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Sunit-Preet Chaudhry,1 Garrick C Stewart2 1Division of Cardiology, St Vincent Indianapolis, Indianapolis, IN, 2Division of Cardiovascular Medicine, Center for Advanced Heart Disease, Brigham and Women’s Hospital, Boston, MA, USA Abstract: Heart failure is a complex clinical syndrome resulting from impairment of ventricular filling or ejection of blood associated with symptoms of dyspnea, fatigue, as well as peripheral and/or pulmonary edema. This syndrome is progressive and characterized by worsening quality of life despite escalating levels of care, affecting 5.7 million Americans with an annual cost of over $30 billion US dollars. Treatment for this syndrome has evolved over three distinct eras: the nonpharmacological era, the pharmacological era, and the device era, with the focus shifting from symptomatic relief to decreasing morbidity and mortality. Over the past 10 years, the field has undergone a renaissance, with the development of new pharmacologic, hemodynamic monitoring, and device therapies proven to improve outcomes in patients with heart failure. This article will review several recent innovations in the management of patients with heart failure. Keywords: heart failure, heart-assist devices, disease management

As prevention of mother-to-child HIV-1 transmission (PMTCT) programs decrease the numbers of HIV-1-infected infants, it remains important to improve growth in HIV-1-exposed, uninfected (EU) infants. To determine the growth rate and predictors of growth faltering in breast-fed and formula-fed EU infants, growth analyses [weight-for-age (WAZ), weight-for-length (WLZ), and length-for-age (LAZ) Z-scores] were conducted by using data from a randomized feeding trial in HIV-1-infected women in Kenya. Growth faltering in EU infants was compared based on randomization to breastfeeding (BF) or formula feeding (FF) using Cox proportional hazards regression models. Linear mixed-effects models determined rate and cofactors of length growth. Among 338 EU infants, 164 (49%) were breast-fed and 174 (51%) formula-fed. In both arms, growth declined steadily during follow-up. By 2 y, 29% of children were underweight (WAZ < -2), 18% were wasted (WLZ < -2), and 58% were stunted (LAZ < -2), with no differences by feeding arm. Higher maternal education (y) and taller stature (cm) were associated with a decreased risk of underweight and stunting [underweight: adjusted HR (aHR) = 0.90 (95% CI: 0.83, 0.99), P = 0.03, and aHR = 0.92 (95% CI: 0.87, 0.97), P = 0.002; and stunting: aHR = 0.91 (95% CI: 0.85, 0.97), P = 0.003, and aHR = 0.96 (95% CI: 0.92, 0.99), P = 0.02, respectively]. Diarrhea was associated with an increased risk of wasting [aHR = 2.26 (95% CI: 1.11, 4.62), P = 0.03]. In multivariate analyses, FF was associated with slower declines in length velocity [0.24 LAZ/y (95% CI: 0.06, 0.43), P = 0.009]. Despite being uninfected, HIV-1-exposed infants showed frequent growth faltering, suggesting the need for vigilance in recognizing stunting within PMTCT programs. The slower rate of decline in length growth with FF may reflect benefits of micronutrients. Because BF is the best option for HIV-1-infected mothers in resource-limited settings, nutritional interventions should be examined for their impact on growth in EU breast-fed infants. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether herpes simplex virus type 2 (HSV-2) infection was associated with risk of intrapartum human immunodeficiency virus type 1 (HIV-1) transmission and to define correlates of HSV-2 infection among HIV-1-seropositive pregnant women. METHODS: We performed a nested case control study within a perinatal cohort in Nairobi, Kenya. Herpes simplex virus type 2 serostatus and the presence of genital ulcers were ascertained at 32 weeks of gestation. Maternal cervical and plasma HIV-1 RNA and cervical HSV DNA were measured at delivery. RESULTS: One hundred fifty-two (87%) of 175 HIV-1-infected mothers were HSV-2-seropositive. Among the 152 HSV-2-seropositive women, nine (6%) had genital ulcers at 32 weeks of gestation, and 13 (9%) were shedding HSV in cervical secretions. Genital ulcers were associated with increased plasma HIV-1 RNA levels (P=.02) and an increased risk of intrapartum HIV-1 transmission (16% of transmitters versus 3% of nontransmitters had ulcers; P = .003), an association which was maintained in multivariable analysis adjusting for plasma HIV-1 RNA levels (P=.04). We found a borderline association for higher plasma HIV-1 RNA among women shedding HSV (P=.07) and no association between cervical HSV shedding and either cervical HIV-1 RNA levels or intrapartum HIV-1 transmission (P=.4 and P=.5, [corrected] respectively). CONCLUSION: Herpes simplex virus type 2 is the leading cause of genital ulcers among women in sub-Saharan Africa and was highly prevalent in this cohort of pregnant women receiving prophylactic zidovudine. After adjusting for plasma HIV-1 RNA levels, genital ulcers were associated with increased risk of intrapartum HIV-1 transmission. These data suggest that management of HSV-2 during pregnancy may enhance mother-to-child HIV-1 prevention efforts. LEVEL OF EVIDENCE: II. [ABSTRACT FROM AUTHOR]

Understanding how the level of human immunodeficiency virus type 1 (HIV-1)-infected breast milk cells (BMCs) affects HIV transmission via breast-feeding can shed light on the mechanism of infection and aid in establishing effective interventions. The proportion of infected cells to total cells was measured in serial breast milk samples collected from 291 HIV-1-infected women in Nairobi, Kenya, by use of real-time DNA polymerase chain reaction amplification of BMCs. The number of infected BMCs per million cells was associated with levels of cell-free viral RNA in breast milk (R=.144; P=.032), levels of cell-free virus in blood plasma (R=.365; P<.001), and the detection of proviral DNA in cervical and vaginal secretions (P<.001 and P = .030, respectively). The number of infected BMCs per million cells was lower in colostrum or early milk than in mature milk (P<.001). Previous studies demonstrated that the concentration of BMCs varies throughout lactation, and we used these data to transform infected BMCs per million cells to infected BMCs per milliliter. The estimated concentration of infected BMCs per milliliter was higher in colostrum or early milk than in mature milk (P<.001). Each log10 increase in infected BMCs per milliliter was associated with a 3.19-fold-increased risk of transmission (P=.002), after adjustment for cell-free virus in plasma (hazard ratio [HR], 2.09; P=.03) and breast milk (HR, 1.01; P=1.00). This suggests that infected BMCs may play a more important role in transmission of HIV via breast-feeding than does cell-free virus. [ABSTRACT FROM AUTHOR]

Background: Exclusive breastfeeding (EBF) in the first six months remains low globally, despite known benefits of lower morbidity and mortality among breastfed infants. It is important to understand factors associated with breastfeeding to support optimal breastfeeding practices, particularly in settings with a high burden of HIV., Methods: We analyzed data from a population-level survey of mother-infant pairs attending 6-week or 9-month immunizations at 141 clinics across Kenya. Primary outcomes included maternal report of (1) EBF at 6-week visit, defined as currently feeding the infant breast milk only, (2) EBF for the first 6-months of life, defined as breastfeeding or feeding the infant breast milk only with no introduction of other liquids or solid foods until 6 months, and (3) continued breastfeeding with complementary feeding at 9-months. Correlates of breastfeeding practices were assessed using generalized Poisson regression models accounting for facility-level clustering., Results: Among 1662 mothers at 6-weeks, nearly all self-reported breastfeeding of whom 93% were EBF. Among 1180 mothers at 9-months, 99% had ever breastfed, 94% were currently breastfeeding and 73% reported 6-month EBF. At 6-weeks, younger age (< 25 years) (adjusted Prevalence Ratio (aPR) 0.96; 95% CI 0.93, 0.99), lower education (aPR 0.96; 95% CI 0.93, 0.99) and recent infant illness (aPR 0.97; 95% CI 0.94, 1.00) were associated with lower EBF prevalence while women living with HIV (WLWH) had higher EBF prevalence (aPR 1.06; 95% CI 1.02, 1.10) than women without HIV. 6-month EBF prevalence was 26% higher in WLWH (aPR 1.26; 95% CI 1.15, 1.35) than women without HIV, 14% lower in women reporting mild or above depressive symptoms (aPR 0.86; 95% CI 0.76, 0.99) than those with none or minimal depressive symptoms, and 15% lower in women with versus without history of intimate partner violence (aPR 0.85; 95% CI 0.74, 0.98). At 9-months, WLWH had a lower prevalence of continued breastfeeding with complementary feeding (aPR 0.73; 95% CI 0.64, 0.84) than women without HIV., Conclusion: WLWH had higher EBF prevalence in the first 6-months, but lower prevalence of continued breastfeeding at 9-months. Strategies to support EBF and continued breastfeeding beyond 6-months postpartum, particularly among WLWH, are needed., (© 2024. The Author(s).)

Routine HIV viral load testing is important for evaluating HIV treatment outcomes, but conventional viral load testing has many barriers including expensive laboratory equipment and lengthy results return times to patients. A point-of-care viral load testing technology, such as GeneXpert HIV-1 quantification assay, could reduce these barriers by decreasing cost and turnaround time, however real-world performance is limited. We conducted a secondary analysis using 900 samples collected from participants in two studies to examine the performance of GeneXpert as point-of-care viral load compared to standard-of-care testing (which was conducted with two centralized laboratories using traditional HIV-1 RNA PCR quantification assays). The two studies, Opt4Kids (n = 704 participants) and Opt4Mamas (n = 820 participants), were conducted in western Kenya from 2019-2021 to evaluate the effectiveness of a combined intervention strategy, which included point-of-care viral load testing. Paired viral load results were compared using four different thresholds for virological non-suppression, namely ≥50, ≥200, ≥400, ≥1000 copies/ml. At a threshold of ≥1000 copies/mL, paired samples collected on the same day: demonstrated sensitivities of 90.0% (95% confidence interval [CI] 68.3, 98.8) and 66.7% (9.4, 99.2), specificities of 98.4% (95.5, 99.7) and 100% (96.5, 100), and percent agreements of 97.7% (94.6, 99.2) and 99.1% (95.0, 100) in Opt4Kids and Opt4Mamas studies, respectively. When lower viral load thresholds were used and the paired samples were collected an increasing number of days apart, sensitivity, specificity, and percent agreement generally decreased. While specificity and percent agreement were uniformly high, sensitivity was lower than expected. Non-specificity of the standard of care testing may have been responsible for the sensitivity values. Nonetheless, our results demonstrate that GeneXpert may be used reliably to monitor HIV treatment in low- and middle- income countries to attain UNAID's 95-95-95 HIV goals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Giang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Left ventricular assist device (LVAD) use remains uncommon in advanced heart failure (HF) patients not dependent on inotropes., Objectives: Before considering a randomized trial comparing a strategy of earlier use of LVAD to continued medical therapy, a better understanding is needed of the clinical trajectory of ambulatory patients with advanced systolic HF on optimal guideline-directed medical therapy (GDMT)., Methods: REVIVAL enrolled 400 patients with advanced ambulatory systolic HF, ≥1 HF mortality risk marker (≥2 HF hospitalizations past year; or HF hospitalization and high natriuretic peptide; or no HF hospitalizations but low peak oxygen consumption, 6-minute walk, serum sodium, HF survival score or Seattle HF model predicted survival), and no LVAD contraindication at 21 LVAD centers from July 2015 to June 2016. Patients were followed for 2 years or until a primary outcome (death, durable ventricular assist device, or urgent transplant). Clinical outcomes and health-related quality of life were evaluated., Results: Mean baseline left ventricular ejection fraction was 21%, median 6-minute walk was 341 m, and 92% were Interagency Registry for Mechanically Assisted Circulatory Support profiles 5 to 7. Adherence to GDMT and electrical device therapies was robust. Composite primary outcome occurred in 22% and 37% at 1 and 2 years, with death alone in 8% and 16%, respectively. Patients surviving for 2 years maintained GDMT intensity and had no decline in health-related quality of life., Conclusion: Structured, serial follow-up at programs with expertise in caring for advanced ambulatory systolic HF patients facilitates triage for advanced therapies. Better strategies are still needed to avoid deaths in a small but significant group of patients who die without advanced therapies. REVIVAL patients not selected for VAD or transplant have robust survival and patient-reported outcomes, which challenges advocacy for earlier VAD implantation. (Registry Evaluation of Vital Information for VADs in Ambulatory Life [REVIVAL]; NCT01369407)., Competing Interests: Funding Support and Author Disclosures Supported by funding from the National Institutes of Health, National Heart, Lung, and Blood Institute (contract number HHSN268201100026C) for REVIVAL and the National Center for Advancing Translational Sciences (grant numbers UL1TR002240 and UM1TR004404) for the Michigan Institute for Clinical and Health Research. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Dr Aaronson has received research support from Medtronic, Abbott, Bioventrix, Amgen; has held ownership interest in Procyrion; and has served as a consultant/on the Advisory Board for Medtronic and Procyrion; at the time of submission of this manuscript, he does not have industry research funding, ownership interests, or ongoing consulting relationships. Dr Stewart has served as a consultant for Abbott and Procyrion. Dr Cascino has received research support from Johnson & Johnson and has served as a consultant for Merck & Co. Dr Stehlik has received honoraria from Medtronic; has served as a consultant for Medtronic, TransMedics, and Natera; and has received research support from Natera and Merck. Dr Lala has received honoraria from Zoll. Dr Pagani has served as a scientific advisor (without compensation) for Abbott, CH Biomedical, FineHeart, and Medtronic; has served as a medical monitor (without compensation) for Abiomed; and has received salary support from Blue Shield of Michigan. Dr Mann has served as a consultant/on the Advisory Board for Novartis and Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Background: Left ventricular assist devices (LVADs) have been implanted as bridge to transplantation (BTT), bridge to candidacy (BTC) or destination therapy (DT) on the basis of relative and absolute contraindications to transplantation. Multiple factors may lead to changes in the strategy of support after LVAD implantation., Methods: Based on INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) 2012-2020 data, 11,262 patients survived to 3 months on continuous-flow LVADs with intent of BTT or DT. Preimplant characteristics and early events post-LVAD were analyzed in relation to changes in BTT or DT strategy during the next 12 months., Results: Among 3216 BTT patients at 3 months, later transplant delisting or death without transplant occurred in 536 (16.7%) and was more common with age, profiles 1-2, renal dysfunction, and independently for prior cardiac surgery (HR 1.25, 95% CI 1.04-1.51; P = 0.02). Post-LVAD events of infections, gastrointestinal bleeding, stroke, and right heart failure as defined by inotropic therapy, predicted delisting and death, as did in-hospital location at 3 months (HR 1.67, 95% CI 1.20-2.33; P = 0.0024). Of 8046 patients surviving to 3 months with the intent of destination therapy, 750 (9.3%) subsequently underwent listing or transplantation, often with initial histories of acute HF (HR 1.70, 95% CI 1.27-2.27; P = 0.0012) or malnutrition-cachexia (1.73, 95% CI 1.14-2.63; P = 0.0099). Multiple gastrointestinal bleeding events (≥ 4) with LVAD increased transition from BTT to DT (HR 4.22, 95% CI 1.46-12.275; P = 0.0078) but also from DT to BTT (HR 5.17, 95% CI 1.92-13.9; P = 0.0011)., Conclusions: Implant strategies change over time in relation to preimplant characteristics and adverse events post implant. Preimplant recognition of factors predicting later change in implant strategy will refine initial triage, whereas further reduction of post-LVAD complications will expand options, including eventual consideration of heart transplantation., Competing Interests: DISCLOSURES None of the authors have any conflicts of interest pertaining to this manuscript. No external funding was received for this project., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The HeartMate 3 (HM 3; Abbott) left ventricular assist device (LVAD) has improved hemocompatibility-related adverse outcomes. In sporadic cases, external compression of the outflow graft causing obstruction (eOGO) can result from substance accumulation between the outflow graft and its bend relief. We sought to evaluate the prevalence, course, and clinical implications of eOGO in an international study., Methods: A multicenter retrospective analysis of HM 3 LVADs implanted between November 2014 and April 2021 (n = 2108) was conducted across 17 cardiac centers in 8 countries. We defined eOGO as obstruction >25% in the cross-sectional area in imaging (percutaneous angiography, computed tomography, or intravascular ultrasound). The prevalence and annual incidence were calculated. Serious adverse events and outcomes (death, transplantation, or device exchange) were analyzed for eOGO cases., Results: Of 2108 patients, 62 were diagnosed with eOGO at a median LVAD support duration of 953 (interquartile range, 600-1267) days. The prevalence of eOGO was 3.0% and the incidence at 1, 2, 3, 4, and 5 years of support was 0.6%, 2.8%, 4.0%, 5.2%, and 9.1%, respectively. Of 62 patients, 9 were observed, 27 underwent surgical revision, 15 underwent percutaneous stent implantation, 8 received a heart transplant, and 2 died before intervention. One patient underwent surgical revision and later stent implantation. The mortality with therapeutic intervention was 9/53 (17.0%)., Conclusions: Although uncommon, HM 3 LVAD-supported patients might develop eOGO with an increasing incidence after 1 year of support. Although engineering efforts to reduce this complication are under way, clinicians must maintain a focus on early detection and remain vigilant., (Copyright © 2022 The American Association for Thoracic Surgery. All rights reserved.)

Stunting (length/height-for-age z-score < -2) is associated with significant morbidity and mortality among children under 5 years of age in sub-Saharan Africa. Children who are stunted and recently hospitalized for acute illness may be at particularly elevated risk for post-discharge mortality. In this cross-sectional analysis, we measured the prevalence of stunting at hospital discharge and identified host, caregiver, and environmental correlates of stunting among children aged 1-59 months in Western Kenya enrolled in the Toto Bora Trial. Child age- and site-adjusted prevalence ratios were estimated using Poisson regression. Of the 1,394 children included in this analysis, 23% were stunted at hospital discharge. Older children (12-23 months and 24-59 months versus 0-5 months) had a higher prevalence of stunting (adjusted prevalence ratio [aPR]: 1.58; 95% CI: 1.04-2.36 and aPR: 1.59; 95% CI: 1.08-2.34, respectively). HIV-exposed, uninfected children (aPR: 1.94; 95% CI: 1.39-2.70), children with HIV infection (aPR: 2.73; 95% CI: 1.45-5.15), and those who were never exclusively breastfed in early life (aPR 2.51; 95% CI: 1.35-4.67) were more likely to be stunted. Caregiver education (primary school or less) and unimproved sanitation (pit latrine without slab floor or open defecation) were associated with increased risk of stunting (aPR: 1.94; 95% CI: 1.54-2.44; aPR: 1.99; 95% CI: 1.20-3.31; aPR: 3.57; 95% CI: 1.77-7.21, respectively). Hospital discharge represents an important opportunity for both identifying and delivering targeted interventions for nutrition-associated poor outcomes among a high-risk population of children.

BACKGROUND: Pregnant women living with HIV (WLHIV) are at high risk for TB. There are limited data to inform whether TB preventive therapy is safe in pregnancy. METHODS: We completed a retrospective study of antenatal and birth records of mother-infant dyads at two health care facilities in Kisumu, Kenya. Among pregnant WLHIV, we assessed the relationship of antenatal isoniazid preventive therapy (IPT) with birth outcomes (preterm birth, low birth weight [LBW], congenital anomalies, and perinatal death). RESULTS: Of 576 mother-infant pairs, most women were on antiretroviral therapy (574, 99.7%) with viral suppression (518, 89.9%) and one-quarter had IPT exposure during pregnancy (152, 26.4%). The prevalence of preterm birth was lower among women with antenatal IPT exposure (21% vs. 30%; P = 0.03). LBW, congenital anomaly and perinatal death were not associated with antenatal IPT; however, we observed a trend toward fewer composite poor birth outcomes among women taking antenatal IPT (26% vs 33%; P = 0.08). Controlling for maternal age and viral load, IPT use during pregnancy was associated with lower odds of preterm birth (aOR 0.62, 95% CI 0.40-0.98; P = 0.04). CONCLUSION: In a programmatic setting in Western Kenya, IPT use was not associated with adverse birth outcomes.

Glansreginin A has been reported to be an indicator of the quality of walnuts (Juglans spp.). However, bioactive properties of glansreginin A have not been adequately explored. In the present study, we quantified concentrations of glansreginin A in black walnuts (Juglans nigra) using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and performed an array of in vitro bioassays to characterize biological activities (e.g., antibacterial, antioxidant, anticancer capacities) of this compound. Results from HPLC-MS/MS analysis indicated that glansreginin A was presented in all 12 black cultivars examined and its contents were variable among black walnut cultivars, ranged from 6.8 mg/kg (Jackson) to 47.0 mg/kg (Hay). Glansreginin A possessed moderate antibacterial activities against Gram-positive pathogens (Staphylococcus aureus and Bacillus anthracis). This compound exhibited no antioxidant activities, did not induce the activity of antioxidant response element signaling pathways, and exerted no antiproliferative effects on tumorigenic alveolar epithelial cells and non-tumorigenic lung fibroblast cells., (© 2023. The Author(s).)

Introduction: Lack of viral suppression (VS) among pregnant and breastfeeding women living with HIV poses challenges for maternal and infant health, and viral load (VL) monitoring via centralized laboratory systems faces many barriers. We aimed to determine the impact of point-of-care (POC) VL and targeted drug resistance mutation (DRM) testing in improving VS among pregnant and postpartum women on antiretroviral therapy., Methods: We conducted a pre/post-intervention prospective cohort study among 820 pregnant women accessing HIV care at five public-sector facilities in western Kenya from 2019 to 2022. The pre-intervention or "control" group consisted of standard-of-care (SOC) centralized VL testing every 6 months and the post-intervention or "intervention" group consisted of a combined strategy of POC VL every 3 months, targeted DRM testing, and clinical management support. The primary outcome was VS (VL ≤1000 copies/ml) at 6 months postpartum; secondary outcomes included uptake and turnaround times for VL testing and sustained VS., Results: At 6 months postpartum, 321/328 (98%) of participants in the intervention group and 339/347 (98%) in the control group achieved VS (aRR 1.00, 95% confidence interval [CI] 0.98, 1.02). When assessing VS using a threshold of <40 copies/ml, VS proportions were lower overall (90-91%) but remained similar between groups. Among women with viraemia (VL>1000 copies/ml) who underwent successful DRM testing in the intervention group, all (46/46, 100%) had some DRMs and 20 (43%) had major DRMs (of which 80% were nucleos(t)ide reverse transcriptase inhibitor mutations). POC VL testing uptake was high (>89%) throughout pregnancy, delivery, and postpartum periods, with a median turnaround time of 1 day (IQR 1, 4) for POC VL in the intervention group and 7 days (IQR 5, 9) for SOC VL in the control group. Sustained VS throughout follow-up was similar between groups with either POC or SOC VL testing (90-91% for <1000 copies/ml, 62-70% for <40 copies/ml)., Conclusions: Our combined strategy markedly decreased turnaround time but did not increase VS rates, which were already very high, or sustained VS among pregnant and postpartum women living with HIV. Further research on how best to utilize POC VL and DRM testing is needed to optimize sustained VS among this population., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Pregnant women and children living with HIV in Kenya achieve viral suppression (VS) at lower rates than other adults. While many factors contribute to these low rates, the acquisition and development of HIV drug resistance mutations (DRMs) are a contributing factor. Recognizing the significance of DRMs in treatment decisions, resource-limited settings are scaling up national DRM testing programs. From provider and patient perspectives, however, optimal ways to operationalize and scale-up DRM testing in such settings remain unclear., Methods: Our mixed methods study evaluates the attitudes towards, facilitators to, and barriers to DRM testing approaches among children and pregnant women on antiretroviral therapy (ART) in five HIV treatment facilities in Kenya. We conducted 68 key informant interviews (KIIs) from December 2019 to December 2020 with adolescents, caregivers, pregnant women newly initiating ART or with a high viral load, and providers, laboratory/facility leadership, and policy makers. Our KII guides covered the following domains: (1) DRM testing experiences in routine care and through our intervention and (2) barriers and facilitators to routine and point-of-care DRM testing scale-up. We used inductive coding and thematic analysis to identify dominant themes with convergent and divergent subthemes., Results: The following themes emerged from our analysis: (1) DRM testing and counseling were valuable to clinical decision-making and reassuring to patients, with timely results allowing providers to change patient ART regimens faster; (2) providers and policymakers desired an amended and potentially decentralized DRM testing process that incorporates quicker sample-to-results turn-around-time, less burdensome procedures, and greater patient and provider "empowerment" to increase comfort with testing protocols; (3) facility-level delays, deriving from overworked facilities and sample tracking difficulties, were highlighted as areas for improvement., Conclusions: DRM testing has the potential to considerably improve patient health outcomes. Key informants recognized several obstacles to implementation and desired a more simplified, time-efficient, and potentially decentralized DRM testing process that builds provider comfort and confidence with DRM testing protocols. Further investigating the implementation, endurance, and effectiveness of DRM testing training is critical to addressing the barriers and areas of improvement highlighted in our study., Trial Registration: NCT03820323., (© 2023. BioMed Central Ltd., part of Springer Nature.)

HIV stigma remains a barrier in achieving optimal HIV treatment. We studied the prevalence and predictors of HIV stigma among adolescents and youth with HIV (AYWHIV) ages 15-24 years in Western Kenya. Of 1011 AYWHIV, 69% were female with a median age of 18 years. Most (59%) attended adolescent clinic days, and 40% attended support groups. One-quarter (27%) had experienced physical, 18% emotional, and 7% sexual violence. The majority of AYWHIV (88%) reported disclosure concerns, 48% reported perceived community stigma, 36% experienced, and 24% internalized stigma. Compared to AYWHIV attending adolescent clinics, those in general/adult clinics had higher internalized stigma. Similarly, having dropped out of school was associated with higher internalized stigma. AYWHIV in sexual relationships had higher experienced stigma and disclosure concerns. Lastly, exposure to violence was associated with higher experienced, internalized, perceived community stigma and disclosure concerns. These risk factors can be targeted when developing stigma-prevention interventions., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There is a lack of consensus about how to prioritize potential implementation strategies for HIV pre-exposure prophylaxis (PrEP) delivery. We compared several prioritization methods for their agreement and pragmatism in practice in a resource-limited setting., Methods: We engaged diverse stakeholders with clinical PrEP delivery and PrEP decision-making experience across 55 facilities in Kenya to prioritize 16 PrEP delivery strategies. We compared four strategy prioritization methods: (1) "past experience surveys" with experienced practitioners reflecting on implementation experience (N = 182); (2 and 3) "pre- and post-small-group ranking" surveys before and after group discussion (N = 44 and 40); (4) "go-zone" quadrant plots of perceived effectiveness vs feasibility. Kendall's correlation analysis was used to compare strategy prioritization using the four methods. Additionally, participants were requested to group strategies into three bundles with up to four strategies/bundle by phone and online survey., Results: The strategy ranking correlation was strongest between the pre- and post-small-group rankings (Tau: 0.648; p < 0.001). There was moderate correlation between go-zone plots and post-small-group rankings (Tau: 0.363; p = 0.079) and between past-experience surveys and post-small-group rankings (Tau: 0.385; p = 0.062). For strategy bundling, participants primarily chose bundles of strategies in the order in which they were listed, reflecting option ordering bias. Neither the phone nor online approach was effective in selecting strategy bundles. Participants agreed that the strategy ranking activities conducted during the workshop were useful in prioritizing a final set of strategies., Conclusions: Both experienced and inexperienced stakeholder participants' strategy rankings tended to prioritize strategies perceived as feasible. Small group discussions focused on feasibility and effectiveness revealed moderately different priorities than individual rankings. The strategy bundling approach, though less time- and resource-intensive, was not effective. Future research should further compare the relative effectiveness and pragmatism of methodologies to prioritize implementation strategies., (© 2023. The Author(s).)

Background: Risk of HIV acquisition is high during pregnancy and postpartum, and pre-exposure prophylaxis (PrEP) is recommended for peripartum populations. Integrating PrEP into maternal and child health (MCH) clinics is feasible and acceptable. Understanding clinics' service availability and readiness is essential for effective scale up., Methods: The PrEP in Pregnancy, Accelerating Reach and Efficiency study (PrEPARE; NCT04712994) engaged PrEP-experienced facilities previously linked to a programmatic or research study in Western Kenya to document available services and commodities via a modified service availability and readiness assessment (SARA) survey with 20 PrEP tracer items covering: staffing/guidelines, services/equipment, and medicines/commodities. Facilities' prior study engagement occurred between 2017 and 2019; SARA survey data was collected between April 2020 and June 2021. Descriptive statistics were stratified by prior study engagement. ANOVA tests assessed associations between facility characteristics and gaps. Fisher's tests assessed differences in commodity availability and stockouts., Results: Of the 55 facilities surveyed, 60% had received PrEP training in the last two years, 95% offered PrEP integrated into MCH, and 64% and 78% had both auditory and visual privacy in PrEP and HIV testing service (HTS) delivery spaces, respectively. Supervision frequency was heterogeneous, but 82% had received a supervision visit within 3 months. Availability of commodities was variable and the most commonly unavailable commodities were PrEP in MCH (71% available) and risk assessment screening tool (RAST) and PrEP cards (60% and 75% available, respectively). The number of service and commodity gaps per facility ranged from zero to eight (median: 3; IQR: 2, 5). The most frequent gaps were: PrEP training and risk assessment cards (40% each), lack of privacy in PrEP (36%) and HIV testing services (31%) spaces, PrEP pills in MCH (29%), and PrEP cards (25%). There were no differences in mean number of gaps by county, previous study engagement, or public vs. private status. Level 4 facilities had fewer gaps (mean 2.2) than level 2, 3, and 5 facilities (mean 5.7, 4.5, and 5.3 respectively; p  < 0.001)., Conclusions: PrEP service availability and readiness was generally high across MCH facilities. However, there is a need for increased frequency of provider training and supportive supervision focused on fidelity. To address key commodity stockouts such as PrEP pills, implementation of electronic logistics management information systems may be needed. Targeting these gaps is essential to effectively scale up integrated PrEP delivery, especially among facilities with limited infrastructure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Hicks, Abuna, Odhiambo, Dettinger, Sila, Oketch, Sifuna, Ngumbau, Gómez, John-Stewart, Kinuthia and Wagner.)

Bacillus anthracis is the zoonotic causal agent of anthrax. Its infectious form is the spore, which can persist in soil. Herbivores usually acquire the disease from grazing in spore-contaminated sites. There are two schools of thought regarding B. anthracis activities in soil. One contends the bacteria are obligate animal parasites and soil-based spores remain inert until taken up by another animal host. Others contend that spores can germinate in soil and the bacteria replicate and re-sporulate to maintain and/or increase spore numbers. This review discusses whether soil replication of B. anthracis is an important part of its life cycle., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Background: Early antiretroviral therapy (ART) during infancy reduces cognitive impairment due to HIV, but the extent of benefit is unclear., Setting: Children were recruited from hospital and health centers providing HIV care and treatment in Nairobi, Kenya., Methods: Cognitive, behavioral, and motor outcomes were assessed in children with HIV and early ART (<1 year), children with HIV and late ART (1.5-6 years), and children HIV-unexposed uninfected (CHUU). Domain z scores and odds neurobehavioral impairment (≤15th percentile in CHUU) were compared in adjusted analyses., Results: Children with HIV initiated ART at median ages 0.4 (early ART) and 3.5 years (late ART). Children were assessed at median ages 6.9 (CHUU, N = 61), 6.9 (early ART, N = 54), and 13.5 (late ART; N = 27) years. Children with late ART vs. children with early ART had significantly lower z scores in 7 domains, specifically global cognition, short-term memory, visuospatial processing, learning, nonverbal test performance, executive function, and motor skills (adjusted mean differences, -0.42 to -0.62, P values ≤ 0.05), and had higher odds impairment in 7 domains (adjusted odds ratios [aORs], 2.87 to 16.22, P values ≤ 0.05). Children with early ART vs. CHUU had lower z scores in 5 domains (global cognition, short-term memory, delayed memory, processing speed, and behavioral regulation [adjusted mean differences, -0.32 to -0.88, P values < 0.05]) and higher impairment for 2 domains (short-term memory [aOR, 3.88] and behavioral regulation [aOR 3.46], P values < 0.05). Children with late ART vs. CHUU had lower z scores in 8 domains (adjusted mean differences, -0.57 to -1.05, P values ≤ 0.05), and higher impairment in 7 domains (aORs 1.98 to 2.32, P values ≤ 0.05)., Conclusion: Early ART in the first year of life attenuates but does not eliminate the neurodevelopmental compromise of HIV., Competing Interests: All authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We estimated the effects of HIV stigma on mental health and treatment outcomes for youth with HIV (YWH)., Design: Secondary analysis of data for YWH ages 15-24 years in Western Kenya., Methods: Participants completed a longitudinal survey (baseline, months 6 and 12) assessing socio-demographics, antiretroviral therapy (ART) adherence, depressive symptoms (PHQ-9), and HIV stigma (10-item Wright scale). First viral load (VL) after enrollment was abstracted from records. We estimated risk of depressive symptoms (score > 4), nonadherence (missing ≥2 days of ART in a month), and detectable VL (≥50 copies/ml) for each standard deviation (SD) increase in HIV stigma score, adjusted for age and sex (and regimen in VL model). The generalizing estimating equation models included measures for the three visits., Results: Median age for the 1011 YWH was 18 years. At baseline, frequency of nonadherence, depressive symptoms and detectable VL was 21%, 21%, and 46%, respectively. Mean stigma score was 25 (SD = 7.0). Each SD stigma score increment was associated with higher risk of depressive symptoms {adjusted relative risk [aRR] 1.31 [95% confidence interval (CI): 1.20-1.44]}, nonadherence [aRR 1.16 (CI: 1.05-1.27)] and detectable VL [aRR 1.20 (CI: 1.08-1.32)]. Experienced and anticipated stigma were associated with detectable VL [aRR 1.16 (CI: 1.10-1.22) and aRR 1.23 (CI: 1.12-1.35), respectively]. Internalized and perceived community stigma were associated with depressive symptoms [aRR 1.31 (CI: 1.21-1.40) and aRR 1.24 (CI: 1.13-1.36), respectively]., Conclusions: Stigma was associated with depressive symptoms, nonadherence and detectable VL. Interventions to decrease stigma may improve virologic and mental health outcomes in YWH., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There is mixed evidence on the influence of self-disclosure of one's HIV status on mental health, health behaviours and clinical outcomes. We studied the patterns of self-disclosure among parents living with HIV, and factors that influence parental disclosure., Methods: This mixed-methods study was among adults in HIV care participating in a study assessing the uptake of pediatric index-case testing. They completed a survey to provide demographic and HIV-related health information, and assess self-disclosure to partners, children and others. We ran generalized linear models to determine factors associated with disclosure and reported prevalence ratios (PR). Eighteen participants also participated in in-depth interviews to explore perceived barriers and facilitators of self-disclosure to one's child. A content analysis approach was used to analyze interview transcripts., Results: Of 493 caregivers, 238 (48%) had a child ≥ 6 years old who could potentially be disclosed to about their parent's HIV status. Of 238 participants, 205 (86%) were female, median age was 35 years, and 132 (55%) were in a stable relationship. Among those in a stable relationship, 96 (73%) knew their partner's HIV status, with 79 (60%) reporting that their partner was living with HIV. Caregivers had known their HIV status for a median 2 years, and the median age of their oldest child was 11 years old. Older caregiver age and older first born child's age were each associated with 10% higher likelihood of having disclosed to a child (PR: 1.10 [1.06-1.13] and PR: 1.10 [1.06-1.15], per year of age, respectively). The child's age or perceived maturity and fear of causing anxiety to the child inhibited disclosure. Child's sexual activity was a motivator for disclosure, as well as the belief that disclosing was the "right thing to do". Caregivers advocated for peer and counseling support to gain insight on appropriate ways to disclose their status., Conclusions: Child's age is a key consideration for parents to disclose their own HIV status to their children. While parents were open to disclosing their HIV status to their children, there is a need to address barriers including anticipated stigma, and fear that disclosure will cause distress to their children., (© 2023. The Author(s).)

Background: Tuberculosis is the leading cause of death among adolescents and young adults living with HIV (YWHIV) and their heightened risk warrants deeper understanding of utilization of tuberculosis-prevention measures within HIV care., Setting: Retrospective study using clinic surveys and medical record data from 86 Kenyan HIV clinics., Methods: Clinic surveys obtained information on tuberculosis preventive therapy (TPT) services. Medical records of YWHIV were abstracted. Bivariate and multivariate analyses used generalized linear models to determine individual-level and clinic-level cofactors of TPT initiation and completion., Results: Among 10,328 eligible YWHIV, 4337 (42.0%) initiated TPT. Of 3295 with ≥6 months follow-up, 1774 (53.8%) completed TPT. A lower patient-to-staff ratio was a clinic-level cofactor of TPT initiation ( P = 0.044) and completion ( P = 0.004); designated adolescent areas were associated with TPT initiation {prevalence ratio 2.05 [95% confidence interval (CI): 1.46 to -2.88]}. Individual cofactors of TPT initiation included younger age at HIV-care enrollment [relative risk (RR) 0.85 (95% CI: 0.80 to 0.90)] and antiretroviral therapy (ART) duration [1-2 vs. <1 year RR 1.31 (95% CI: 1.18 to 1.45)]. TPT completion was associated with younger age [RR 0.91 (95% CI: 0.85 to 0.98)] and ART duration [2-5 vs. <1 year RR 1.27 (95% CI: 1.03 to 1.57)]. In multivariate models, TPT initiation was associated with younger age and ART duration [1-2 vs. 1 year; adjusted RR 1.30 (95% CI: 1.16 to 1.46)] and TPT completion with ART duration [2-5 vs. 1 year adjusted RR 1.23 (95% CI: 0.99 to 1.52)]., Conclusion: Over half of YWHIV did not initiate and >40% did not complete TPT, with distinct clinic-level and individual-level cofactors. Approaches to enhance adolescent-friendly infrastructure and support older YWHIV are necessary to improve TPT use., Competing Interests: D.A.B. is a Predoctoral Fellow funded by the NIH-supported University of Washington STD and AIDS Research Training Program under Award 5T32AI007140-44. D.A.B. is employed by Merative, a healthcare analytics company. Her work with Merative does not involve any products or competing products that play a role in this manuscript. The parent study was funded by the National Institutes of Health (NIH) under Award 5R01HD089850-05. For the remaining authors, no funding or conflicts of interest were declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Racial disparities in access to advanced therapies for heart failure (HF) patients are well documented, although the reasons remain uncertain. We sought to determine the association of race on utilization of ventricular assist device (VAD) and transplant among patients with access to care at VAD centers and if patient preferences impact the effect., Methods: We performed an observational cohort study of ambulatory chronic systolic HF patients with high-risk features and no contraindication to VAD enrolled at 21 VAD centers and followed for 2 years in the REVIVAL study (Registry Evaluation of Vital Information for VADs in Ambulatory Life). We used competing events cause-specific proportional hazard methodology with multiple imputation for missing data. The primary outcomes were (1) VAD/transplant and (2) death. The exposures of interest included race (Black or White), additional demographics, captured social determinants of health, clinician-assessed HF severity, patient-reported quality of life, preference for VAD, and desire for therapies., Results: The study included 377 participants, of whom 100 (26.5%) identified as Black. VAD or transplant was performed in 11 (11%) Black and 62 (22%) White participants, although death occurred in 18 (18%) Black and 36 (13%) White participants. Black race was associated with reduced utilization of VAD and transplant (adjusted hazard ratio, 0.45 [95% CI, 0.23-0.85]) without an increase in death. Preferences for VAD or life-sustaining therapies were similar by race and did not explain racial disparities., Conclusions: Among patients receiving care by advanced HF cardiologists at VAD centers, there is less utilization of VAD and transplant for Black patients even after adjusting for HF severity, quality of life, and social determinants of health, despite similar care preferences. This residual inequity may be a consequence of structural racism and discrimination or provider bias impacting decision-making., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01369407.

BxpB (also known as ExsFA) and ExsFB are an exosporium basal layer structural protein and a putative interspace protein of Bacillus anthracis that are known to be required for proper incorporation of the BclA collagen-like glycoprotein on the spore surface. Despite extensive similarity of the two proteins, their distribution in the spore is markedly different. We utilized a fluorescent fusion approach to examine features of the two genes that affect spore localization. The timing of expression of the bxpB and exsFB genes and their distinct N-terminal sequences were both found to be important for proper assembly into the exosporium basal layer. Results of this study provided evidence that the BclA nap glycoprotein is not covalently attached to BxpB protein despite the key role that the latter plays in BclA incorporation. Assembly of the BxpB- and ExsFB-containing outer basal layer appears not to be completely abolished in mutants lacking the ExsY and CotY basal layer structural proteins despite these spores lacking a visible exosporium. The BxpB and, to a lesser extent, the ExsFB proteins, were found to be capable of self-assembly in vitro into higher-molecular-weight forms that are stable to boiling in SDS under reducing conditions. IMPORTANCE The genus Bacillus consists of spore-forming bacteria. Some species of this genus, especially those that are pathogens of animals or insects, contain an outermost spore layer called the exosporium. The zoonotic pathogen B. anthracis is an example of this group. The exosporium likely contributes to virulence and environmental persistence of these pathogens. This work provides important new insights into the exosporium assembly process and the interplay between BclA and BxpB in this process.

Background: Viral suppression (VS) is a marker of effective HIV therapy, and viral load (VL) testing is critical for treatment monitoring, especially in high-risk groups such as children and pregnant/postpartum women. Although routine VL testing, via centralized laboratory networks, was implemented in Kenya starting in 2014, optimization and sustainable scale up of VL testing are still needed., Methods: We conducted a mixed methods study to evaluate the impact of higher frequency, point-of-care (POC) VL testing in optimizing VS among children and pregnant/postpartum women on antiretroviral treatment (ART) in five HIV treatment facilities in western Kenya in the Opt4Kids and Opt4Mamas studies. We conducted 68 key informant interviews (KIIs) from December 2019 to December 2020 with children and pregnant women living with HIV, child caregivers, providers, laboratory/facility leadership, and county- or national-level policymakers. Our KII guide covered the following domains: (1) barriers and facilitators to ART use and VS, (2) literacy and experiences with VL in routine care and via study, and (3) opinions on how to scale up VL testing for optimal programmatic use. We used inductive coding and thematic analysis to identify dominant themes with convergent and divergent subthemes., Results: Three main themes regarding VL testing emerged from our analysis. (1) Key informants uniformly contrasted POC VL testing's faster results turnaround, higher accessibility, and likely cost-effectiveness against centralized VL testing. (2) Key informants also identified areas of improvement for POC VL testing in Kenya, such as quality control, human resource and infrastructure capacity, supply chain management, and integration of VL testing systems. (3) To enable successful scale-up of VL testing, key informants proposed expanding the POC VL testing scheme, electronic medical records systems, conducting quality checks locally, capacity building and developing strong partnerships between key stakeholders., Conclusion: The more accessible, decentralized model of POC VL testing was deemed capable of overcoming critical challenges associated with centralized VL testing and was considered highly desirable for optimizing VS for children and pregnant/postpartum women living with HIV. While POC VL testing has the potential to improve VS rates among these populations, additional research is needed to develop strategies for ensuring the sustainability of POC VL testing programs., Trial Registration: NCT03820323, 29/01/2019., (© 2022. The Author(s).)

Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis are the major pathogens of the spore-forming genus Bacillus and possess an outer spore layer, the exosporium, not found in many of the nonpathogenic species. The exosporium consists of a basal layer with the ExsY, CotY, and BxpB proteins being the major structural components and an exterior nap layer containing the BclA glycoprotein. During the assembly process, the nascent exosporium basal layer is attached to the spore coat by a protein linker that includes the CotO and CotE proteins. Using transmission electron microscopy, Western blotting, immunofluorescence, and fluorescent fusion protein approaches, we examined the impact of single, double, and triple mutants of the major exosporium proteins on exosporium protein content and distribution. Plasmid-based expression of exsY and cotE resulted in increased production of exosporium lacking spores, and the former also resulted in outer spore coat disruptions. The exosporium bottlecap produced by exsY null spores was found to be more stable than previously reported, and its spore association was partially dependent on CotE. Deletion mutants of five putative spore genes ( bas1131 , bas1142 , bas1143 , bas2277 , and bas3594 ) were created and shown not to have obvious effects on spore morphology or BclA and BxpB content. The BclC collagen-like glycoprotein was found to be present in the spore and possibly localized to the interspace region. IMPORTANCE B. anthracis is an important zoonotic animal pathogen causing sporadic outbreaks of anthrax worldwide. Spores are the infectious form of the bacterium and can persist in soil for prolonged periods of time. The outermost B. anthracis spore layer is the exosporium, a protein shell that is the site of interactions with both the soil and with the innate immune system of infected hosts. Although much is known regarding the sporulation process among members of the genus Bacillus , significant gaps in our understanding of the exosporium assembly process exist. This study provides evidence for the properties of key exosporium basal layer structural proteins. The results of this work will guide future studies on exosporium protein-protein interactions during the assembly process.

Background: The World Health Organization (WHO) recommends tuberculosis (TB) diagnostic evaluation for children with HIV (CHIV) who have history of TB contact, poor weight gain, cough, or fever. These screening criteria were developed based on studies of symptomatic CHIV with incomplete microbiologic confirmation. We performed routine TB microbiologic evaluation of hospitalized CHIV with and without symptoms to develop a data-driven TB symptom screen., Methods: Among hospitalized antiretroviral therapy-naive Kenyan CHIV enrolled in the Pediatric Urgent Start of Highly Active Antiretroviral Therapy (PUSH) trial, we performed Xpert MTB/RIF and mycobacterial culture of respiratory and stool specimens independent of TB symptoms. We evaluated performance of WHO and other published pediatric TB screening criteria and derived optimized criteria using a combination of symptoms., Results: Of 168 CHIV who underwent TB microbiologic evaluation, 13 (8%) had confirmed TB. WHO TB symptom screening had 100% sensitivity and 4% specificity to detect confirmed TB. Published TB screening criteria that relied on prolonged symptoms missed cases of confirmed TB (sensitivity 85%-92%). An optimized symptom screen including weight loss, cough, anorexia, or TB contact had 100% sensitivity and improved specificity (31%) compared with the WHO pediatric TB symptom screen., Conclusions: The WHO TB symptom screen was highly sensitive but resulted in a high proportion of hospitalized CHIV who would require TB diagnostic evaluation. Other published TB screening criteria missed CHIV with confirmed TB. Our optimized screening tool increased specificity while preserving sensitivity. Future multicenter studies are needed to improve TB screening tools for CHIV in both inpatient and outpatient settings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Video-based pre-test information is used in high resource settings to increase HIV testing coverage but remains untested in resource-limited settings. We conducted formative and evaluative focus group discussions with healthcare workers (HCWs) and caregivers of children in Kenya to develop and refine a pediatric HIV pre-test informational video. We then assessed HIV knowledge among caregivers sequentially enrolled in one of three pre-test information groups: (1) individual HCW-led (N = 50), (2) individual video-based (N = 50), and (3) group video-based (N = 50) sessions. A brief video incorporating information on national pediatric testing, modes of HIV transmission, and dramatized testimonials of caregivers who tested children was produced in three languages. Compared to individual HCW-led sessions (mean: 7.2/9; standard deviation [SD]: 1.3), both the group video-based (mean: 7.7; SD: 0.9) and individual video-based (mean: 7.6; SD: 0.9) sessions had higher mean knowledge scores. Video-based pre-test information could enhance existing pediatric HIV testing services., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Clinical pediatric tuberculosis (TB) diagnosis may lead to overdiagnosis particularly among children with human immunodeficiency virus (CHIV). We assessed the performance of monocyte-lymphocyte ratio (MLR) as a diagnostic biomarker and constructed a clinical prediction score to improve specificity of TB diagnosis in CHIV with limited access to microbiologic testing., Methods: We pooled data from cohorts of children aged ≤13 years from Vietnam, Cameroon, and South Africa to validate the use of MLR ≥0.378, previously found as a TB diagnostic marker among CHIV. Using multivariable logistic regression, we created an internally validated prediction score for diagnosis of TB disease in CHIV., Results: The combined cohort had 601 children (median age, 1.9 [interquartile range, 0.9-5.3] years); 300 (50%) children were male, and 283 (47%) had HIV. Elevated MLR ≥0.378 had sensitivity of 36% (95% confidence interval [CI], 23%-51%) and specificity of 79% (95% CI, 71%-86%) among CHIV in the validation cohort. A model using MLR ≥0.28, age ≥4 years, tuberculin skin testing ≥5 mm, TB contact history, fever >2 weeks, and chest radiograph suggestive of TB predicted active TB disease in CHIV with an area under the receiver operating characteristic curve of 0.85. A prediction score of ≥5 points had a sensitivity of 94% and specificity of 48% to identify confirmed TB, and a sensitivity of 82% and specificity of 48% to identify confirmed and unconfirmed TB groups combined., Conclusions: Our score has comparable sensitivity and specificity to algorithms including microbiological testing and should enable clinicians to rapidly initiate TB treatment among CHIV when microbiological testing is unavailable., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Spores are an infectious form of the zoonotic bacterial pathogen, Bacillus anthracis. The outermost spore layer is the exosporium, comprised of a basal layer and an external glycoprotein nap layer. The major structural proteins of the inner basal layer are CotY (at the mother cell central pole or bottlecap) and ExsY around the rest of the spore. The basis for the cap or noncap specificity of the CotY and ExsY proteins is currently unknown. We investigated the role of sequence differences between these proteins in localization during exosporium assembly. We found that sequence differences were less important than the timing of expression of the respective genes in the positioning of these inner basal layer structural proteins. Fusion constructs with the fluorescent protein fused at the N-terminus resulted in poor incorporation whereas fusions at the carboxy terminus of CotY or ExsY resulted in good incorporation. However, complementation studies revealed that fusion constructs, although accurate indicators of protein localization, were not fully functional. A model is presented that explains the localization patterns observed. Bacterial two-hybrid studies in Escherichia coli hosts were used to examine protein-protein interactions with full-length and truncated proteins. The N-terminus amino acid sequences of ExsY and CotY appear to be recognized by spore proteins located in the spore interspace, consistent with interactions seen with ExsY and CotY with the interspace proteins CotE and CotO, known to be involved with exosporium attachment., (© 2022 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Background: Feasible, scalable, and cost-effective approaches to ensure virological suppression among children living with HIV are urgently needed. The aim of the Opt4Kids study was to determine the effect of point of care viral load and targeted drug resistance mutation testing in improving virological suppression among children on antiretroviral therapy (ART) in Kenya., Methods: In this open-label, individually randomised controlled trial, we enrolled children living with HIV aged 1-14 years and who were either newly initiating or already receiving ART at five study facilities in Kenya. Participants were randomly allocated 1:1 to receive the intervention of point-of-care viral load testing every 3 months, targeted drug resistance mutation testing, and clinical decision support (point-of-care testing) or to receive the standard care (control group), stratified by facility site and age groups (1-9 years vs 10-14 years). Investigators were masked to the randomised group. The primary efficacy outcome was virological suppression (defined as a viral load of <1000 copies per mL) by point-of-care viral load testing at 12 months after enrolment in all participants with an assessment. This study is registered with ClinicalTrials.gov, NCT03820323., Findings: Between March 7, 2019, and December 31, 2020, we enrolled 704 participants. Median age at enrolment was 9 years (IQR 7-12), 344 (49%) participants were female and 360 (51%) were male, and median time on ART was 5·8 years (IQR 3·1-8·6). 536 (76%) of 704 had documented virological suppression at enrolment. At 12 months after enrolment, the proportion of participants achieving virological suppression in the intervention group (283 [90%] of 313 participants with a 12 month point-of-care viral load test) did not differ from that in the control group (289 [92%] of 315; risk ratio [RR] 0·99, 95% CI 0·94-1·03; p=0·55). We identified 138 episodes of viraemia in intervention participants, of which 107 (89%) samples successfully underwent drug resistance mutation testing and 91 (85%) had major drug resistance mutations. The median turnaround time for viral load results was 1 day (IQR 0-1) in the intervention group and 15 days (10-21) in the control group., Interpretation: Point-of-care viral load testing decreased turnaround time and targeted drug resistance mutation testing identified a high prevalence of HIV drug resistance mutations in children living with HIV, but the combined approach did not increase rates of virological suppression. Further research in combination interventions, including point-of-care viral load and drug resistance mutation testing coupled with psychosocial support, is needed to optimise virological suppression for children living with HIV., Funding: National Institutes of Mental Health of the US National Institutes of Health, Thrasher Research Fund., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Pediatric HIV testing remains suboptimal. The OraQuick test [saliva-based test (SBT)] is validated in pediatric populations ≥18 months. Understanding caregiver and health care worker (HCW) acceptability of pediatric SBT is critical for implementation., Methods: A trained qualitative interviewer conducted 8 focus group discussions (FGDs): 4 with HCWs and 4 with caregivers of children seeking health services in western Kenya. FGDs explored acceptability of pediatric SBT and home- and facility-based SBT use. Two reviewers conducted consensus coding and thematic analyses of transcripts using Dedoose., Results: Most HCWs but few caregivers had heard of SBT. Before seeing SBT instructions, both had concerns about potential HIV transmission through saliva, which were mostly alleviated after kit demonstration. Noted benefits of SBT included usability and avoiding finger pricks. Benefits of facility-based pediatric SBT included shorter client waiting and service time, higher testing coverage, and access to HCWs, while noted challenges included ensuring confidentiality. Benefits of caregivers using home-based SBT included convenience, privacy, decreased travel costs, increased testing, easier administration, and child comfort. Perceived challenges included not receiving counseling, disagreements with partners, child neglect, and negative emotional response to a positive test result. Overall, HCWs felt that SBT could be used for pediatric HIV testing but saw limited utility for caregivers performing SBT without an HCW present. Caregivers saw utility in home-based SBT but wanted easy access to counseling in case of a positive test result., Conclusions: SBT was generally acceptable to HCWs and caregivers and is a promising strategy to expand testing coverage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Children and adolescents living with HIV have poorer rates of HIV testing, treatment, and virologic suppression than adults. Strategies that use a systems approach to optimize these multiple, linked steps simultaneously are critical to close these gaps., Methods: The Systems Analysis and Improvement Approach (SAIA) was adapted and piloted for the pediatric and adolescent HIV care and treatment cascade (SAIA-PEDS) at 6 facilities in Kenya. SAIA-PEDS includes three tools: continuous quality improvement (CQI), flow mapping, and pediatric cascade analysis (PedCAT). A predominately qualitative evaluation utilizing focus group discussions (N = 6) and in-depth interviews (N = 19) was conducted with healthcare workers after implementation to identify determinants of implementation. Data collection and analysis were grounded in the Consolidated Framework for Implementation Research (CFIR)., Results: Overall, the adapted SAIA-PEDS strategy was acceptable, and the three tools complemented one another and provided a relative advantage over existing processes. The flow mapping and CQI tools were compatible with existing workflows and resonated with team priorities and goals while providing a structure for group problem solving that transcended a single department's focus. The PedCAT was overly complex, making it difficult to use. Leadership and hierarchy were complex determinants. All teams reported supportive leadership, with some describing in detail how their leadership was engaged and enthusiastic about the SAIA-PEDS process, by providing recognition, time, and resources. Hierarchy was similarly complex: in some facilities, leadership stifled rapid innovation by insisting on approving each change, while at other facilities, leadership had strong and supportive oversight of processes, checking on the progress frequently and empowering teams to test innovative ideas., Conclusion: CQI and flow mapping were core components of SAIA-PEDS, with high acceptability and consistent use, but the PedCAT was too complex. Leadership and hierarchy had a nuanced role in implementation. Future SAIA-PEDS testing should address PedCAT complexity and further explore the modifiability of leadership engagement to maximize implementation., (© 2022. The Author(s).)

Background: The immunologic correlates of risk of Mycobacterium tuberculosis (Mtb) infection after BCG vaccination are unknown. The mechanism by which BCG influences the tuberculin skin test (TST) remains poorly understood. We evaluated CD4+ T-cell responses in infants exposed to HIV and uninfected (HEU) who received BCG at birth and examined their role in susceptibility to Mtb infection and influence on TST induration., Methods: HEU infants were enrolled in a randomised clinical trial of isoniazid (INH) to prevent Mtb infection in Kenya. We measured mycobacterial antigen-specific Th1 and Th17 cytokine responses at 6-10 weeks of age prior to INH randomisation and compared responses between Mtb infected and uninfected infants. Outcomes at 14 months of age included TST, QuantiFERON-Plus (QFT-Plus), and ESAT-6/CFP-10-specific non-IFN-γ cytokines measured in QFT-Plus supernatants., Findings: A monofunctional mycobacterial antigen-specific TNF+ CD4+ effector memory (CCR7-CD45RA-) T-cell response at 6-10 weeks of age was associated with Mtb infection at 14 months of age as measured by ESAT-6/CFP-10-specific IFN-γ and non-IFN-γ responses (Odds Ratio 2.26; Confidence Interval 1.27-4.15; P = 0.006). Mycobacterial antigen-specific polyfunctional effector memory Th1 responses at 6-10 weeks positively correlated with TST induration in infants without evidence of Mtb infection at 14 months, an association which was diminished by INH therapy., Interpretation: Induction of monofunctional TNF+ CD4+ effector memory T-cell responses may be detrimental in TB vaccine development. This study also provides mechanistic insight into the association of BCG-induced immune responses with TST induration and further evidence that TST-based diagnoses of Mtb infection in infants are imprecise., Funding: Thrasher Research Fund., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Children and adolescents lag behind adults in achieving UNAIDS 95-95-95 targets for HIV testing, treatment, and viral suppression. The Systems Analysis and Improvement Approach (SAIA) is a multi-component implementation strategy previously shown to improve the HIV care cascade for pregnant women and infants. SAIA merits adaptation and testing to reduce gaps in the pediatric and adolescent HIV cascade., Methods: We adapted the SAIA strategy components to be applicable to the pediatric and adolescent HIV care cascade (SAIA-PEDS) in Nairobi and western Kenya. We tested whether this SAIA-PEDS strategy improved HIV testing, linkage to care, antiretroviral treatment (ART), viral load (VL) testing, and viral load suppression for children and adolescents ages 0-24 years at 5 facilities. We conducted a pre-post analysis with 6 months pre- and 6 months post-implementation strategy (coupled with an interrupted time series sensitivity analysis) using abstracted routine program data to determine changes attributable to SAIA-PEDS., Results: Baseline levels of HIV testing and care cascade indicators were heterogeneous between facilities. Per facility, the monthly average number of children/adolescents attending outpatient and inpatient services eligible for HIV testing was 842; on average, 253 received HIV testing services, 6 tested positive, 6 were linked to care, and 5 initiated ART. Among those on treatment at the facility, an average of 15 had a VL sample taken and 13 had suppressed VL results returned. Following the SAIA-PEDS training and mentorship, there was no substantial or significant change in the ratio of HIV testing (RR: 0.803 [95% CI: 0.420, 1.532]) and linkage to care (RR: 0.831 [95% CI: 0.546, 1.266]). The ratio of ART initiation increased substantially and trended towards significance (RR: 1.412 [95% CI: 0.999, 1.996]). There were significant and substantial improvements in the ratio of VL tests ordered (RR: 1.939 [95% CI: 1.230, 3.055]) but no substantial or significant change in the ratio of VL results suppressed (RR: 0.851 [95% CI: 0.554, 1.306])., Conclusions: The piloted SAIA-PEDS implementation strategy was associated with increases in health system performance for indicators later in the HIV care cascade, but not for HIV testing and treatment indicators. This strategy merits further rigorous testing for effectiveness and sustainment., (© 2022. The Author(s).)

Background: Pregnancy is a risk factor for progression from latent tuberculosis infection to symptomatic tuberculosis. However, how pregnancy influences T-cell responses to Mycobacterium tuberculosis is unknown., Methods: We measured M. tuberculosis-specific cytokines, T-cell memory markers, and overall CD4+ and CD8+ T-cell activation by flow cytometry from 49 women (18 with and 31 without HIV) who became pregnant while enrolled in a randomized controlled trial of preexposure prophylaxis for HIV. We analyzed data using COMPASS, an established statistical method for evaluating overall antigen-specific T-cell responses., Results: Pregnant women with latent tuberculosis infection demonstrated significantly diminished M. tuberculosis-specific CD4+ cytokine responses in the third trimester (COMPASS polyfunctional score [PFS], 0.07) compared before (PFS, 0.15), during (PFS, 0.13 and 0.16), and after pregnancy (PFS, 0.14; P = .0084, Kruskal-Wallis test). Paradoxically, M. tuberculosis-specific CD8+ cytokines and nonspecifically activated T-cells increased during late pregnancy. Nonspecific T-cell activation, a validated biomarker for progression from latent tuberculosis infection to tuberculosis disease, increased in latent tuberculosis infection-positive women postpartum, compared with latent tuberculosis infection-negative women., Conclusions: Pregnancy-related functional T-cell changes were most pronounced during late pregnancy. Both M. tuberculosis-specific T-cell changes during pregnancy and increases in immune activation postpartum may contribute to increased risk for tuberculosis progression., Clinical Trials Registration: NCT0557245., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The Fried Frailty Phenotype predicts adverse outcomes in geriatric populations, but has not been well-studied in advanced heart failure (HF). The Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life (REVIVAL) study prospectively collected frailty measures in patients with advanced HF to determine relevant assessments and their impact on clinical outcomes., Methods and Results: HF-Fried Frailty was defined by 5 baseline components (1 point each): (1) weakness: hand grip strength less than 25% of body weight; (2) slowness based on time to walk 15 feet; (3) weight loss of more than 10 lbs in the past year; (4) inactivity; and (5) exhaustion, both assessed by the Kansas City Cardiomyopathy Questionnaire. A score of 0 or 1 was deemed nonfrail, 2 prefrail, and 3 or greater was considered frail. The primary composite outcome was durable mechanical circulatory support implantation, cardiac transplant or death at 1 year. Event-free survival for each group was determined by the Kaplan-Meier method and the hazard of prefrailty and frailty were compared with nonfrailty with proportional hazards modeling. Among 345 patients with all 5 frailty domains assessed, frailty was present in 17%, prefrailty in 40%, and 43% were nonfrail, with 67% (n = 232) meeting the criteria based on inactivity and 54% (n = 186) for exhaustion. Frail patients had an increased risk of the primary composite outcome (unadjusted hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.52-5.24; adjusted HR 3.41, 95% CI 1.79-6.52), as did prefrail patients (unadjusted HR 1.97, 95% CI 1.14-3.41; adjusted HR 2.11, 95% CI 1.21-3.66) compared with nonfrail patients, however, the predictive value of HF-Fried Frailty criteria was modest (Harrel's C-statistic of 0.603, P = .004)., Conclusions: The HF-Fried Frailty criteria had only modest predictive power in identifying ambulatory patients with advanced HF at high risk for durable mechanical circulatory support, transplant, or death within 1 year, driven primarily by assessments of inactivity and exhaustion. Focus on these patient-reported measures may better inform clinical trajectories in this population., (Copyright © 2021. Published by Elsevier Inc.)

Background: Perinatal HIV and antiretroviral therapy exposure may influence neurocognitive outcomes, although evidence is mixed and most studies are limited to outcomes in the first 24 months. We compared neurocognitive outcomes in school-aged children who were HIV exposed uninfected (CHEU) with those in children who were HIV unexposed uninfected (CHUU)., Setting: Children were recruited from a health center in Nairobi, Kenya., Methods: Key inclusion criteria were children aged 5-12 years and confirmed child and maternal HIV status; for CHEU, mothers reported knowing HIV-positive status before or at delivery of the index child. Children underwent a detailed battery of neuropsychological tests and behavioral assessment, and comparisons of scores between CHEU and CHUU were conducted using linear regression., Results: Among 56 CHEU and 65 CHUU, the median age and sex distributions were 6.8 and 7.0 years (P = 0.8) and 48% and 60% girls (P = 0.2), respectively. In analyses adjusted for child's age and sex and caregiver's age, education, and household rent, CHEU had significantly lower mean z scores for global cognitive ability than CHUU [-0.35, 95% confidence interval (CI): -0.64 to -0.05; P = 0.02], short-term memory (-0.44, 95% CI: -0.76 to -0.12; P = 0.008), delayed memory (-0.43, 95% CI: -0.79 to -0.08; P = 0.02), attention (-0.41, 95% CI: -0.78 to -0.05; P = 0.03), and processing speed (-0.76, 95% CI: -1.37 to -0.16; P = 0.01). Models adjusted for child nutritional status, household food security, and orphanhood yielded similar results., Conclusions: Children exposed to HIV had poorer long-term neurocognitive outcomes than CHUU. These data suggest that long-term studies of neurocognitive and educational attainment in CHEU are warranted., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: With the growing population of HIV-exposed uninfected (HEU) children globally, it is important to determine population-level growth differences between HEU and HIV-unexposed uninfected (HUU) children., Methods: We analyzed data from a population-level survey enrolling mother-infant pairs attending 6-week and 9-month immunizations in 140 clinics across Kenya. Weight-for-age (WAZ), length-for-age (LAZ), head circumference-for-age (HCAZ) z-scores and underweight (WAZ < -2), stunting (LAZ < -2), and microcephaly (HCAZ < -2), were compared between HEU and HUU. Correlates of growth faltering and poor growth were assessed using generalized Poisson and linear regression models., Results: Among 2457 infants, 456 (19%) were HEU. Among mothers living with HIV, 64% received antiretroviral therapy (ART) and 22% were on antiretroviral prophylaxis during pregnancy. At 9 months, 72% of HEU and 98% of HUU were breastfeeding. At 6 weeks, HEU had lower mean WAZ (-0.41 vs. -0.09; P < 0.001) and LAZ (-0.99 vs. -0.31; P = 0.001) than HUU. Stunting was higher in HEU than HUU at 6 weeks (34% vs. 18%, P < 0.001) and 9 months (20% vs. 10%, P < 0.001). In multivariable analyses, HEU had lower mean LAZ at 6 weeks (-0.67, 95% confidence interval [CI]: -1.07, -0.26) and 9 months (-0.57, 95% CI: -0.92, -0.21) and HEU had higher stunting prevalence (week-6 adjusted prevalence ratio [aPR]: 1.88, 95% CI: 1.35, 2.63; month-9 aPR: 2.10, 95% CI: 1.41, 3.13). HEU had lower mean head circumference (-0.49, 95% CI: -0.91, -0.07) and higher prevalence of microcephaly (aPR: 2.21, 95% CI: 1.11, 4.41) at 9 months., Conclusion: Despite high maternal ART coverage, HEU had poorer growth than HUU in this large population-level comparison. Optimizing breastfeeding practices in HEU may be useful to improve growth., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Patients with ambulatory advanced heart failure (HF) are increasingly considered for durable mechanical circulatory support (MCS) and heart transplantation and their effective triage requires careful assessment of the clinical trajectory., Methods: REVIVAL, a prospective, observational study, enrolled 400 ambulatory advanced HF patients from 21 MCS/transplant centers in 2015-2016. Study design included a clinical re-assessment of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile within 120 days after enrollment. The prognostic impact of a worsening INTERMACS Profile assigned by the treating physician was assessed at 1 year after the Early Relook., Results: Early Relook was done in 325 of 400 patients (81%), of whom 24% had a worsened INTERMACS Profile, associated with longer HF history and worse baseline INTERMACS profile, but no difference in baseline LVEF (median 0.20), 6-minute walk, quality of life, or other baseline parameters. Early worsening predicted higher rate of the combined primary endpoint of death, urgent MCS, or urgent transplant by 1 year after Early Relook, (28% vs 15%), with hazard ratio 2.2 (95% CI 1.2- 3.8; p = .006) even after adjusting for baseline INTERMACS Profile and Seattle HF Model score. Deterioration to urgent MCS occurred in 14% vs 5% (p = .006) during the year after Early Relook., Conclusions: Early Relook identifies worsening of INTERMACS Profile in a significant population of ambulatory advanced HF, who had worse outcomes over the subsequent year. Early reassessment of ambulatory advanced HF patients should be performed to better define the trajectory of illness and inform triage to advanced therapies., Competing Interests: Disclosure P.S. reports the following grant support: American Heart Association/Enduring Hearts Scientist Development Grant, Merck, Haemonetrics, and Medtronic. Consulting: NuPulse CV and Ortho Clinical Diagnostics. K.D.A. reports the following related to the submitted work: the National Institutes of Health/National Heart, Lung, and Blood Institute (contract) and outside the submitted work: Medtronic (research support and consultant [Independent Physician Quality Panel member]), Abbott (research support), Procyrion (consultant), NuPulseCV (consultant), Bioventrix (research support). M.K., A.V.A., S.P., J.T., N.A.G., G.A.E., J.S., M.P., J.D.E., J.T.B., W.T.P., T.M.C., N.J., L.W.S., D.L.M., G.C.S., M.Y., B.R., and S.K have no conflicts of interest to disclose., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)