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It is unclear if SARS CoV-2 infection during pregnancy is associated with adverse neurodevelopmental repercussions to infants. We assessed pediatric neurodevelopmental outcomes in children born to mothers with laboratory-confirmed SARS CoV-2 infection during pregnancy. Neurodevelopmental outcomes of in-utero exposed children were compared to that of pre-pandemic control children in Los Angeles (LA), CA, USA and Rio de Janeiro, Brazil. Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), the gold standard tool for evaluating neurodevelopment until 36 months of age and Ages and Stages Questionnaires (ASQ-3), a frequently used screening instrument for evaluating neurodevelopment in this same age group were the assessment tools used. Developmental delay (DD) was defined as having a score

PurposeGay, bisexual, and other cisgender men who have sex with men, and racial minority youth are at elevated risk of acquiring HIV infection. The Adolescent Trials Network 147 recruited youth with acute/recent HIV-infection for early antiretroviral treatment. The cohort make-up is described here.MethodsTreatment-naïve, recently identified HIV + youth, aged 12-24 years, from Los Angeles and New Orleans were recruited from community centers, clinics, social media, and a high-risk seronegative cohort (n = 1,727, the Adolescent Trials Network 149) using point-of-care assays. Acute HIV infection was determined by Fiebig staging. HIV RNA viral load (VL) and CD4 cell counts, along with demographic and behavioral data were assessed at enrollment.ResultsBetween July 2017 and July 2021, 103 newly diagnosed youth were enrolled, initiating antiretroviral treatment within a week. Mean age was 20.8 years (standard deviation: 2.4); 90.3% identified as cis male, 83.5% were single or in casual relationships, 71.8% were gay, bisexual, and other cisgender men who have sex with men; 60.2% were Black. One-fourth (24.3%) reported homelessness ever; 10.7% within last 4 months. At enrollment, median plasma VL was 37,313 HIV RNA copies/ml (interquartile range: 5,849-126,162) and median CD4 count 445.5 cells/mm3 (interquartile range: 357-613). 40% of youth reported acute retroviral symptoms before or at enrollment. Acutely infected, seroconverting youth had the highest VL. Sexually transmitted coinfections were present at enrollment in 56% of the cohort, with syphilis being most frequent (39%).DiscussionEarly identification and treatment of HIV can increase positive HIV outcomes. A high sexually transmitted infection burden was present in recently HIV-infected youth. Acute retroviral symptoms were not reported by most participants, demonstrating that broad universal HIV screening is needed for identification of recent infection in youth.

BackgroundAccording to the World Health Organization, in 2018, 37.9 million people were living with HIV globally. More than two-thirds were residing in sub-Saharan Africa, where the HIV prevalence in the adult population (aged 15-49 years) was 3.9%. This population included 1.3 million pregnant women, of whom 82% had received antiretroviral therapy (ART) for the prevention of HIV mother-to-child transmission. In these countries, one challenge is an insufficient level of treatment adherence, particularly in HIV-positive pregnant women. Among the causes, the lack of involvement from a male partner is a significant contributor to the problem. This issue has strongly emerged in Malawi, one of the countries with the highest HIV prevalence in the world: 9.2% of its adult population were living with HIV in 2018. ObjectiveThis study aims to assess 3 interventions that are aimed at improving ART adherence and retention among HIV-positive women through engagement with their male partners in 4 Malawian health care centers. MethodsThe prospective, controlled before-and-after study is conducted in 3 phases (total duration: 24 months): preintervention, intervention, and postintervention analyses. The number of selected clusters (clinical centers) is limited to 4: one for each intervention, plus a cluster where no intervention is performed (control arm). The interventions are as follows: opening the facility on one Saturday per month only for men, defined as a special day; testing peer-to-peer counseling among men, male champions; and providing a noneconomic incentive to all women who are accompanied by their partners to the facility, nudge. The primary outcome of the study is to evaluate the differences in retention in care and adherence to therapeutic protocols among women; the intermediate outcome is the assessment of differences in male involvement. The level of male involvement in the health of their partners (intermediate outcome) will be evaluated through a dedicated questionnaire administered at baseline and in the postintervention phase. Data will be collected at the clinical centers and stored in 2 electronic databases managed using 2 different types of software. ResultsThe analysis of data collected in the 4 centers during the preintervention phase is ongoing, as enrollment ended on March 31, 2020. The total number of patients enrolled was 452 (Namandanje: 133; Kapeni: 78; Kapire: 75; and Balaka: 166). Meanwhile, several meetings have been conducted to organize the intervention phase. ConclusionsThe study will identify the best intervention that enhances the involvement of male partners in women’s health, using an approach that considers a broad spectrum of behaviors. An important aspect is the use of educational tools focused on messages, thereby initiating a reflective discussion of stereotypes and false beliefs related to the idea of masculinity present in the Malawian culture. International Registered Report Identifier (IRRID)DERR1-10.2196/19384

Respiratory distress (RD) has been reported in SARS-CoV-2 exposed uninfected (SEU) term neonates. Prior studies suggest that prenatal exposure to Coronavirus Disease 19 (COVID-19) may activate an inflammatory cascade in the newborn airway. In this study, we examine the relationship between maternal COVID-19 vaccination and neonatal RD using a longitudinal cohort of mother-infant pairs in Los Angeles, CA. Two-hundred and twenty-one mothers with laboratory confirmed SARS-CoV-2 during pregnancy and 227 exposed fetuses are enrolled in our study. Maternal disease severity and neonatal RD variables were defined based on current accepted clinical criteria. To explore the multifactorial associations between maternal COVID-19 parameters and infant RD, we utilize a multivariable logistic regression model and a proteomic sub-analysis to propose a pathway for the development of RD following in utero exposure to SARS-CoV-2. Unusually high rates of RD are observed in SEU infants (17%). The odds ratio of RD is 3.06 (95% CI:1.08-10.21) in term neonates born to unvaccinated individuals versus those born to individuals vaccinated prior to maternal infection. Proteomic analysis reveals a robust inflammatory response associated with ciliary dysregulation and enhanced IgE production among SEU neonates with RD. Maternal vaccination against COVID-19 reduces the frequency of neonatal RD.

BACKGROUND: On the basis of available data, at least 1 ultrasound assessment of pregnancies recovering from SARS-CoV-2 infection is recommended. However, reports on prenatal imaging findings and potential associations with neonatal outcomes following SARS-CoV-2 infection in pregnancy have been inconclusive. OBJECTIVE: This study aimed to describe the sonographic characteristics of pregnancies after confirmed SARS-CoV-2 infection and assess the association of prenatal ultrasound findings with adverse neonatal outcomes. STUDY DESIGN: This was an observational prospective cohort study of pregnancies diagnosed with SARS-CoV-2 by reverse transcription polymerase chain reaction between March 2020 and May 2021. Prenatal ultrasound evaluation was performed at least once after diagnosis of infection, with the following parameters measured: standard fetal biometric measurements, umbilical and middle cerebral artery Dopplers, placental thickness, amniotic fluid volume, and anatomic survey for infection-associated findings. The primary outcome was the composite adverse neonatal outcome, defined as ≥1 of the following: preterm birth, neonatal intensive care unit admission, small for gestational age, respiratory distress, intrauterine fetal demise, neonatal demise, or other neonatal complications. Secondary outcomes were sonographic findings stratified by trimester of infection and severity of SARS-CoV-2 infection. Prenatal ultrasound findings were compared with neonatal outcomes, severity of infection, and trimester of infection. RESULTS: A total of 103 SARS-CoV-2-affected mother-infant pairs with prenatal ultrasound evaluation were identified; 3 cases were excluded because of known major fetal anomalies. Of the 100 included cases, neonatal outcomes were available in 92 pregnancies (97 infants); of these, 28 (29%) had the composite adverse neonatal outcome, and 23 (23%) had at least 1 abnormal prenatal ultrasound finding. The most common abnormalities seen on ultrasound were placentomegaly (11/23; 47.8%) and fetal growth restriction (8/23; 34.8%). The latter was associated with a higher rate of the composite adverse neonatal outcome (25% vs 1.5%; adjusted odds ratio, 22.67; 95% confidence interval, 2.63-194.91; P

BACKGROUND: It is important to understand the dynamics of SARS-CoV-2 transmission in close-contact settings such as households. We hypothesized that children would most often acquire SARS-CoV-2 from a symptomatic adult caregiver. METHODS: This prospective cohort study was conducted from April 2020 to July 2022 in a low-resource, urban settlement in Brazil. We recruited families who brought their children to a public clinic. We collected nasopharyngeal and oral swabs from household members and tracked symptoms and vaccination. RESULTS: In total, 1256 participants in 298 households were tested for SARS-CoV-2. A total of 4073 RT-PCR tests were run with 893 SARS-CoV-2 positive results (21.9%). SARS-CoV-2 cases were defined as isolated cases (N = 158) or well-defined transmission events (N = 175). The risk of household transmission was lower if the index case was a child (OR: 0.3 [95% CI: 0.16-0.55], P < .001) or was vaccinated (OR: 0.29 [95% CI: 0.1-0.85], P = .024), and higher if the index was symptomatic (OR: 2.53 [95% CI: 1.51-4.26], P < .001). The secondary attack rate for child index cases to child contacts was 0.29, whereas the secondary attack rate for adult index cases to child contacts was 0.47 (P = .08). CONCLUSIONS: In this community, children were significantly less infectious to their household contacts than adolescents or adults. Most children were infected by a symptomatic adult, usually their mother. There was a double benefit of vaccination as it protected the vaccine from severe illness and prevented onward transmission to household contacts. Our findings may also be valid for similar populations throughout Latin America.

AimTo assess the inter-assessor reliability of the Motor Optimality Score-Revised (MOS-R) when used in infants at elevated likelihood for adverse neurological outcome.MethodsMOS-R were assessed in three groups of infants by two assessors/cohort. Infants were recruited from longitudinal projects in Sweden (infants born extremely preterm), India (infants born in low-resource communities) and the USA (infants prenatally exposed to SARS-CoV-2). Intraclass correlation coefficients (ICC) and kappa (κw) were applied. ICC of MOS-R subcategories and total scores were presented for cohorts together and separately and for age-spans: 9-12, 13-16 and 17-25-weeks post-term age.Results252 infants were included (born extremely preterm n = 97, born in low-resource communities n = 97, prenatally SARS-CoV-2 exposed n = 58). Reliability of the total MOS-R was almost perfect (ICC: 0.98-0.99) for all cohorts, together and separately. Similar result was found for age-spans (ICC: 0.98-0.99). Substantial to perfect reliability was shown for the MOS-R subcategories (κw: 0.67-1.00), with postural patterns showing the lowest value 0.67.ConclusionThe MOS-R can be used in high-risk populations with substantial to perfect reliability, both in regards of total/subcategory scores as well as in different age groups. However, the subcategory postural patterns as well as the clinical applicability of the MOS-R needs further study.

PurposeThis study aims to describe the cohort of Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) research program participants and evaluate whether the ATN's recently completed 5-year cycle recruited study participants who parallel the populations most impacted by HIV in the United States.MethodsHarmonized measures across ATN studies collected at baseline were aggregated for participants aged 13-24 years. Pooled means and proportions stratified by HIV status (at risk for or living with HIV) were calculated using unweighted averages of study-specific aggregate data. Medians were estimated using a weighted median of medians method. Public use 2019 Centers for Disease Control and Prevention surveillance data for state-level new HIV diagnoses and HIV prevalence among US youth aged 13-24 years were obtained for use as reference populations for ATN at-risk youth and youth living with HIV (YLWH), respectively.ResultsData from 3,185 youth at-risk for HIV and 542 YLWH were pooled from 21 ATN study phases conducted across the United States. Among ATN studies tailored to at-risk youth, a higher proportion of participants were White and a lower proportion were Black/African American and Hispanic/Latinx compared to youth newly diagnosed with HIV in the United States in 2019. Participants in ATN studies tailored to YLWH were demographically similar to YLWH in the United States.DiscussionThe development of data harmonization guidelines for ATN research activities facilitated this cross-network pooled analysis. These findings suggest the ATN's YLWH are representative, but that future studies of at-risk youth should prioritize recruitment strategies to enroll more participants from African American and Hispanic/Latinx populations.

ObjectivesTo identify factors associated with adverse maternal outcomes during the coronavirus disease 2019 (COVID-19) pandemic.MethodsThis was a single-centre prospective cohort study at a maternity department in a public general hospital in Rio de Janeiro. All pregnant women evaluated for emergency care, labour and delivery, respiratory symptoms, obstetric reasons or medical reasons between May 2020 and March 2022 at the study institution were invited to enrol in this study. The endpoint was maternal mortality or intensive care unit (ICU) admission.ResultsIn total, 1609 pregnant women were enrolled in this study. Of these, 25.5% (n=410) were infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) based on reverse transcription polymerase chain reaction or an antigen test. There were 21 deaths and 67 ICU admissions in 4% of the cohort. The incidence of severe maternal morbidity and mortality was higher during the Gamma wave than during the Delta wave (P=0.003). Vaccination conferred protection against the endpoint [relative risk (RR) 0.4, 95% confidence interval (CI) 0.1-0.9; P=0.0169]. Factors associated with severe morbidity and mortality included caesarean section (RR 3.7, 95% CI 1.7-7.9; P=0.0008), SARS-CoV-2 infection in the third trimester (RR 2.4, 95% CI 1.1-5.6; P=0.0006) and comorbidities (RR 3, 95% CI 1.8-5.2; P

BackgroundThere are limited data on how coronavirus disease 2019 (COVID-19) severity, timing of infection, and subsequent vaccination impact transplacental transfer and persistence of maternal and infant antibodies.MethodsIn a longitudinal cohort of pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, maternal/infant sera were collected at enrollment, delivery/birth, and 6 months. Anti-SARS-CoV-2 spike immunoglobulin (Ig)G, IgM, and IgA were measured by enzyme-linked immunosorbent assay.ResultsTwo-hundred fifty-six pregnant women and 135 infants were enrolled; 148 maternal and 122 neonatal specimens were collected at delivery/birth; 45 maternal and 48 infant specimens were collected at 6 months. Sixty-eight percent of women produced all anti-SARS-CoV-2 isotypes at delivery (IgG, IgM, IgA); 96% had at least 1 isotype. Symptomatic disease and vaccination before delivery were associated with higher maternal IgG at labor and delivery. Detectable IgG in infants dropped from 78% at birth to 52% at 6 months. In the multivariate analysis evaluating factors associated with detectable IgG in infants at delivery, significant predictors were 3rd trimester infection (odds ratio [OR] = 4.0), mild/moderate disease (OR = 4.8), severe/critical disease (OR = 6.3), and maternal vaccination before delivery (OR = 18.8). No factors were significant in the multivariate analysis at 6 months postpartum.ConclusionsVaccination in pregnancy post-COVID-19 recovery is a strategy for boosting antibodies in mother-infant dyads.

BACKGROUND: There is interest in lingering non-specific symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, referred to as Long coronavirus disease 2019 (Long COVID-19). It remains unknown whether the risk of Long COVID-19 is associated with pre-existing comorbidities or initial COVID-19 severity, including infections due to new Omicron lineages which predominated in 2023. OBJECTIVES: The aim of this case report was to characterize the clinical features of acute XBB.1.5 infection followed by Long COVID-19. METHODS: We followed a 73-year old female resident of Rio de Janeiro with laboratory-confirmed SARS-CoV-2 during acute infection and subsequent months. The SARS-CoV-2 lineage was determined by genome sequencing. FINDINGS: The participant denied comorbidities and had completed a two-dose vaccination schedule followed by two booster doses eight months prior to SARS-CoV-2 infection. Primary infection by viral lineage XBB.1.5. was clinically mild, but the participant subsequently reported persistent fatigue. MAIN CONCLUSIONS: This case demonstrates that Long COVID-19 may develop even after mild disease due to SARS-CoV-2 in fully vaccinated and boosted individuals without comorbidities. Continued monitoring of new SARS-CoV-2 lineages and associated clinical outcomes is warranted. Measures to prevent infection should continue to be implemented including development of new vaccines and antivirals effective against novel variants.

BackgroundOutcomes of SARS CoV-2 infection in infants, children and young adults are reported less frequently than in older populations. The evolution of SARS-CoV-2 cases in LA County youths followed at a large health network in southern California over two years was evaluated.MethodsA prospective cohort study of patients aged 0-24 years diagnosed with COVID-19 was conducted. Demographics, age distribution, disease severity, circulating variants of concern (VOCs), and immunization rates were compared between first and second pandemic years. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) of factors associated with severe/critical COVID-19.ResultsIn total, 61,208 patients 0-24 years of age were tested for SARS-CoV-2 by polymerase chain reaction (PCR); 5263 positive patients (8.6%) with available data were identified between March 2020 and March 2022. In Year 1, 5.8% (1622/28,088) of youths tested positive, compared to 11% (3641/33,120) in Year 2 (p < 0.001). Most youths had mild/asymptomatic illness over two years. SARS-CoV-2 positivity was >12% across all age groups in the second half of Year 2, when Omicron prevailed. Pulmonary disease was associated with higher risk of severe COVID-19 in both years (OR: 2.4, 95% CI: 1.4-4.3, p = 0.002, Year 1; OR: 11.3, 95% CI: 4.3-29.6, Year 2, p < 0.001). Receipt of at least one COVID-19 vaccine dose was protective against severe COVID-19 (OR: 0.3, 95% CI: 0.11-0.80, p < 0.05).ConclusionsDespite different VOCs and higher rates of test positivity in Year 2 compared to Year 1, most youths with COVID-19 had asymptomatic/mild disease. Underlying pulmonary conditions increased the risk of severe COVID-19, while vaccination was highly protective against severe disease in youths.

Zika virus (ZIKV) causes microcephaly and congenital eye disease. The cellular and molecular basis of congenital ZIKV infection are not well understood. Here, we utilized a biologically relevant cell-based system of human fetal retinal pigment epithelial cells (FRPEs), hiPSC-derived retinal stem cells (iRSCs), and retinal organoids to investigate ZIKV-mediated ocular cell injury processes. Our data show that FRPEs were highly susceptible to ZIKV infection exhibiting increased apoptosis, whereas iRSCs showed reduced susceptibility. Detailed transcriptomics and proteomics analyses of infected FRPEs were performed. Nucleoside analogue drug treatment inhibited ZIKV replication. Retinal organoids were susceptible to ZIKV infection. The Asian genotype ZIKV exhibited higher infectivity, induced profound inflammatory response, and dysregulated transcription factors involved in retinal organoid differentiation. Collectively, our study shows that ZIKV affects ocular cells at different developmental stages resulting in cellular injury and death, further providing molecular insight into the pathogenesis of congenital eye disease.

ObjectiveTo evaluate neuromotor repertoires and developmental milestones in infants exposed to antenatal COVID-19.DesignLongitudinal cohort study.SettingHospital-based study in Los Angeles, USA and Rio de Janeiro, Brazil between March 2020 and December 2021.ParticipantsInfants born to mothers with COVID-19 during pregnancy and prepandemic control infants from the Graz University Database.InterventionsGeneral movement assessment (GMA) videos between 3 and 5 months post-term age were collected and clinical assessments/developmental milestones evaluated at 6-8 months of age. Cases were matched by gestational age, gender and post-term age to prepandemic neurotypical unexposed controls from the database.Main outcome measuresMotor Optimality Scores Revised (MOS-R) at 3-5 months. Presence of developmental delay (DD) at 6-8 months.Results239 infants were enrolled; 124 cases (83 in the USA/41 in Brazil) and 115 controls. GMA was assessed in 115 cases and 115 controls; 25% were preterm. Median MOS-R in cases was 23 (IQR 21-24, range 9-28) vs 25 (IQR 24-26, range 20-28) in controls, p

The burden of arbovirus diseases in Brazil has increased within the past decade due to the emergence of chikungunya and Zika and endemic circulation of all four dengue serotypes. Changes in temperature and rainfall patterns may alter conditions to favor vector-host transmission and allow for cyclic re-emergence of disease. We sought to determine the impact of climate conditions on arbovirus co-circulation in Rio de Janeiro, Brazil. We assessed the spatial and temporal distributions of chikungunya, dengue, and Zika cases from Brazil's national notifiable disease information system (SINAN) and created autoregressive integrated moving average models (ARIMA) to predict arbovirus incidence accounting for the lagged effect of temperature and rainfall. Each year, we estimate that the combined arboviruses were associated with an average of 8429 to 10,047 lost Disability-Adjusted Life Years (DALYs). After controlling for temperature and precipitation, our model predicted a three cycle pattern where large arbovirus outbreaks appear to be primed by a smaller scale surge and followed by a lull of cases. These dynamic arbovirus patterns in Rio de Janeiro support a mechanism of susceptibility enhancement until the theoretical threshold of population immunity allows for temporary cross protection among certain arboviruses. This suspected synergy presents a major public health challenge due to overlapping locations and seasonality of arbovirus diseases, which may perpetuate disease burden and overwhelm the health system.

The extent to which perinatally HIV-infected children, following cART initiation, develop a low proviral reservoir burden over time, as measured by HIV DNA droplet-digital polymerase chain reaction (ddPCR) and the effect on HIV antibody is not well characterized. We measured proviral HIV DNA and plasma RNA virus load (VL) in 37 perinatally HIV-infected children at 6 months of age who initiated stable cART. At 6-11 years of age, HIV proviral DNA, HIV VL (RNA), and HIV antibody by Western Blot (WB) were assessed. CART was initiated before 6 months of age in 13 children and after 6 months in 24. At school age, the HIV DNA levels did not differ by the timing of cART, and the HIV DNA levels were lower in children with negative/indeterminate WB (p = 0.0256). Children with undetectable HIV RNA VL > 50% of the time since cART initiation had lower median DNA VL than children with undetectable VL < 50% of the time (p = 0.07). Long-term viral suppression in perinatally HIV-infected children is associated with a decrease in HIV antibodies and reduced HIV reservoirs.

ObjectivesThe aim of this study was to characterize SARS-CoV-2 infection patterns in Los Angeles (LA) County youth followed at our institution during the first pandemic year.DesignA prospective cohort of patients aged < 25 years who tested positive for SARS-CoV-2 using reverse-transcriptase polymerase chain reaction (RT-PCR) assays between March 13, 2020, and March 31, 2021, was evaluated at a large LA County health network. Demographics, age distribution, and disease severity were analyzed.ResultsThere were 28,088 youth aged < 25 years tested for SARS-CoV-2 using RT-PCR, with 1849 positive results identified (7%). Among the positive results, 475 of 11,922 (4%) were identified at the pandemic onset (March-September 2020) (Cohort 1) and 1374 of 16,166 (9%) between October 2020 and March 2021 (Cohort 2), P < 0.001. When disease severity was compared across cohorts, Cohort 2 had a greater proportion of asymptomatic and mild/moderate disease categories than Cohort 1 (98% vs 80%, respectively); conversely, Cohort 1 had a near-10-fold higher proportion of severe disease than Cohort 2 (17% vs 1.8%). Cohort 2 comprised younger patients with a mean age of 13.7 years vs 17.3 years in Cohort 1. Older age was associated with a higher percentage of infection, with 63% of all confirmed cases found in participants aged 19 to 25 years in Cohort 1, compared with 38% of confirmed cases in Cohort 2. Age increase was also associated with greater disease severity by linear regression modeling (P< 0.001).ConclusionCoronavirus disease 2019 (COVID-19) disease severity in youth decreased over time in LA County during the first pandemic year, likely a reflection of changing demographics, with younger children infected. A higher infection rate in youth did not lead to higher disease severity over time.

Pregnant women at public medical centers in Porto Alegre, Brazil, were recruited for a study on screening and treatment of sexually transmitted infections (STIs). STIs were detected in 79 (23%) of 350 pregnant women and were found to be associated with infant low birth weight (adjusted odds ratio 5.8; 95% confidence interval 1.9-18).

BackgroundIdentify early predictors of poor neurodevelopment in infants with antenatal Zika virus (ZIKV) exposure.MethodsAnalysis of a prospective cohort of infants with antenatal ZIKV exposure confirmed by maternal or infant RT-PCR or IgM during the epidemic in Rio de Janeiro, Brazil. Clinical findings before 3 months of age were associated with Bayley-III Scales of Infant and Toddler Development conducted after 6 months of age.ResultsZIKV exposure was confirmed in 219 cases; 162 infants were normocephalic, 53 were microcephalic, 4 had no head circumference recorded because of perinatal death/LTFU. Seven of the 112 normocephalic infants developed secondary microcephaly between 3 weeks and 8 months of age. Among the normocephalic at birth cohort, the mean HCZ among normal, at risk, and developmentally delayed children was significantly different (ANOVA, P = 0.02). In particular, the mean HCZ of the developmentally delayed group was significantly lower than that of the normal group (Tukey's test, P = 0.014). HCZ was more strongly associated with lower expressive language scores (P = 0.04) than receptive language scores (P = 0.06). The rate of auditory abnormalities differed among the normal, at risk, and developmentally delayed groups (Chi-squared test, P = 0.016), which was driven by the significant difference between the normal and at risk groups (post hoc test, P = 0.011, risk ratio 3.94). Auditory abnormalities were associated with both expressive and receptive language delays (P = 0.02 and P = 0.02, respectively).ConclusionsClear predictors of neurodevelopment in normocephalic ZIKV-exposed children have not been previously identified. Our findings demonstrate that smaller HCZ and auditory abnormalities in these infants correlate with poor neurodevelopment as toddlers. Language delay is the most prominent developmental concern among these children, who will require frequent auditory and speech evaluations throughout childhood.

IntroductionThe increasing burden of non-communicable diseases and limited public financing are major challenges facing health care systems in Latin America. Although COVID-19 severely impacted the Brazilian health care system, it is crucial to further characterize the degree of disruption caused to public health efforts, in order to address and manage long term effects of this pandemic. We therefore quantified the demand for preventive and treatment services from the Brazilian Unified Health System (Sistema Único de Saúde/SUS) in 2020 to evaluate potential repercussions of COVID-19 in this setting.MethodsUsing the SUS database, we compared preventative and treatment services rendered in 2020 to the same services rendered from 2017 to 19. We also evaluated the frequency of respiratory infection (RI) diagnoses during the pandemic, relative to the preceding years.ResultsCompared to 2017-19, in 2020 non-urgent medical appointments decreased 1.4-fold (p = 0.0017), dental consultations 2.8-fold (p = 0.05), and immunization coverage 1.5 fold (p = 0.0005). The number of RI visits to SUS ambulatory care units in 2020 was 4.2 times higher than in preceding years (p = 0.0014), with a peak of 280,898 diagnoses in July 2020.ConclusionThe COVID-19 pandemic appears to have led to a dramatic decline in preventative and treatment services provided by SUS to the Brazilian population. Our findings may aid decision-makers in formulating policies to increase the availability of outpatient services in the aftermath of the pandemic. Counter measures will be critical to avoid a resurgence in vaccine-preventable diseases and complications stemming from non-communicable, chronic health conditions.

We describe a case of prolonged COVID-19 caused by the SARS-CoV-2 Gamma variant in a fully vaccinated healthcare worker, 387 days after an infection caused by lineage B.1.1.33. Infections were confirmed by whole-genome sequencing and corroborated by the detection of neutralizing antibodies in convalescent serum samples. Considering the permanent exposure of this healthcare worker to SARS-CoV-2, the waning immunity after the first infection, the low efficacy of the inactivated vaccine at preventing COVID-19, the immune escape of the Gamma variant (VOC), and the burden of post-COVID syndrome, this individual would have benefited from an additional dose of a heterologous vaccine.

BackgroundThe 2017-2018 yellow fever virus (YFV) outbreak in southeastern Brazil marked a reemergence of YFV in urban states that had been YFV-free for nearly a century. Unlike earlier urban YFV transmission, this epidemic was driven by forest mosquitoes. The objective of this study was to evaluate environmental drivers of this outbreak.Methodology/principal findingsUsing surveillance data from the Brazilian Ministry of Health on human and non-human primate (NHP) cases of YFV, we traced the spatiotemporal progression of the outbreak. We then assessed the epidemic timing in relation to drought using a monthly Standardized Precipitation Evapotranspiration Index (SPEI) and evaluated demographic risk factors for rural or outdoor exposure amongst YFV cases. Finally, we developed a mechanistic framework to map the relationship between drought and YFV. Both human and NHP cases were first identified in a hot, dry, rural area in northern Minas Gerais before spreading southeast into the more cool, wet urban states. Outbreaks coincided with drought in all four southeastern states of Brazil and an extreme drought in Minas Gerais. Confirmed YFV cases had an increased odds of being male (OR 2.6; 95% CI 2.2-3.0), working age (OR: 1.8; 95% CI: 1.5-2.1), and reporting any recent travel (OR: 2.8; 95% CI: 2.3-3.3). Based on this data as well as mosquito and non-human primate biology, we created the "Mono-DrY" mechanistic framework showing how an unusual drought in this region could have amplified YFV transmission at the rural-urban interface and sparked the spread of this epidemic.Conclusions/significanceThe 2017-2018 YFV epidemic in Brazil originated in hot, dry rural areas of Minas Gerais before expanding south into urban centers. An unusually severe drought in this region may have created environmental pressures that sparked the reemergence of YFV in Brazil's southeastern cities.

An out-of-season H3N2 type A influenza epidemic occurred in the State of Rio de Janeiro, Brazil during October-November 2021, in between the Delta and Omicron SARS-CoV-2 surges, which occurred in July-October 2021 and January-April 2022, respectively. We assessed the contribution of climate change and influenza immunization coverage in this unique, little publicized phenomenon. State weather patterns during the influenza epidemic were significantly different from the five preceding years, matching typical winter temperatures, associated with the out-of-season influenza. We also found a mismatch between influenza vaccine strains used in the winter of 2021 (trivalent vaccine with two type A strains (Victoria/2570/2019 H1N1, Hong Kong/2671/2019 H3N2) and one type B strain (Washington/02/2019, wild type) and the circulating influenza strain responsible for the epidemic (H3N2 Darwin type A influenza strain). In addition, in 2021, there was poor influenza vaccine coverage with only 56% of the population over 6 months old immunized. Amid the COVID-19 pandemic, we should be prepared for out-of-season outbreaks of other respiratory viruses in periods of COVID-19 remission, which underscore novel disease dynamics in the pandemic era. The availability of year-round influenza vaccines could help avoid unnecessary morbidity and mortality given that antibodies rapidly wane. Moreover, this would enable unimmunized individuals to have additional opportunities to vaccinate during out-of-season outbreaks.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, causes respiratory failure and damage to multiple organ systems. The emergence of viral variants poses a risk of vaccine failures and prolongation of the pandemic. However, our understanding of the molecular basis of SARS-CoV-2 infection and subsequent COVID-19 pathophysiology is limited. In this study, we have uncovered a critical role for the evolutionarily conserved Hippo signaling pathway in COVID-19 pathogenesis. Given the complexity of COVID-19-associated cell injury and immunopathogenesis processes, we investigated Hippo pathway dynamics in SARS-CoV-2 infection by utilizing COVID-19 lung samples and human cell models based on pluripotent stem cell-derived cardiomyocytes (PSC-CMs) and human primary lung air-liquid interface (ALI) cultures. SARS-CoV-2 infection caused activation of the Hippo signaling pathway in COVID-19 lung and in vitro cultures. Both parental and Delta variant of concern (VOC) strains induced Hippo pathway. The chemical inhibition and gene knockdown of upstream kinases MST1/2 and LATS1 resulted in significantly enhanced SARS-CoV-2 replication, indicating antiviral roles. Verteporfin, a pharmacological inhibitor of the Hippo pathway downstream transactivator, YAP, significantly reduced virus replication. These results delineate a direct antiviral role for Hippo signaling in SARS-CoV-2 infection and the potential for this pathway to be pharmacologically targeted to treat COVID-19.

Histoplasmosis is the most common endemic fungal infection in the USA. The majority of cases are asymptomatic and have clear exposure to endemic regions. In contrast, we present an adolescent immunocompromised patient with systemic and relatively non-specific symptoms including abdominal pain, weight loss, lower extremity edema, and scabbing skin lesions, without known exposure to endemic areas for histoplasmosis. Histologic analysis of gastrointestinal and skin biopsies eventually revealed a diagnosis of disseminated histoplasmosis; the patient was successfully treated with amphotericin B followed by itraconazole maintenance therapy. Ultimately, a high bar of suspicion for fungal disease must be maintained in immunosuppressed individuals even without apparent exposure history to endemic areas. This case report serves as a valuable reference for practitioners evaluating differential diagnosis of infections in immunocompromised patients.

Sexual and gender minority (SGM) and racial or ethnic minority youth at-risk for or living with HIV may have higher risk of SARS-CoV-2 infection. However, there are few data on vaccine hesitancy/acceptance and COVID-19 self-protective behaviors among this population. Youth aged 15-24 years (n = 440), predominantly African American and Latine (73%, n = 320) SGM, from Los Angeles and New Orleans reported their vaccine attitudes and COVID-19 and HIV preventive behaviors in October 2020. Latent class analyses categorized individuals into groups based on their vaccine attitudes and preventive behaviors. Relationships between these groups and other factors were analyzed using Fisher's exact tests, ANOVA, and logistic regression. Most youth had accepting vaccine attitudes (70.2%, n = 309), with 20.7% hesitant (n = 91), and 9.1% resistant (n = 40). SGM and African Americans were significantly less accepting than their cis-gender and heterosexual peers. About two-thirds (63.2%, n = 278) of the respondents reported consistent COVID-19 self-protective behaviors. Youth with pro-vaccine attitudes were most consistently self-protective; however, only 54.4% (n= 168/309) intended to take a COVID-19 vaccine. Homelessness history, race, and sexual orientation were associated with vaccine attitudes. Accepting vaccine attitudes and consistent COVID-19 self-protective behaviors were closely related. COVID-19 attitudes/behaviors were not associated with HIV risk and only loosely associated with SARS-CoV-2 vaccine intentions.

BackgroundRecognition of viral invasion by innate antiviral immune system triggers activation of the type I interferon (IFN-I) and proinflammatory signaling pathways. Subsequently, IFN-I induction regulates expression of a group of genes known as IFN-I-stimulated genes (ISGs) to block viral infection. The tripartite motif containing 22 (TRIM22) is an ISG with strong antiviral functions.ResultsHere we have shown that the TRIM22 has been strongly upregulated both transcriptionally and translationally upon Zika virus (ZIKV) infection. ZIKV infection is associated with a wide range of clinical manifestations in human from mild to severe symptoms including abnormal fetal brain development. We found that the antiviral function of TRIM22 plays a crucial role in counterattacking ZIKV infection. Overexpression of TRIM22 protein inhibited ZIKV growth whereas deletion of TRIM22 in host cells increased ZIKV infectivity. Mechanistically, TRIM22, as a functional E3 ubiquitin ligase, promoted the ubiquitination and degradation of ZIKV nonstructural protein 1 (NS1) and nonstructural protein 3 (NS3). Further studies showed that the SPRY domain and Ring domain of TRIM22 played important roles in protein interaction and degradation, respectively. In addition, we found that TRIM22 also inhibited other flaviviruses infection including dengue virus (DENV) and yellow fever virus (YFV).ConclusionThus, TRIM22 is an ISG with important role in host defense against flaviviruses through binding and degradation of the NS1 and NS3 proteins.

Sexually transmitted infections (STIs) can adversely affect a woman's pregnancy and the health of the developing fetus. The source of these infections may be the male sexual partner who remains under-diagnosed and un-treated due to a combination of lack of symptoms, decreased access to health care, and poor health-seeking behaviors. From September 2018 to November 2019, we offered a cohort of pregnant women (gestational age range: 4.6-41 weeks) clinic-based STI testing for HIV and syphilis (via lateral flow assay rapid tests) and for Neisseria (N.) gonorrhoeae, Chlamydia (C.) trachomatis, and Trichomonas (T.) vaginalis (via PCR-based testing) at Santa Casa Hospital and 10 affiliated prenatal clinics in Porto Alegre, Brazil. 400 women between the ages of 18 and 46 years (mean age: 27 years) enrolled and 24% were diagnosed with an STI. Each woman enrolled agreed to invite their male partners to clinic for the same panel of STI testing, and 255 men (64%) between the ages of 18 and 64 years (mean age: 29 years) attended clinic and all accepted full intervention. In these male partners, 40 (16%) were diagnosed with an STI including 22 (8.7%) testing positive for C. trachomatis, 15 (6%) for treponemal antibody (syphilis), 7 (2.8%) for T. vaginalis, 3 (1.2%) for N. gonorrhoeae, and 1 (0.4%) for HIV antibody. In our multivariate analysis, having symptoms of an STI (AOR 4.5, 95% CI 1.3-15.2) and arguing about jealousy (AOR 3.1, 95% CI 1.2-8.2) remained significantly associated with male diagnosis of an STI. Sexually transmitted infections are common in sexual partners of pregnant women in Brazil and should be addressed to prevent reinfection of pregnant women.

While pregnancy increases the risk for severe COVID-19, the clinical and immunological implications of COVID-19 on maternal-fetal health remain unknown. Here, we present the clinical and immunological landscapes of 93 COVID-19 mothers and 45 of their SARS-CoV-2-exposed infants through comprehensive serum proteomics profiling for >1,400 cytokines of their peripheral and cord blood specimens. Prenatal SARS-CoV-2 infection triggers NF-κB-dependent proinflammatory immune activation. Pregnant women with severe COVID-19 show increased inflammation and unique IFN-λ antiviral signaling, with elevated levels of IFNL1 and IFNLR1. Furthermore, SARS-CoV-2 infection re-shapes maternal immunity at delivery, altering the expression of pregnancy complication-associated cytokines, inducing MMP7, MDK, and ESM1 and reducing BGN and CD209. Finally, COVID-19-exposed infants exhibit induction of T cell-associated cytokines (IL33, NFATC3, and CCL21), while some undergo IL-1β/IL-18/CASP1 axis-driven neonatal respiratory distress despite birth at term. Our findings demonstrate COVID-19-induced immune rewiring in both mothers and neonates, warranting long-term clinical follow-up to mitigate potential health risks.

To investigate the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a vulnerable population of children and their household contacts. SARS-CoV-2 reverse transcription polymerase chain reaction assays and coronavirus disease 2019 (COVID-19) immunoglobulin G serology tests were performed in children and their household contacts after enrollment during primary health care clinic visits. Participants were followed prospectively with subsequent specimens collected through household visits in Manguinhos, an impoverished urban slum (a favela) in Rio de Janeiro at 1, 2, and 4 weeks and quarterly post study enrollment. Six hundred sixty-seven participants from 259 households were enrolled from May to September 2020. This included 323 children (0-13 years), 54 adolescents (14-19 years), and 290 adults. Forty-five (13.9%) children had positive test results for SARS-CoV-2 polymerase chain reaction. SARS-CoV-2 infection was most frequent in children aged

HIV-negative individuals in serodiscordant partnerships experience reduced risk of HIV acquisition when their partners adhere to ART and achieve undetectable viral loads. Partnership support may encourage ART adherence, reducing viral load and the risk of HIV transmission. This study aims to determine whether HIV viral suppression is associated with partnership status and partnership support among 201 HIV positive (HIV+ individuals in serodiscordant partnerships and 100 HIV+ unpartnered individuals receiving care at Hospital Nossa Senhora da Conceição in Porto Alegre, Brazil between 2014 and 2016. Clinical data and patient-reported questionnaire data were assessed, and propensity scores were used to control for confounding variables in adjusted logistic regression models. Viral suppression did not significantly differ between HIV+ partnered (78.5% virally suppressed) and unpartnered (76.0% virally suppressed) individuals. Among individuals in partnerships, viral suppression was significantly associated with having a partner who attended monthly clinic visits (AOR 2.99; 95% CI 1.00-8.93). Instrumental social support-attending monthly visits-may improve the odds of viral suppression among HIV+ individuals in serodiscordant relationships.

While the influenza vaccine is recommended for all pregnant women, influenza vaccine coverage among this high-risk population remains inadequate. Factors associated with vaccine coverage among pregnant women, including insurance status, are poorly understood. In a cross-sectional study of the National Health Interview Survey (NHIS) data from 2012 to 2018, we evaluated predictors of self-reported influenza vaccine coverage in pregnant women. Among 1,942 pregnant women surveyed, 39% reported receiving the influenza vaccine in accordance with national recommendations. Influenza vaccine coverage increased by 8 percentage points from 2012 to 2018. Only 15% of uninsured pregnant women received the influenza vaccine, compared to 41% of those with insurance (design-corrected F-test, p-value

ObjectivesRates of maternal syphilis have increased five-fold in Brazil in the past decade. While penicillin remains the only appropriate treatment for maternal syphilis, we hypothesized that low non-treponemal titers (

In perinatally HIV-infected (PHIV) children, neurodevelopment occurs in the presence of HIV-infection, and even with combination antiretroviral therapy (cART) the brain can be a reservoir for latent HIV. Consequently, patients often demonstrate long-term cognitive deficits and developmental delay, which may be reflected in altered functional brain activity. Our objective was to examine brain function in PHIV on cART by quantifying the amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo). Further, we studied ALFF and ReHo changes with neuropsychological performance and measures of immune health including CD4 count and viral loads in the HIV-infected youths. We found higher ALFF and ReHo in cerebral white matter in the medial orbital lobe for PHIV (N = 11, age mean ± sd = 22.5 ± 2.9 years) compared to controls (N = 16, age = 22.5 ± 3.0 years), with age and gender as co-variates. Bilateral cerebral white matter showed increased spontaneous regional activity in PHIV compared to healthy controls. No brain regions showed lower ALFF or ReHo in PHIV compared to controls. Higher log10 viral load was associated with higher ALFF and ReHo in PHIV in bilateral cerebral white matter and right cerebral white matter respectively after masking the outcomes intrinsic to the brain regions that showed significantly higher ALFF and ReHo in the PHIV compared to the control. Reductions in social cognition and abstract thinking in PHIV were correlated with higher ALFF at the left cerebral white matter in the left medial orbital gyrus and higher ReHo at the right cerebral white matter in the PHIV patients. Although neuroinflammation and associated neuro repair were not directly measured, the findings support their potential role in PHIV impacting neurodevelopment and cognition.

BackgroundPorto Alegre, Brazil, has the highest rates of congenital syphilis and HIV in the country. Other treatable sexually transmitted infections (STIs) are associated with poor pregnancy and neonatal outcomes, but are only diagnosed by syndromic algorithms.MethodsBetween September 2018 and November 2019, we offered all pregnant women clinic-based STI testing for HIV antibody and treponemal antibody (via lateral flow assay rapid tests provided by the Brazilian Government) and for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis (via polymerase chain reaction-based testing provided by Gene Xpert, Sunnyvale, CA) in 10 public prenatal health clinics in Porto Alegre. Participating women answered a brief survey via audio computer-assisted survey instrument regarding demographics, partnerships, and sexual behaviors. All infected individuals received appropriate treatment and referrals.ResultsOf 400 pregnant women recruited, 94 (24%) were diagnosed with an STI, including 2% with HIV, 11% with syphilis, 9% with chlamydia, 1% with gonorrhea, 5% with trichomoniasis, and 3% with more than 1 STI. In our multivariate analysis, younger age (adjusted odds ratio [AOR], 1.1; 95% confidence interval [CI], 1-1.2), being non-White (AOR, 1.8; 95% CI, 1.1-3.1), having less education (AOR, 2; 95% CI, 1.2-3.4), and having a relationship

Objective: To understand which social, epidemiologic, and clinical risk factors are associated with SARS-CoV-2 infection in youth accessing care in a large, urban academic institution. Methods: We conducted a prospective cohort study with case-control analyses in youth who received testing for SARS-CoV-2 at our academic institution in Los Angeles during the first wave of the COVID-19 pandemic (March-September 2020). Results: A total of 27,976 SARS-CoV-2 assays among 11,922 youth aged 0-24 years were performed, including 475 youth with positive SARS-CoV-2 results. Positivity rate was higher among older, African American, and Hispanic/Latinx youth. Cases were more likely to be from non-English-speaking households and have safety-net insurance. Zip codes with higher proportion of Hispanic/Latinx and residents living under the poverty line were associated with increased SARS-CoV-2 cases. Youth were more likely to have positive results if tested for exposure (OR 21.5, 95% CI 14.6-32.1) or recent travel (OR 1.5, 95% CI 1.0-2.3). Students were less likely to have positive results than essential worker youth (OR 0.5, 95% CI 0.3-0.8). Patterns of symptom presentation varied significantly by age group; number of symptoms correlated significantly with age in SARS-CoV-2 cases (r = 0.030, p < 0.001). SARS-CoV-2 viral load did not vary by symptom severity, but asymptomatic youth had lower median viral load than those with symptoms (21.5 vs. 26.7, p = 0.009). Conclusions: Socioeconomic factors are important drivers of SARS-CoV-2 infection in youth. Presence of symptoms, exposure, and travel can be used to drive testing in older youth. Policies for school reopening and infection prevention should be tailored differently for elementary schools and universities.

While the annual incidence of HIV diagnosis in pregnancy in Brazil remains relatively stable, rates of maternal syphilis increased over six-fold in the past decade. We hypothesized that maternal HIV and syphilis are two distinct epidemics. Data on all cases of maternal HIV or syphilis detected in pregnancy between January 1, 2010 to December 31, 2018 were requested from the Brazilian Ministry of Health. In order to evaluate how the epidemics evolved over the time period, ArcGIS software was used to generate spatiotemporal maps of annual rates of detection of maternal HIV and syphilis in 2010 and 2018. We utilized Euclidean-distance hot spot analysis to identify state-specific clusters in 2010 and 2018. From 2010 to 2018, there were 66,631 cases of maternal HIV, 225,451 cases of maternal syphilis, and 150,414 cases of congenital syphilis in Brazil. The state of Rio Grande do Sul had the highest rate of maternal HIV detection in both 2010 and 2018. Hot spots of maternal HIV were identified in the three most Southern states in both 2010 and 2018 (99% confidence, z-score >2.58, p 30 per 1,000 live births in 2018 in four states, only the two coastal states of Rio de Janeiro and Espirito Santo in Southeastern Brazil were significant hot spots (90% confidence, z-score 1.65-1.95, p

The Zika virus (ZIKV) epidemic in Brazil occurred in regions where dengue viruses (DENV) are historically endemic. We investigated the differences in adverse pregnancy/infant outcomes in two cohorts comprising 114 pregnant women with PCR-confirmed ZIKV infection in Rio de Janeiro, Southeastern Brazil (n = 50) and Manaus, in the north region of the country (n = 64). Prior exposure to DENV was evaluated through plaque reduction neutralizing antibody assays (PRNT 80) and DENV IgG serologies. Potential associations between pregnancy outcomes and Zika attack rates in the two cities were explored. Overall, 31 women (27%) had adverse pregnancy/infant outcomes, 27 in Rio (54%) and 4 in Manaus (6%), p < 0.001. This included 4 pregnancy losses (13%) and 27 infants with abnormalities at birth (24%). A total of 93 women (82%) had evidence of prior DENV exposure, 45 in Rio (90%) and 48 in Manaus (75%). Zika attack rates differed; the rate in Rio was 10.28 cases/10,000 and in Manaus, 0.6 cases/10,000, p < 0.001. Only Zika attack rates (Odds Ratio: 17.6, 95% Confidence Interval 5.6-55.9, p < 0.001) and infection in the first trimester of pregnancy (OR: 4.26, 95% CI 1.4-12.9, p = 0.011) were associated with adverse pregnancy and infant outcomes. Pre-existing immunity to DENV was not associated with outcomes (normal or abnormal) in patients with ZIKV infection during pregnancy.

Chlamydial trachomatis infection has been associated with adverse pregnancy and neonatal outcomes such as premature rupture of membranes, preterm birth, low birth weight, conjunctivitis, and pneumonia in infants. This review evaluates existing literature to determine potential benefits of antenatal screening and treatment of C. trachomatis in preventing adverse outcomes. A literature search revealed 1824 studies with 156 full-text articles reviewed. Fifteen studies were selected after fulfilling inclusion criteria. Eight studies focused on chlamydial screening and treatment to prevent adverse pregnancy outcomes such as premature rupture of membranes, preterm birth, low birth weight, growth restriction leading to small for gestational age infants, and neonatal death. Seven studies focused on the effects of chlamydial screening and treatment on adverse infant outcomes such as chlamydial infection including positive mucosal cultures, pneumonia, and conjunctivitis. Given the heterogeneity of those studies, this focused review was exclusively qualitative in nature. When viewed collectively, 13 of 15 studies provided some degree of support that antenatal chlamydial screening and treatment interventions may lead to decreased adverse pregnancy and infant outcomes. However, notable limitations of these individual studies also highlight the need for further, updated research in this area, particularly from low and middle-income settings.