: low (HR = 1.2, 95 % CI = 1.1-1.2), moderate (HR = 1.9, 95 % CI = 1.7-2.0), high (HR = 2.6, 95 % CI = 2.4-2.8). LIMITATIONS: Limited substance use information prevented adjustment for this potentially important covariate. DISCUSSION: Adults with psychological distress were at greater risk of drug overdose death, relative to those without psychological distress. Adults with psychological distress were also at increased risk of death due to other causes, though the association was not as strong.

    • Zoonotic and Vectorborne Diseases
      1. Neurological disease associated with chikungunya in Indonesia
        Myint KS, Mawuntu AH, Haryanto S, Imran D, Dian S, Dewi YP, Ganiem AR, Anggreani R, Iskandar MM, Bernadus JB, Maharani K, Susanto D, Estiasari R, Dewi H, Kristiani A, Gaghiwu L, Johar E, Yudhaputri FA, Antonjaya U, Ledermann JP, van Crevel R, Hamers RL, Powers AM.
        Am J Trop Med Hyg. 2022 Jun 13;107(2):291-5.
        Chikungunya virus (CHIKV) is recognized but rarely considered as a cause of central nervous system infection in endemic areas. A total of 244 patients with acute meningoencephalitis in Indonesia were retrospectively tested to identify whether any CHIKV infection was associated with neurological manifestations, especially in provinces known for CHIKV endemicity. Cerebrospinal fluid and blood specimens were tested using CHIKV-specific real-time reverse transcription polymerase chain reaction and IgM ELISA, alongside a panel of neurotropic viruses. We report four cases of suspected or confirmed CHIKV-associated neurological disease, including CHIKV RNA detection in cerebrospinal fluid (CSF) of one patient and in acute serum of another, and CHIKV IgM in CSF of three patients and in serum of a fourth. In conclusion, CHIKV should be considered as a cause of neurologic disease in endemic areas and especially during outbreaks, in addition to the more common arboviral diseases such as dengue and Japanese encephalitis viruses.

      2. Design and evaluation of neutralizing and fusion inhibitory peptides to Crimean-Congo hemorrhagic fever virus
        Mears MC, Rodriguez SE, Schmitz KS, Padilla A, Biswas S, Cajimat MN, Mire CE, Welch SR, Bergeron É, Alabi CA, Porotto M, Bente DA.
        Antiviral Res. 2022 Aug 29:105401.
        Crimean-Congo hemorrhagic fever (CCHF) is a medically relevant tick-borne viral disease caused by the Bunyavirus, Crimean-Congo hemorrhagic fever virus (CCHFV). CCHFV is endemic to Asia, the Middle East, South-eastern Europe, and Africa and is transmitted in enzootic cycles among ticks, mammals, and birds. Human infections are mostly subclinical or limited to mild febrile illness. Severe disease may develop, resulting in multi-organ failure, hemorrhagic manifestations, and case-fatality rates up to 30%. Despite the widespread distribution and life-threatening potential, no treatments have been approved for CCHF. Antiviral inhibitory peptides, which antagonize viral entry, are licensed for clinical use in certain viral infections and have been experimentally designed against human pathogenic bunyaviruses, with in vitro and in vivo efficacies. We designed inhibitory peptides against CCHFV with and without conjugation to various polyethylene glycol and sterol groups. These additions have been shown to enhance both cellular uptake and antiviral activity. Peptides were evaluated against pseudotyped and wild-type CCHFV via neutralization tests, Nairovirus fusion assays, and cytotoxicity profiling. Four peptides neutralized CCHFV with two of these peptides shown to inhibit viral fusion. This work represents the development of experimental countermeasures for CCHF, describes a nairovirus immunofluorescence fusion assay, and illustrates the utility of pseudotyped CCHFV for the screening of entry antagonists at low containment settings for CCHF.

      3. Laboratory evaluation of RealStar Yellow Fever Virus RT-PCR kit 1.0 for potential use in the global yellow fever laboratory network
        Basile AJ, Niedrig M, Lambert AJ, Meurant R, Brault AC, Domingo C, Goodman CH, Johnson BW, Mossel EC, Mulders MN, Velez JO, Hughes HR.
        PLoS Negl Trop Dis. 2022 Sep 6;16(9):e0010770.
        BACKGROUND: Early detection of human yellow fever (YF) infection in YF-endemic regions is critical to timely outbreak mitigation. African National Laboratories chiefly rely on serological assays that require confirmation at Regional Reference Laboratories, thus delaying results, which themselves are not always definitive often due to antibody cross-reactivity. A positive molecular test result is confirmatory for YF; therefore, a standardized YF molecular assay would facilitate immediate confirmation at National Laboratories. The WHO-coordinated global Eliminate Yellow Fever Epidemics Laboratory Technical Working Group sought to independently evaluate the quality and performance of commercial YF molecular assays relevant to use in countries with endemic YF, in the absence of stringent premarket assessments. This report details a limited laboratory WHO-coordinated evaluation of the altona Diagnostics RealStar Yellow Fever Virus RT-PCR kit 1.0. METHODOLOGY AND PRINCIPAL FINDINGS: Specific objectives were to assess the assay's ability to detect YF virus strains in human serum from YF-endemic regions, determine the potential for interference and cross-reactions, verify the performance claims as stated by the manufacturer, and assess usability. RNA extracted from normal human serum spiked with YF virus showed the assay to be precise with minimal lot-to-lot variation. The 95% limit of detection calculated was approximately 1,245 RNA copies/ml [95% confidence interval 497 to 1,640 copies/ml]. Positive results were obtained with spatially and temporally diverse YF strains. The assay was specific for YF virus, was not subject to endogenous or exogenous interferents, and was clinically sensitive and specific. A review of operational characteristics revealed that a positivity cutoff was not defined in the instructions for use, but otherwise the assay was user-friendly. CONCLUSIONS AND SIGNIFICANCE: The RealStar Yellow Fever Virus RT-PCR kit 1.0 has performance characteristics consistent with the manufacturer's claims and is suitable for use in YF-endemic regions. Its use is expected to decrease YF outbreak detection times and be instrumental in saving lives.

DISCLAIMER: Articles listed in the CDC Science Clips are selected by the Stephen B. Thacker CDC Library to provide current awareness of the public health literature. An article's inclusion does not necessarily represent the views of the Centers for Disease Control and Prevention nor does it imply endorsement of the article's methods or findings. CDC and DHHS assume no responsibility for the factual accuracy of the items presented. The selection, omission, or content of items does not imply any endorsement or other position taken by CDC or DHHS. Opinion, findings and conclusions expressed by the original authors of items included in the Clips, or persons quoted therein, are strictly their own and are in no way meant to represent the opinion or views of CDC or DHHS. References to publications, news sources, and non-CDC Websites are provided solely for informational purposes and do not imply endorsement by CDC or DHHS.

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