BACKGROUND: Case identification remains a challenge to reaching the United Nations 95-95-95 targets for children with HIV. While the World Health Organization approved oral mucosal HIV self-testing (HIVST) for children over 2 years in 2019, there is little information on HIVST for pediatric case identification in Ethiopia. SETTING: Nine health facilities across Ethiopia. METHODS: We implemented a pilot program from November 2021-April 2022 to assess acceptability and feasibility of using HIVST to screen children 2-14 years of adult index clients, (i.e., parents/caregivers living with HIV and on antiretroviral therapy). HIV-positive adults who had children with unknown HIV status were given HIVST kits (OraQuick®) to screen their children at home. Parents/caregivers were asked to report results telephonically and bring children screening positive to the health facility for confirmatory HIV testing. We defined HIVST acceptability as ≥50% of parents/caregivers accepting testing and ≥50% reporting results within seven days of receiving a test kit. Feasibility was defined as ≥60% of children with a reactive HIVST receiving confirmatory testing and <5 serious social harms reported per 1000 kits distributed. RESULTS: Overall, 1496 of 1651 (91%) parents/caregivers accepted HIVST kits to test their children at home and 1204 (71%) reported results within seven days. Of 17 children (1%) with reactive results, 13 (76%) received confirmatory testing; of which 7 (54%) were confirmed to be HIV-positive. One serious social harm was reported. CONCLUSION: Providing adult parents/caregivers with HIVST kits to screen their children at home is an acceptable and feasible strategy to reach untested children and improve pediatric case finding in a low prevalence setting.

BACKGROUND: Tuberculosis (TB) preventive treatment (TPT) is recommended by the World Health Organization (WHO) for persons living with HIV, including pregnant and breastfeeding women. Given the President's Emergency Plan for AIDS Relief (PEPFAR)'s investment in TPT services for persons living with HIV as a strategy to prevent TB as well as uncertainty in guidelines and policy regarding use of TPT during pregnancy and the postpartum period, we conducted a review of current relevant national guidelines among PEPFAR-supported countries. METHODS: Our review included 44/49 PEPFAR-supported countries to determine if TB screening and TPT are recommended specifically for pregnant and breastfeeding women living with HIV (WLHIV). National guidelines reviewed and abstracted included TB, HIV, prevention of vertical HIV transmission, TPT, and any other relevant guidelines. We abstracted information regarding TB screening, including screening tools and frequency; and TPT, including timing, regimen, frequency, and laboratory monitoring. RESULTS: Of 44 PEPFAR-supported countries for which guidelines were reviewed, 66% were high TB incidence countries; 41% were classified by WHO as high TB burden countries, and 43% as high HIV-associated TB burden countries. We found that 64% (n = 28) of countries included TB screening recommendations for pregnant WLHIV in their national guidelines, and most (n = 35, 80%) countries recommend TPT for pregnant WLHIV. Fewer countries included recommendations for breastfeeding as compared to pregnant WLHIV, with only 32% (n = 14) mentioning TB screening and 45% (n = 20) specifically recommending TPT for this population; most of these recommend isoniazid-based TPT regimens for pregnant and breastfeeding WLHIV. However, several countries also recommend isoniazid combined with rifampicin (3RH) or rifapentine (3HP). CONCLUSIONS: Despite progress in the number of PEPFAR-supported countries that specifically include TB screening and TPT recommendations for pregnant and breastfeeding WLHIV in their national guidelines, many PEPFAR-supported countries still do not include specific screening and TPT recommendations for pregnant and breastfeeding WLHIV.

The development of resistance of Neisseria gonorrhoeae to available first-line antibiotics, including penicillins, tetracyclines, fluoroquinolones and cephalosporins, has led to the circulation of multidrug-resistant gonorrhea at a global scale. Advancements in high-throughput whole-genome sequencing (WGS) provide useful tools that can be used to enhance gonococcal detection, treatment and management capabilities, which will ultimately aid in the control of antimicrobial resistant gonorrhea worldwide. In this minireview, we discuss the application of WGS of N. gonorrhoeae to strain typing, phylogenomic, molecular surveillance and transmission studies. We also examine the application of WGS analyses to the public health sector as well as the potential usage of WGS-based transcriptomic and epigenetic methods to identify novel gonococcal resistance mechanisms.

CONTEXT: Numerous reports of suicide among individuals who received cadaver-derived human growth hormone (c-hGH) through the National Hormone Pituitary Program (NHPP) raised the alarm for potentially increased suicide risk. OBJECTIVE: We conducted a study to assess suicide risk in the NHPP cohort and identify contributing factors to facilitate early recognition and intervention. METHODS: The study population consisted of patients receiving NHPP c-hGH starting from 1957, and cohort deaths with an ICD code consistent with suicide or possible suicide through 2020 were evaluated. Descriptive data were extracted from medical records. Standardized mortality ratios (SMRs) to compare the observed number of suicide deaths in the cohort to the expected number were calculated using general population suicide rates by sex, age group, and time period. RESULTS: Among 6272 patients there were 1200 all-cause cohort deaths, of which 55 (52 male, 3 female) were attributed to suicide. Of these, 47 were identified by ICD code alone compared to an expected count of 37.8 (SMR = 1.25, 95% CI 0.91-1.66). Among male cohort members, the SMR was 1.33 (95% CI 0.97-1.78). Elevated risk of suicide was detected for cohort members aged 25-34 (SMR = 1.79, 95% CI 1.06-2.83) and during the period from September 19, 1985, to December 31, 1998 (SMR = 1.70, 95% CI 1.02-2.65). CONCLUSION: Overall, the observed number of suicides among NHPP c-hGH recipients was not significantly higher than expected. However, certain subgroups may be at elevated risk of suicide. Studies are needed to better understand the nature and magnitude of suicide risk among c-hGH recipients to facilitate early intervention to prevent suicide deaths.

Key populations (KP) in the Democratic Republic of the Congo (DRC), including female sex workers (SW), are disproportionally affected by HIV. Quantitative feedback surveys were conducted at seven health facilities in DRC with 70 KP clients enrolled in pre-exposure prophylaxis (PrEP) services to measure benefits and concerns. The surveys also assessed satisfaction with PrEP services and experiences of stigma at the health facilities. Thirty healthcare workers (HCW) were surveyed to measure attitudes, beliefs, and acceptability of providing services to KP. KP client survey participants were primarily female SW. KP clients reported that the primary concern about taking PrEP was fear of side effects (67%) although few KP reported having experienced side effect (14%). HCW concurred with clients that experienced and anticipated side effects were a primary PrEP uptake concern, along with costs of clinic visits.

BACKGROUND: Clinical management of multisystem inflammatory syndrome in children (MIS-C) has varied over time and by medical institution. METHODS: Data on patients with MIS-C were collected from 4 children's hospitals between March 16, 2020 and March 10, 2021. Relationships between MIS-C treatments and patient demographics, clinical characteristics, and outcomes were described. Propensity score matching was utilized to assess the relative risk of outcomes dependent on early treatment with intravenous immunoglobulin (IVIG) or low-dose steroids, controlling for potential confounding variables. RESULTS: Of 233 patients diagnosed with MIS-C, the most commonly administered treatments were steroids (88.4%), aspirin (81.1%), IVIG (77.7%) and anticoagulants (71.2%). Compared with those patients without respiratory features, patients with respiratory features were less likely to receive IVIG and steroids on the same day (combination treatment) (44.1%). Controlling for confounding variables, patients receiving IVIG within 1 day of hospitalization were less likely to have hospital length of stay ≥8 days (RR = 0.53, 95% CI: 0.31-0.88). Patients receiving low-dose steroids within 1 day of hospitalization were less likely to develop ventricular dysfunction (RR = 0.45, 95% CI: 0.26-0.77), have increasingly elevated troponin levels (RR = 0.55, 95% CI: 0.40-0.75) or have hospital length of stay ≥8 days (RR = 0.46, 95% CI: 0.29-0.74). CONCLUSION: Treatments for MIS-C differed by hospital, patient characteristics and illness severity. When IVIG and low-dose steroids were administered in combination or low-dose steroids were administered alone within 1 day of hospitalization, the risk of subsequent severe outcomes was decreased.

BACKGROUND: The long-term effects of children hospitalized with multisystem inflammatory syndrome in children (MIS-C) or acute COVID-19 are not well known. Our objective was to determine long-term outcomes. METHODS: Children hospitalized with MIS-C or COVID-19 at 3 US hospitals from March 2020, through February 2021 were followed to assess health through 2 years post-hospitalization using medical records and patient surveys. RESULTS: Medical record abstraction was performed for 183 patients hospitalized with MIS-C, 53 of whom participated in surveys, and 97 patients hospitalized with COVID-19, 35 of whom participated in surveys. Patients with MIS-C were younger (median, 9 vs. 14 years of age for COVID-19 patients; P = 0.004), more frequently male (62% vs. 39%; P < 0.001) and had more cardiac (14% vs. 2%; P = 0.001) and neurologic sequelae (8% vs. 1%; P = 0.023). Children with COVID-19 more often had other comorbidities (59% vs. 19%; P < 0.001). Full mental recovery at the time of survey 2 (median, 16 months post-hospitalization for patients with MIS-C and 20 months for patients with COVID-19) was 85% and 88%, respectively; full physical recovery was 87% and 81%, respectively; and nearly all had resumption of normal activities. Patients with MIS-C reported more frequent headache at 1 month (45% vs. 20%; P = 0.037). Patients with COVID-19 were more likely to report cough at 1 month (37% vs. 17%; P = 0.045). Fatigue persisted >1 year in 15%-20% of patients in both groups. CONCLUSIONS: Approximately 20% of children with MIS-C and COVID-19 continued to have symptoms including fatigue and headache >1 year after hospital discharge. The duration of these findings emphasizes the importance of providers following patients until sequelae have resolved.

Neisseria gonorrhoeae is a bacterial pathogen responsible for the sexually transmitted infection, gonorrhea. Emergence of antimicrobial resistance (AMR) of N. gonorrhoeae worldwide has resulted in limited therapeutic choices for this infection. Men who seek treatment often have symptomatic urethritis; in contrast, gonococcal cervicitis in women is usually minimally symptomatic, but may progress to pelvic inflammatory disease. Previously, we reported the first analysis of gonococcal transcriptome expression determined in secretions from women with cervical infection. Here, we defined gonococcal global transcriptional responses in urethral specimens from men with symptomatic urethritis and compared these with transcriptional responses in specimens obtained from women with cervical infections, and of in vitro-grown N. gonorrhoeae isolates. This is the first comprehensive comparison of gonococcal gene expression in infected men and women. RNA sequencing analysis revealed that 9.4% of gonococcal genes showed increased expression exclusively in men and included genes involved in host immune cell interactions and 4.3% showed increased expression exclusively in women and included phage-associated genes. Infected men and women displayed comparable antibiotic resistant-genotypes and in vitro –phenotypes, but a 4-fold higher expression of the Mtr efflux pump-related genes was observed in men. These results suggest that expression of AMR genes is programmed genotypically, and also driven by sex-specific environments. Collectively, our results indicate that distinct N. gonorrhoeae gene expression signatures are detected during genital infection in men and women. We propose that therapeutic strategies could target sex specific differences in expression of antibiotic resistance genes.

Recent reports suggest that mosaic-like sequences within the mtr (multiple transferable resistance) efflux pump locus of Neisseria gonorrhoeae likely originating from commensal Neisseria sp. by transformation can increase the ability of gonococci to resist structurally diverse antimicrobials. Thus, acquisition of numerous nucleotide changes within the mtrR gene encoding the transcriptional repressor (MtrR) of the mtrCDE efflux pump-encoding operon or overlapping promoter region for both along with those that cause amino acid changes in the MtrD transporter protein were recently reported to decrease gonococcal susceptibility to numerous antimicrobials, including azithromycin (Azi) (Wadsworth et al. 2018. MBio. doi.org/10.1128/mBio.01419-18). We performed detailed genetic and molecular studies to define the mechanistic basis for why such strains can exhibit decreased susceptibility to MtrCDE antimicrobial substrates including Azi. We report that a strong cis-acting transcriptional impact of a single nucleotide change within the -35 hexamer of the mtrCDE promoter as well gain-of-function amino acid changes at the C-terminal region of MtrD can mechanistically account for the decreased antimicrobial susceptibility of gonococci with a mosaic-like mtr locus.IMPORTANCE Historically, after introduction of an antibiotic for treatment of gonorrhea, strains of N. gonorrhoeae emerge that display clinical resistance due to spontaneous mutation or acquisition of resistance genes. Genetic exchange between members of the Neisseria genus occurring by transformation can cause significant changes in gonococci that impact the structure of an antibiotic target or expression of genes involved in resistance. The results presented herein provide a framework for understanding how mosaic-like DNA sequences from commensal Neisseria that recombine within the gonococcal mtr efflux pump locus function to decrease bacterial susceptibility to antimicrobials including antibiotics used in therapy of gonorrhea.

Key populations (KP) in the Democratic Republic of the Congo (DRC), including female sex workers (FSW), are disproportionally affected by HIV. Quantitative feedback surveys were conducted at seven health facilities in DRC with 70 KP clients enrolled in services to measure pre-exposure prophylaxis (PrEP) benefits and concerns. The surveys also assessed satisfaction with PrEP services and experiences of stigma at the health facilities. Thirty healthcare workers (HCW) were surveyed to measure attitudes, beliefs, and acceptability of providing services to KP. KP client survey participants were primarily female SW. KP clients reported that the primary concern about taking PrEP was fear of side effects. HCW concurred with clients that experienced and anticipated side effects were a primary PrEP uptake concern, along with costs of clinic visits. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

BACKGROUND: The diagnosis of SARS-CoV-2-associated multisystem inflammatory syndrome in adults (MIS-A) requires distinguishing it from acute COVID-19 and may impact clinical management. METHODS: In this retrospective cohort study, we applied the U.S. Centers for Disease Control and Prevention case definition to identify adults hospitalized with MIS-A at six academic medical centers during March 1, 2020-December 31, 2021. MIS-A patients were matched on age group, sex, site, and admission date at a 1:2 ratio to patients hospitalized with acute symptomatic COVID-19. Conditional logistic regression was used to compare demographics, presenting symptoms, laboratory and imaging results, treatments administered, and outcomes between cohorts. RESULTS: Through medical record review of 10,223 patients hospitalized with SARS-CoV-2-associated illness, we identified 53 MIS-A cases. Compared with 106 matched COVID-19 patients, MIS-A patients were more likely to be non-Hispanic Black and less likely to be non-Hispanic White. MIS-A patients more likely had laboratory-confirmed COVID-19 ≥ 14 days prior to hospitalization, more likely had positive in-hospital SARS-CoV-2 serologic testing, and more often presented with gastrointestinal symptoms and chest pain. They were less likely to have underlying medical conditions and to present with cough and dyspnea. On admission, MIS-A patients had higher neutrophil-to-lymphocyte ratio, C-reactive protein, ferritin, procalcitonin and D-dimer, compared with COVID-19 patients. MIS-A patients had longer hospitalization and more likely required intensive care admission, invasive mechanical ventilation, and vasopressors. Mortality was 6% in both cohorts. CONCLUSIONS: Compared with patients with acute symptomatic COVID-19, adults with MIS-A more often manifest certain symptoms and laboratory findings early during hospitalization. These features may facilitate diagnosis and management.

BACKGROUND: Guidance for preparing powdered infant formula (PIF) helps to ensure it meets the nutritional needs of infants and is safe to consume. Among safety concerns is Cronobacter sakazakii contamination which can lead to serious infections and death. PIF preparation guidance varies; there is a lack of consensus on whether there is a need to boil water to inactivate potential Cronobacter and for how long to let the water cool before reconstitution. We sought to quantify the burden of burn injuries among infants related to water heating for PIF preparation. Estimating this burden may help inform preparation recommendations. METHODS: Burn injuries among infants <18 months of age were identified from 2017 to 2019 National Electronic Injury Surveillance System data collected from sampled hospital emergency departments. Injuries were classified as related to PIF water heating, potentially related to PIF water heating but with undetermined causation, related to other infant feeding aspects, or unrelated to infant formula or breast milk feeding. Unweighted case counts for each injury classification were determined. RESULTS: Across sampled emergency departments, 7 PIF water heating injuries were seen among the 44,395 injuries reported for infants <18 months. No reported PIF water heating injuries were fatal, but 3 required hospitalization. Another 238 injuries potentially related to PIF water heating but with undetermined causation were also seen. CONCLUSION: Preparation guidance should consider both the potential risk for Cronobacter infection and the potential risk for burns.

BACKGROUND: Repeat HIV testing during pregnancy and breastfeeding identifies women with incident infections, those living with HIV who have been lost to care, and infants at risk for HIV infection. We report data from repeat testing for women in maternal and child health (MCH) services at 10 health facilities in Mozambique. METHODS: Routinely collected data from health facility registers are reported from April-November 2019. From antenatal care (ANC), we report numbers and proportions of women eligible for retesting; returned for care when retesting eligible; retested; and HIV-positive (HIV+) at retesting. From child welfare clinics (CWC), we report mothers retested; tested HIV-positive; HIV+ mothers linked to ART services; HIV-exposed infants (HEI) tested for HIV with polymerase chain reaction (PCR) tests; HEI testing PCR positive; PCR-positive infants linked to care. RESULTS: In ANC, 28,233 pregnant women tested HIV-negative at first ANC visit, 40.7% had a follow-up visit when retesting eligible, among whom 84.8% were retested and 0.3%(N = 26) tested HIV+. In CWC, 26,503 women were tested; 0.8%(N = 212) tested HIV+ and 74.1%(N = 157) of HIV+ women were linked to care. Among 157 HEI identified in CWC, 68.4%(N = 145) received PCR testing and 19.3%(N = 28) tested positive. CONCLUSION: In ANC, less than half of pregnant women eligible for retesting returned for follow-up visits, and test positivity was low among women retested in ANC and CWC. In CWC, linkage to infant testing was poor and almost 20% of HEI were PCR-positive. Implementing retesting for pregnant and breastfeeding women is challenging due to high numbers of women and low testing yield.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a multiorgan hyperinflammatory condition following SARS-CoV-2 infection. Data on COVID-19 vaccine adverse events and vaccine attitudes in children with prior MIS-C are limited. We described characteristics associated with COVID-19 vaccination, vaccine adverse events and vaccine attitudes in children with a history of MIS-C or COVID-19 and their parents/guardians. METHODS: We enrolled children previously hospitalized for MIS-C or COVID-19 from 3 academic institutions. We abstracted charts and interviewed children and parents/guardians regarding vaccine adverse events and acceptability. RESULTS: Of 163 vaccine-eligible children enrolled with a history of MIS-C and 70 with history of COVID-19, 51 (31%) and 34 (49%), respectively, received mRNA COVID-19 vaccine a median of 10 (Interquartile Range 6-13) months after hospital discharge. Among 20 children with MIS-C and parents/guardians who provided interviews, local injection site reaction of brief duration (mean 1.8 days) was most commonly reported; no children required medical care within 2 weeks postvaccination. Vaccine survey results of interviewed, vaccinated children and their parents/guardians: of 20 children with MIS-C and 15 children with COVID-19, 17 (85%) and 13 (87%), respectively, listed doctors in the top 3 most trusted sources for vaccine information; 13 (65%) and 9 (60%) discussed vaccination with their doctor. CONCLUSIONS: COVID-19 vaccination was well tolerated in children with prior MIS-C or COVID-19 participating in our investigation. Parents/guardians regarded their children's doctors as a trusted source of information for COVID-19 vaccines, and most vaccinated children's parents/guardians had discussed COVID-19 vaccination for their child with their doctor.

BACKGROUND: Kawasaki disease (KD) can result in severe coronary artery abnormalities (CAAs). Corticosteroids added to initial standard intravenous immunoglobulin (IVIG) treatment may decrease the risk for these complications. Different corticosteroid regimens (single-day high dose pulse vs multiple lower doses) may contribute to the discrepant results of prior studies. METHODS: Using data from the 22nd, 23(rd) , and 24th Japanese nationwide KD surveys (2011-2016), we identified KD patients who did not have CAAs at first presentation and who were treated with either pulse or multiple-dose corticosteroids as part of their initial treatment. Occurrence of subsequent CAAs and treatment failure were compared between the treatment regimens and adjusted odds ratios were calculated controlling for sex, age group, illness day at first treatment, survey, and recurrent KD. RESULTS: There were 782 KD patients who received pulse corticosteroid treatment and 4,817 who received multiple dose treatment. Patients receiving multiple dose treatment were less likely to develop CAAs (5.5% vs 8.3%, OR 0.64; 95% CI: 0.48-0.85) or treatment failure (21.4% vs 41.6%; OR: 0.38; 95% CI: 0.33-0.45). Adjusted analyses showed similar protective effects of multiple-dose treatment against CAAs (OR: 0.67, 95% CI: 0.51-0.90) and treatment failure (OR: 0.39, 95% CI: 0.33-0.46). CONCLUSIONS: Multiple-dose corticosteroid combination treatment resulted in substantially improved outcomes in KD patients compared to pulse treatment. For patients who may be at elevated risk of treatment failure or CAA, use of multiple-dose corticosteroids in conjunction with IVIG is likely to provide considerable clinical benefit.

THIS REPORT SUMMARIZES THE EVIDENCE AND RATIONALE SUPPORTING THE COMPONENTS OF THE CSTE/CDC MIS-C SURVEILLANCE CASE DEFINITION AND DESCRIBES THE METHODS USED TO DEVELOP THE DEFINITION. THESE METHODS INCLUDED CONVENING MIS-C CLINICAL EXPERTS (I.E., CONSULTANTS): regarding identification of MIS-C and its distinction from other pediatric conditions, a review of available literature comparing MIS-C phenotype with that of pediatric COVID-19 and other hyperinflammatory syndromes, and retrospective application of different criteria to data from MIS-C cases previously reported to CDC.

BACKGROUND: We describe tuberculosis (TB) disease among antiretroviral treatment (ART) eligible children living with HIV (CLHIV) in South Africa to highlight TB prevention opportunities. METHODS: In our secondary analysis among 0- to 12-year-old ART-eligible CLHIV in five Eastern Cape Province health facilities from 2012 to 2015, prevalent TB occurred 90 days before or after enrollment; incident TB occurred >90 days after enrollment. Characteristics associated with TB were assessed using logistic and Cox proportional hazards regression with generalized estimating equations. RESULTS: Of 397 enrolled children, 114 (28.7%) had prevalent TB. Higher-income proxy [adjusted odds ratio (aOR) 1.8 [95% confidence interval (CI) 1.3-2.6] for the highest, 1.6 (95% CI 1.6-1.7) for intermediate]; CD4+ cell count <350 cells/µl [aOR 1.6 (95% CI 1.1-2.2)]; and malnutrition [aOR 1.6 (95% CI 1.1-2.6)] were associated with prevalent TB. Incident TB was 5.2 per 100 person-years and was associated with delayed ART initiation [hazard ratio (HR) 4.7 (95% CI 2.3-9.4)], malnutrition [HR 1.8 (95% CI 1.1-2.7)] and absence of cotrimoxazole [HR 2.3 (95% CI 1.0-4.9)]. Among 362 children with data, 8.6% received TB preventive treatment. CONCLUSIONS: Among these CLHIV, prevalent and incident TB were common. Early ART, cotrimoxazole and addressing malnutrition may prevent TB in these children. | BACKGROUND: We describe tuberculosis (TB) in children living with HIV (CLHIV) eligible for HIV treatment in South Africa to highlight opportunities to prevent TB. METHODS: We analyzed additional data from our original study of CLHIV who were 0–12 years old and due to start HIV treatment in five health facilities in Eastern Cape Province from 2012 to 2015 and assessed characteristics associated with existing and new TB. RESULTS: Of 397 enrolled children, 114 (28.7%) had existing TB. Children with a higher measure of household income had higher odds of existing TB. CD4+ cell count <350 cells/µl and malnutrition were also associated with existing TB. There were 5.2 new cases of TB for every 100 child-years. New TB was 4.7 times more likely for children with delayed HIV treatment start, 1.8 times more likely for children with malnutrition and 2.3 times more likely for children who did not get cotrimoxazole. Among 362 children with data, 8.6% received treatment to prevent TB. CONCLUSIONS: Among these CLHIV, existing and new TB were common. Early HIV treatment, cotrimoxazole and addressing malnutrition may prevent TB in these children. | eng

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a novel severe postinfectious condition associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The purpose of this report is to describe nationwide trends in the evolving clinical management of MIS-C. METHODS: Patients with MIS-C were reported from state and local jurisdictions to the Centers for Disease Control and Prevention's (CDC's) MIS-C national surveillance system. Patients' case reports were reviewed to ensure that they met the CDC MIS-C case definition and had sufficient data for analysis. The prevalence of use of treatments for MIS-C, temporal trends in use of these treatments, and frequency of administration of different treatment combinations were analyzed. RESULTS: There were 4470 patients meeting the MIS-C case definition with onset dates from 19 February 2020 to 31 July 2021. The proportion of patients admitted to an intensive care unit (ICU) has declined over time, from 78.7% in April 2020 to 57.5% in June 2021 (P = .001). The most common treatments were intravenous immunoglobulin (IVIG), given to 85.6% of patients; steroids (77.7%), and antiplatelet medications (73.7%); use of each of these treatments has increased over time, particularly in patients not requiring admission to an ICU (all P < .001). Older patients and non-Hispanic Black patients were more likely to receive additional modes of therapy including vasoactive medication, noninvasive respiratory support, anticoagulation medication, and intubation/mechanical ventilation. CONCLUSIONS: IVIG, steroids, and antiplatelet medication have become increasingly utilized as standard treatment for MIS-C patients, while the use of other treatments may be contingent on the type and severity of clinical findings.

Tuberculosis (TB) primarily affects women during their reproductive years and contributes to maternal mortality and poor pregnancy outcomes. For pregnant women living with HIV (WLHIV), TB is the leading cause of non-obstetric maternal mortality, and pregnant WLHIV with TB are at increased risk of transmitting both TB and HIV to their infants. TB diagnosis among pregnant women, particularly WLHIV, remains challenging, and TB preventive treatment (TPT) coverage among pregnant WLHIV is limited. This project aimed to strengthen integrated TB and reproductive, maternal, neonatal and child health (RMNCH) services in Eswatini to improve screening and treatment for TB disease, TPT uptake and completion among women receiving RMNCH services. The project was conducted from April-December 2017 at four health facilities in Eswatini and introduced enhanced monitoring tools and on-site technical support in RMNCH services. We present data on TB case finding among women, and TPT coverage and completion among eligible WLHIV. A questionnaire (S1 Appendix) measured healthcare provider perspectives on the project after three months of project implementation, including feasibility of scaling-up integrated TB and RMNCH services. A total of 5,724 women (HIV-negative or WLHIV) were screened for active TB disease while attending RMNCH services; 53 (0.9%) were identified with presumptive TB, of whom 37 (70%) were evaluated for TB disease and 6 (0.1% of those screened) were diagnosed with TB. Among 1,950 WLHIV who screened negative for TB, 848 (43%) initiated TPT and 462 (54%) completed. Forty-three healthcare providers completed the questionnaire, and overall were highly supportive of integrated TB and RMNCH services. Integration of TB/HIV services in RMNCH settings was feasible and ensured high TB screening coverage among women of reproductive age, however, symptom screening identified few TB cases, and further studies should explore various screening algorithms and diagnostics that optimize case finding in this population. Interventions should focus on working with healthcare providers and patients to improve TPT initiation and completion rates.

BACKGROUND: and Setting: The Botswana Combination Prevention Project (BCPP) demonstrated a 30% reduction in community HIV incidence through expanded HIV testing, enhanced linkage to care, and universal antiretroviral treatment and exceeded the Joint United Nations Programme on HIV/AIDS 90-90-90 targets. We report rates and characteristics of incident HIV infections. METHODS: BCPP was a community-randomized controlled trial conducted in 30 rural/peri-urban Botswana communities from 2013 to 2017. Home-based and mobile HIV-testing campaigns were conducted in 15 intervention communities, with 39% of participants testing at least twice. We assessed the HIV incidence rate (IR; number of new HIV infections per 100 person-years (py) at risk) among repeat testers and risk factors with a Cox proportional hazards regression model. RESULTS: During 27,517py, 195 (women,79%) of 18,597 became HIV-infected (0.71/100py). Women had a higher IR (1.01/100py; 95% CI, 0.99 to 1.02) than men (0.34/100py; 95% CI, 0.33 to 0.35). The highest IRs were among women aged 16-24 years (1.87/100py) and men aged 25-34 years (0.56/100py). The lowest IRs were among those aged 35-64 years (women,0.41/100py; men,0.20/100py). Hazard of incident infection was highest among women aged 16-24 (HR=7.05). Sex and age were significantly associated with incidence (both P<0.0001). CONCLUSIONS: Despite an overall reduction in HIV incidence and approaching the UNAIDS 95-95-95 targets, high HIV incidence was observed in adolescent girls and young women. These findings highlight the need for additional prevention services [pre-exposure prophylaxis (PrEP), DREAMS] to achieve epidemic control in this subpopulation and increased efforts with men with undiagnosed HIV.

BACKGROUND: Pregnant and breastfeeding adolescents and young women living with HIV (AYWLH) have lower retention in prevention of mother-to-child transmission (PMTCT) services compared to older women. METHODS: We evaluated a differentiated service model for pregnant and postnatal AYWLH at seven health facilities in western Kenya aimed at improving retention in antiretroviral treatment (ART) services. All pregnant AYWLH < 25 years presenting for antenatal care (ANC) were invited to participate in group ANC visits including self-care and peer-led support sessions conducted by health facility nurses per national guidelines. ART register data were used to assess loss to follow-up (LTFU) among newly-enrolled pregnant adolescent (< 20 years) and young women (20-24 years) living with HIV starting ART in the pre-period (January-December 2016) and post-period (during implementation; December 2017-January 2019). Poisson regression models compared LTFU incidence rate ratios (IRR) in the first six months after PMTCT enrollment and risk ratios compared uptake of six week testing for HIV-exposed infants (HEI) between the pre- and post-periods. RESULTS: In the pre-period, 223 (63.2%) of 353 pregnant AYWLH newly enrolled in ANC had ART data, while 320 (71.1%) of 450 in the post-period had ART data (p = 0.02). A higher proportion of women in the post-period (62.8%) had known HIV-positive status at first ANC visit compared to 49.3% in the pre-period (p < 0.001). Among pregnant AYWLH < 20 years, the incidence rate of LTFU in the first six months after enrollment in ANC services declined from 2.36 per 100 person months (95%CI 1.06-5.25) in the pre-period to 1.41 per 100 person months (95%CI 0.53-3.77) in the post-period. In both univariable and multivariable analysis, AYWLH < 20 years in the post-period were almost 40% less likely to be LTFU compared to the pre-period, although this finding did not meet the threshold for statistical significance (adjusted incidence rate ratio 0.62, 95%CI 0.38-1.01, p = 0.057). Testing for HEI was 10% higher overall in the post-period (adjusted risk ratio 1.10, 95%CI 1.01-1.21, p = 0.04). CONCLUSIONS: Interventions are urgently needed to improve outcomes among pregnant and postnatal AYWLH. We observed a trend towards increased retention among pregnant adolescents during our intervention and a statistically significant increase in uptake of six week HEI testing.

BACKGROUND: The serologic and cytokine responses of children hospitalized with multisystem inflammatory syndrome (MIS-C) vs coronavirus disease 2019 (COVID-19) are poorly understood. METHODS: We performed a prospective, multicenter, cross-sectional study of hospitalized children who met the Centers for Disease Control and Prevention case definition for MIS-C (n = 118), acute COVID-19 (n = 88), or contemporaneous healthy controls (n = 24). We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) immunoglobulin G (IgG) titers and cytokine concentrations in patients and performed multivariable analysis to determine cytokine signatures associated with MIS-C. We also measured nucleocapsid IgG and convalescent RBD IgG in subsets of patients. RESULTS: Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG than children with acute COVID-19 (median, 2783 vs 146; P < .001), and titers correlated with nucleocapsid IgG. For patients with MIS-C, RBD IgG titers declined in convalescence (median, 2783 vs 1135; P = .010) in contrast to patients with COVID-19 (median, 146 vs 4795; P < .001). MIS-C was characterized by transient acute proinflammatory hypercytokinemia, including elevated levels of interleukin (IL) 6, IL-10, IL-17A, and interferon gamma (IFN-γ). Elevation of at least 3 of these cytokines was associated with significantly increased prevalence of prolonged hospitalization ≥8 days (prevalence ratio, 3.29 [95% CI, 1.17-9.23]). CONCLUSIONS: MIS-C was associated with high titers of SARS-CoV-2 RBD IgG antibodies and acute hypercytokinemia with IL-6, IL-10, IL-17A, and IFN-γ.

BACKGROUND: Distinguishing multisystem inflammatory syndrome in children (MIS-C) from coronavirus disease 2019 (COVID-19), Kawasaki disease (KD), and toxic shock syndrome (TSS) can be challenging. Because clinical management of these conditions can vary, timely and accurate diagnosis is essential. METHODS: Data were collected from patients <21 years of age hospitalized with MIS-C, COVID-19, KD, and TSS in 4 major health care institutions. Patient demographics and clinical and laboratory data were compared among the 4 conditions, and a diagnostic scoring tool was developed to assist in clinical diagnosis. RESULTS: A total of 233 patients with MIS-C, 102 with COVID-19, 101 with KD, and 76 with TSS were included in the analysis. Patients with MIS-C had the highest prevalence of decreased cardiac function (38.6%), myocarditis (34.3%), pericardial effusion (38.2%), mitral regurgitation (31.8%) and pleural effusion (34.8%) compared with patients with the other conditions. Patients with MIS-C had increased peak levels of C-reactive protein and decreased platelets and lymphocyte nadir counts compared with patients with COVID-19 and KD and elevated levels of troponin, brain natriuretic peptide and pro-brain natriuretic peptide compared with COVID-19. Diagnostic scores utilizing clinical findings effectively distinguished MIS-C from COVID-19, KD, and TSS, with internal validation showing area under the curve ranging from 0.87 to 0.97. CONCLUSIONS: Compared with COVID-19, KD, and TSS, patients with MIS-C had significantly higher prevalence of cardiac complications, elevated markers of inflammation and cardiac damage, thrombocytopenia, and lymphopenia. Diagnostic scores can be a useful tool for distinguishing MIS-C from COVID-19, KD, and TSS.

High-throughput sequencing has become commonplace in evolutionary studies. Large, rapidly collected genomic datasets are used to capture biodiversity and for monitoring global and national scale disease transmission patterns, among many other applications. Updating homologous sequence datasets with new samples is cumbersome, requiring excessive program runtimes and data processing. We describe Extensiphy, a bioinformatics tool to efficiently update multiple sequence alignments with whole-genome short-read data. Extensiphy performs reference based sequence assembly and alignment in one process while maintaining the alignment length of the original alignment. Input data-types for Extensiphy are any multiple sequence alignment in fasta format and whole-genome, short-read fastq sequences. To validate Extensiphy, we compared its results to those produced by two other methods that construct whole-genome scale multiple sequence alignments. We measured our comparisons by analysing program runtimes, base-call accuracy, dataset retention in the presence of missing data and phylogenetic accuracy. We found that Extensiphy rapidly produces high-quality updated sequence alignments while preventing alignment shrinkage due to missing data. Phylogenies estimated from alignments produced by Extensiphy show similar accuracy to other commonly used alignment construction methods. Extensiphy is suitable for updating large sequence alignments and is ideal for studies of biodiversity, ecology and epidemiological monitoring efforts. © 2021 The Authors. Methods in Ecology and Evolution published by John Wiley & Sons Ltd on behalf of British Ecological Society

Key populations, ie, female sex workers, men who have sex with men, transgender people, people who inject drugs, and people in prisons and other closed settings, experience stigma, discrimination, and structural barriers when accessing HIV prevention and care. Public health facilities in Myanmar became increasingly involved in HIV service delivery, leading to an urgent need for healthcare workers to provide client-centred, key population-friendly services. Between July 2017-June 2018, the Myanmar Ministry of Health and Sports and National AIDS Programme collaborated with ICAP at Columbia University and the US Centers for Disease Control and Prevention to implement a quasi-experimental, multicomponent intervention including healthcare worker sensitization training with pre- and post- knowledge assessments, healthcare worker and client satisfaction surveys, and structural changes. We observed modest improvements among healthcare workers (n = 50) in knowledge assessments. Classification of clients into key population groups increased and fewer clients were classified as low risk. Key population clients reported favourable perceptions of the quality and confidentiality of care through self-administered surveys. Our findings suggest public health facilities can deliver HIV services that are valued by key population clients.

Transitions between services for continued antiretroviral treatment (ART) during and after pregnancy are a commonly overlooked aspect of the HIV care cascade, but ineffective transitions can lead to poor health outcomes for women and their children. In this qualitative study, we conducted interviews with 15 key stakeholders from Ministries of Health along with PEPFAR-supported and other in-country non-governmental organizations actively engaged in national programming for adult HIV care and prevention of mother-to-child-transmission of HIV (PMTCT) services in Côte d'Ivoire, Lesotho and Malawi. We aimed to understand perspectives regarding transitions into and out of PMTCT services for continued ART. Thematic analysis revealed that, although transitions of care are necessary and a potential point of loss from ART care in all three countries, there is a lack of clear guidance on transition approach and no formal way of monitoring transition between services. Several opportunities were identified to monitor and strengthen transitions of care for continued ART along the PMTCT cascade.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe hyperinflammatory condition in persons aged <21 years associated with antecedent SARS-CoV-2 infection. Our objective was to describe MIS-C cases reported to CDC's national surveillance since the COVID-19 pandemic began. METHODS: We included patients meeting the MIS-C case definition with onset date from February 19, 2020 through July 31, 2021, using CDC's MIS-C case report form, which collects information on demographics, clinical presentation, and laboratory results. Trends over time across 3 MIS-C pandemic waves were assessed using Cochran-Armitage test for categorical and Jonckheere-Terpstra test for continuous variables. RESULTS: Of 4,901 reported cases, 4,470 met inclusion criteria. Median patient age increased over time (P<0.001), with a median of 9 years (interquartile range, 5-13 years) during the most recent (third) wave. Male predominance also increased (62% in third wave, P<0.001). A significant (P<0.001) increase in severe hematologic and gastrointestinal involvement was observed across the study period. Frequency of several cardiovascular complications (i.e., cardiac dysfunction, myocarditis, and shock/ vasopressor receipt) and renal failure declined (P<0.001). Provision of critical care including mechanical ventilation (P<0.001) and extracorporeal membrane oxygenation (ECMO; P=0.046) decreased, as did duration of hospitalization and mortality (each P<0.001). CONCLUSIONS: Over the first 3 pandemic waves of MIS-C in the United States, cardiovascular complications and clinical outcomes including length of hospitalization, receipt of ECMO, and death decreased over time. These data serve as a baseline for monitoring future trends associated with SARS-CoV-2 B.1.617.2 (Delta) or other variants and increased COVID-19 vaccination among children.

BACKGROUND: Multisystem inflammatory syndrome in adults (MIS-A) was reported in association with the COVID-19 pandemic. MIS-A was included in the list of adverse events to be monitored as part of the emergency use authorizations issued for COVID-19 vaccines. METHODS: Reports of MIS-A patients received by the Centers for Disease Control and Prevention (CDC) after COVID-19 vaccines became available were assessed. Data collected on the patients included clinical and demographic characteristics and their vaccine status. The Vaccine Adverse Events Reporting System (VAERS) was also reviewed for possible cases of MIS-A. RESULTS: From December 14, 2020 to April 30, 2021, 20 patients who met the case definition for MIS-A were reported to CDC. Their median age was 35 years (range, 21-66 years), and 13 (65%) were male. Overall, 16 (80%) patients had a preceding COVID-19-like illness a median of 26 days (range 11-78 days) before MIS-A onset. All 20 patients had laboratory evidence of SARS-CoV-2 infection. Seven MIS-A patients (35%) received COVID-19 vaccine a median of 10 days (range, 6-45 days) before MIS-A onset; 3 patients received a second dose of COVID-19 vaccine 4, 17, and 22 days before MIS-A onset. Patients with MIS-A predominantly had gastrointestinal and cardiac manifestations and hypotension or shock. CONCLUSIONS: Although 7 patients were reported to have received COVID-19 vaccine, all had evidence of prior SARS-CoV-2 infection. Given the widespread use of COVID-19 vaccines, the lack of reporting of MIS-A associated with vaccination alone, without evidence of underlying SARS-CoV-2 infection, is reassuring.

BACKGROUND: To accelerate progress toward the UNAIDS 90-90-90 targets, US Centers for Disease Control and Prevention Nigeria country office (CDC Nigeria) initiated an Antiretroviral Treatment (ART) Surge in 2019 to identify and link 340,000 people living with HIV/AIDS (PLHIV) to ART. Coronavirus disease 2019 (COVID-19) threatened to interrupt ART Surge progress following the detection of the first case in Nigeria in February 2020. To overcome this disruption, CDC Nigeria designed and implemented adapted ART Surge strategies during February-September 2020. METHODS: Adapted ART Surge strategies focused on continuing expansion of HIV services while mitigating COVID-19 transmission. Key strategies included an intensified focus on community-based, rather than facility-based, HIV case-finding; immediate initiation of newly-diagnosed PLHIV on 3-month ART starter packs (first ART dispense of 3 months of ART); expansion of ART distribution through community refill sites; and broadened access to multi-month dispensing (MMD) (3-6 months ART) among PLHIV established in care. State-level weekly data reporting through an Excel-based dashboard and individual PLHIV-level data from the Nigeria National Data Repository facilitated program monitoring. RESULTS: During February-September 2020, the reported number of PLHIV initiating ART per month increased from 11,407 to 25,560, with the proportion found in the community increasing from 59 to 75%. The percentage of newly-identified PLHIV initiating ART with a 3-month ART starter pack increased from 60 to 98%. The percentage of on-time ART refill pick-ups increased from 89 to 100%. The percentage of PLHIV established in care receiving at least 3-month MMD increased from 77 to 93%. Among PLHIV initiating ART, 6-month retention increased from 74 to 92%. CONCLUSIONS: A rapid and flexible HIV program response, focused on reducing facility-based interactions while ensuring delivery of lifesaving ART, was critical in overcoming COVID-19-related service disruptions to expand access to HIV services in Nigeria during the first eight months of the pandemic. High retention on ART among PLHIV initiating treatment indicates immediate MMD in this population may be a sustainable practice. HIV program infrastructure can be leveraged and adapted to respond to the COVID-19 pandemic.

IMPORTANCE: Multisystem inflammatory syndrome in adults (MIS-A) has not been well described. Improved diagnosis and treatment of MIS-A might mitigate COVID-19 morbidity and mortality. OBJECTIVE: To summarize the descriptive epidemiology and clinical characteristics of MIS-A. EVIDENCE REVIEW: This systematic review identified patients with MIS-A using 3 strategies: (1) literature review from May 1, 2020, to May 25, 2021, by searching MEDLINE, Embase, Global Health, CAB Abstracts, PsycINFO, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Academic Search Complete, Scopus, World Health Organization Global COVID-19 Literature Database, and Google Scholar; (2) voluntary reports of MIS-A to the Centers for Disease Control and Prevention (CDC); and (3) reports among persons aged 18 to 20 years in the CDC surveillance system for MIS in children. FINDINGS: Of 221 patients with MIS-A, the median age was 21 (interquartile range [IQR], 19-34) years, and 154 of 219 (70%) with data available were men. Sixty of 169 patients (36%) were non-Hispanic Black individuals, and 122 of 209 (58%) had no underlying comorbidity. One hundred two of 149 patients (68%) noted a previous symptomatic COVID-19-like illness (median, 28 [IQR, 20-36] days previously). Most patients with MIS-A presented with fever (197 of 205 [96%]), hypotension (133 of 220 [60%]), cardiac dysfunction (114 of 210 [54%]), shortness of breath (102 of 198 [52%]), and/or diarrhea (102 of 197 [52%]). The median number of organ systems involved was 5 (IQR, 4-6). Median hospital stay was 8 (IQR, 5-12) days; 115 of 201 patients (57%) were admitted to the intensive care unit; 101 of 213 (47%) required respiratory support, and 15 of 220 (7%) died. Most patients (176 of 195 [90%]) had elevated markers of coagulopathy and/or inflammation and a positive SARS-CoV-2 serologic finding (139 of 194 [72%]). Ten patients with MIS-A presented with Kawasaki disease. CONCLUSIONS AND RELEVANCE: These findings suggest that MIS-A is a serious hyperinflammatory condition that presents approximately 4 weeks after onset of acute COVID-19 with extrapulmonary multiorgan dysfunction.