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Background: Reduced bone mineral mass by dual x-ray absorptiometry is reported in children living with HIV (CLWH), but few studies of bone microarchitecture, particularly in sub-Saharan Africa, have been conducted. Here, we compare bone architecture and strength in black South African CLWH and uninfected control children by peripheral quantitative computed tomography (pQCT). Setting and Methods: One hundred seventy-two CLWH on antiretroviral therapy (ART) and 98 controls in the CHANGES Bone Study in Johannesburg, South Africa received pQCT scans of the radius and tibia. Measurements included trabecular and cortical volumetric bone mineral density (vBMD) and bone strength, estimated by the polar strength strain index (SSI), a validated measure of fracture risk. Results: CLWH (51% boys) and controls (63% boys) were an average of age 10.4 years. Mean ART duration for CLWH was 9.5 years, with 70.9% on an efavirenz-based, 28.5% on a lopinavir/ritonavir-based, and 1 child on an atazanavir/ritonavir-based regimen. Male CLWH had lower trabecular vBMD at the radius than controls after adjustment for age, radial length, and Tanner stage (β = -17.3, standard error = 7.2, P = 0.018). Bone strength by polar SSI was lower in CLWH than controls (778 vs. 972 mm³, P < 0.01). CLWH on an LPV/r-based regimen had lower trabecular vBMD (199 vs. 222 mg/cm³, P < 0.001) and cortical vBMD (1074 vs. 1093 mg/cm³, P = 0.004) than those on an efavirenz-based regimen. No difference in bone strength by polar SSI was observed between treatment groups. Conclusion: CLWH initiated on ART early in life with wellcontrolled HIV have deficits in bone architecture and reductions in bone strength as detected by pQCT. [ABSTRACT FROM AUTHOR]

Background: Younger age at antiretroviral therapy (ART) initiation has been associated with smaller HIV reservoirs. We investigated whether younger age of ART initiation is associated with testing negative and weaker signal on a standard HIV diagnostic test in treated children. Methods: At exit from a longitudinal study at 2 sites in Johannesburg, South Africa, 316 school-aged, HIV-infected children on continuous ART started at a median age of 6.3 months, were tested with standard total nucleic acid PCR used for infant diagnosis. All negative results were repeated. Simultaneous viral load (VL) and CD4+ T-cell counts/percentages, along with data collected over the prior 4 years, were used in multivariable regression to predict negative PCR results and higher cycle threshold (Ct) values (weaker signal). Results: Seven children (2.2%, 95% confidence interval: 0.6 to 3.8) in the full cohort had negative PCR results; all 7 were in a subset of 102 (6.9%, 95% confidence interval: 2.0 to 11.8) who had initiated ART at age 0-4 months and had VL,50 copies/mL at the time of PCR testing. Only one repeat tested as negative. Younger age at ART initiation, VL <50 copies/mL at time of test, sustained VL,400 copies/mL, lower CD4+ T-cell counts, and ever treated with efavirenz were significant predictors of weaker signal on the diagnostic test. Conclusions: In a small proportion of children who start ART in the first months of life and remain on continuous therapy, standard diagnostic HIV PCR tests may result as negative. Repeat testing may resolve uncertainty of diagnosis. [ABSTRACT FROM AUTHOR]

Highlights • EID CAP/CTM and Xpert Ct values strongly predict plasma RNA viral load. • EID Ct value can identify HIV-infected infants at highest risk of advanced disease. • Almost 20% of HIV-infected infants at birth had an HIV viral load <3.0 log 10 cps/ml. • Negative plasma RNA cannot exclude HIV-infection among infants exposed to ARVs. Abstract Background HIV-1 viral load (VL) has been found to be an independent predictor for disease progression among untreated HIV-infected children. However, qualitative polymerase chain reaction (PCR) assays are routinely used for early infant diagnosis (EID). Objectives To predict HIV-1 VL at birth using qualitative EID real-time PCR cycle-threshold (Ct) values. Study design This study was a secondary analysis of results from a cohort of intrauterine HIV-1 infected neonates. Neonates were enrolled at Rahima Moosa Mother & Child Hospital in Johannesburg, South Africa between June 2014 and November 2017. Laboratory EID HIV-1 PCR testing was performed at birth using COBAS AmpliPrep/COBAS TaqMan HIV-1 Qualitative Test v2.0 (EID CAP/CTM). Some infants had simultaneous EID point-of-care (POC) testing using Xpert HIV-1 Qualitative assay (EID Xpert). Neonates with a confirmed HIV-1 detected EID result and plasma HIV-1 RNA VL test were included in this analysis. Bland-Altman analysis was used to determine extent of agreement between Ct values of both EID assays. Multivariable linear regression models adjusting for time between EID and VL testing were used to describe the association between EID Ct values and VL and to predict VL at given EID Ct values. Results Among 107 HIV-1 infected neonates included in the study, 59 had POC EID testing. Median VL was 28 400 copies per millilitre (cps/ml) (IQR: 1 918-218 358) - two neonates had VL < 100 cps/ml prior to antiretroviral therapy initiation. There was good correlation between Ct values of both EID assays (Spearman correlation coefficient 0.9, 95% CI: 0.8–1.0). The limits of agreement between EID CAP/CTM and Xpert Ct values were 4–11 cycles. For every one cycle increase in Ct value there was 0.3 log 10 RNA decrease (95% CI: −0.3 to −0.2) for both EID assays. An EID CAP/CTM Ct value ≤ 23 and an EID Xpert Ct value ≤ 31 predicted a VL of > 5.0 log 10 cps/ml in 82.2% (95% CI: 73.9–88.3) and 84.7% (95% CI: 73.7–91.8) of cases, respectively. Conclusion EID Ct values at birth predict VL and accurately identify infants with VL > 5.0 log 10 cps/ml. [ABSTRACT FROM AUTHOR]

Relapse is a major challenge in treating opioid addiction, including oxycodone. During abstinence, oxycodone seeking progressively increases, a phenomenon termed incubation of oxycodone craving. We previously demonstrated a causal role of orbitofrontal cortex (OFC) in this incubation. Here, we studied the interaction between glutamatergic projections from OFC and dopamine 1-family receptor (D1R) signaling in dorsal striatum (DS) in this incubation in male rats. We first examined the causal role of D1R signalling in DS in incubated oxycodone seeking. Next, we combined fluorescence-conjugated cholera toxin subunit B (CTb-555, a retrograde tracer) with Fos (a neuronal activity marker) to assess whether the activation of OFC→DS projections was associated with incubated oxycodone seeking. We then used a pharmacological asymmetrical disconnection procedure to examine the role of the interaction between projections from OFC and D1R signalling in DS in incubated oxycodone seeking. We also tested the effect of unilateral pharmacological inactivation of OFC or unilateral D1R blockade of DS on incubated oxycodone seeking. Finally, we assessed whether contralateral disconnection of OFC→DS projections impacted non-incubated oxycodone seeking on abstinence day 1. We found that D1R blockade in DS decreased incubated oxycodone seeking and OFC→DS projections were activated during incubated oxycodone seeking. Moreover, anatomical disconnection of OFC→DS projections, but not unilateral inactivation of OFC or unilateral D1R blockade in DS, decreased incubated oxycodone seeking. Lastly, contralateral disconnection of OFC→DS projections had no effect on oxycodone seeking on abstinence day 1. Together, these results demonstrated a causal role of OFC→DS projections in incubation of oxycodone craving., (© 2024 The Author(s). Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Objective: To investigate the role of early antiretroviral therapy (ART) on growth trajectories of infants with human immunodeficiency virus (IHIV) in the first year of life., Study Design: As part of a clinical trial of early ART in Johannesburg, South Africa (2015-2018), 116 IHIV diagnosed within 48 hours of birth were started on ART as soon as possible, and 80 uninfected infants born to mothers living with HIV (IHEU) were enrolled. Both groups were followed prospectively from birth through 48 weeks and growth parameters collected. The groups were compared and risk factors for poor growth investigated, in the full cohort and among IHIV separately., Results: IHIV had lower mean weight-for-age Z-scores (WAZ) than IHEU at 4 and 8 weeks (-1.17 [SE:0.14] vs -0.72 [0.14], P = .035 and -1.23 [0.15] vs -0.67 [0.14], P = .012). Although there was some closing of the gap over time, means remained lower in IHIV through 48 weeks. In length-for-age Z-scores (LAZ), differences widened over time and IHIV had lower Z-scores by 48 weeks (-1.41 [0.15] vs -0.80 [0.18], P = .011). Deficits in WAZ and LAZ in IHIV vs IHEU were most marked among girls. IHIV with pre-ART viral load ≥1000 copies/ml had significantly lower weight-for-length and mid-upper arm circumference Z-scores across all time points through 48 weeks., Conclusions: IHIV on early ART had deficits in WAZ over the first 8 weeks of life and lower LAZ at 48 weeks than IHEU. Among IHIV, higher pre-ART viral load was associated with worse anthropometric indicators through 48 weeks., Competing Interests: Declaration of Competing Interest Funding: The Latency and Early Neonatal Provision of Antiretroviral Drugs (LEOPARD) study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institute of Allergy and Infectious Disease, National Institutes of Health (U01HD080441), the South African National HIV Programme, and South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa (84177)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Develop, implement, and monitor for adverse effects of, a novel hemoperfusion therapy in adult horses., Methods: A prospective, observational feasibility study using three healthy adult horses from the North Carolina State University teaching herd. Health status was determined by physical exam, complete blood count, coagulation panel, and serum biochemistry. Each horse was instrumented with a 14 Fr × 25 cm double-lumen temporary hemodialysis catheter and underwent a 240 min polymer-based hemoperfusion session. Horses were administered unfractionated heparin to maintain anti-coagulation during the session. Given the novelty of this therapy in horses, each horse was treated as a learning opportunity that informed an iterative process of protocol development and modification., Measurements and Main Results: Our long-term goal is to investigate potential clinical applications of hemoperfusion in horses, including cytokine reduction in horses with severe SIRS/sepsis. Horses were monitored for changes in clinical exam, biochemistry and hematology parameters. Additionally, cytokines were quantified to determine whether extracorporeal hemadsorption therapy alone caused an inflammatory response. Our results show that hemoperfusion therapy was associated with decreased platelet counts and serum albumin concentration. There was no significant change in plasma cytokine concentrations with hemoperfusion therapy. In one horse, the cytokine concentrations decreased, as previously reported with hemoperfusion therapy in humans., Hypothesis: We hypothesized that hemoperfusion therapy could be performed in healthy adult horses without significant adverse effects., Conclusion: Polymer-based hemoperfusion is a feasible extracorporeal therapy (ECT) modality for adult horses. Additional studies are needed to further establish clinical protocols, as well as establish efficacy of polymer-based hemoperfusion for treatment of various conditions in horses, including intoxications, immune-mediated conditions, and sepsis., 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., (Copyright © 2024 Hobbs, Le Sueur, Burke, Cooper, Sheats and Ueda.)

Objective: Plasma cytokine adsorption has shown benefit as an adjunctive therapy in human sepsis but has yet to be investigated in horses. We hypothesized that ex vivo filtration of equine plasma with a novel cytokine adsorption device would significantly reduce concentrations of lipopolysaccharide-stimulated cytokines. We also hypothesized that the device would adsorb medications commonly used to treat sepsis., Animals: 8 horses owned by North Carolina State University., Methods: Four liters of heparinized whole blood was collected from healthy adult horses (n = 8) and stimulated with lipopolysaccharide (100 ng/mL) for 6 hours (37 °C.) from June 4, 2023, to December 15, 2023. Plasma was filtered through a cytokine adsorption device or sham circuit. Samples were collected at 11 time points for multiplex cytokine analysis. Chemistry analysis was performed before and after filtration. To investigate the impact of the device on medication concentrations, equine plasma containing potassium penicillin, gentamicin, and flunixin meglumine was filtered through the cytokine adsorption device or sham for 6 hours. Drug concentrations before and after filtration were determined by ultra-high-performance liquid chromatography. Prefiltration versus postfiltration sample concentrations were analyzed by Student paired t test using GraphPad Prism 9.0 (P < .05)., Results: Filtration of lipopolysaccharide-stimulated equine plasma (n = 8) for 6 hours resulted in significant mean reductions in the cytokines IL-10, IL-5, IL-8, tumor necrosis factor-α (TNF-α), and IL-1β, as well as albumin. Drug concentrations of potassium penicillin, gentamicin, and flunixin meglumine were also significantly reduced by filtration., Clinical Relevance: This work provides proof of concept for further investigation of extracorporeal cytokine adsorption as a potential adjunct treatment for equine sepsis.

Relapse to oxycodone seeking progressively increases after abstinence in rats, a phenomenon termed incubation of oxycodone craving. We have previously shown that the orbitofrontal cortex (OFC) plays a critical role in incubation of oxycodone craving in male rats. Here, we examined the effect of oestrous cycle on incubated oxycodone seeking in female rats, and whether the critical role of OFC in incubated oxycodone seeking generalizes to female rats. We first assessed oxycodone self-administration and incubated oxycodone seeking on abstinence day 15 across the oestrous cycle. Next, we determined the effect of chemogenetic inactivation of OFC by JHU37160 (J60), a novel agonist for Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), on incubated oxycodone seeking on abstinence day 15. Finally, we determined the effect of J60 alone on incubated oxycodone seeking on abstinence day 15. We found no difference in oxycodone intake across oestrus, pro-oestrus, and metoestrus stages during oxycodone self-administration training. Incubated oxycodone seeking was also similar between nonoestrus and oestrus female rats. Moreover, chemogenetic inactivation of OFC by J60 decreased incubated oxycodone seeking on abstinence day 15, while J60 alone had no effect on incubated oxycodone seeking in no-DREADD control rats. Taken together, results here show that the oestrous cycle has no effect on oxycodone intake and incubated oxycodone seeking in female rats under our experimental conditions. Furthermore, consistent with our previous findings in male rats, results here show that OFC also plays a critical role in incubated oxycodone seeking in female rats., (© 2023 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Allergic disease is on the rise. Waitlists for specialists are long, and many referred patients have already received prior allergic assessment, either by a certified Allergist, Primary Care Provider, or other Specialist. It is important to understand the prevalence and motivating factors for multiple-opinion referrals, to deliver timely assessment for patients with allergic disease., Methods: A retrospective chart review of demographic information, number of previous consultations, and motivation for new consults and multiple-opinion referrals, of pediatric patients aged 8 months-17 years to BC Children's Hospital Allergy Clinic from September 1, 2016-August 31, 2017, was performed. Referral data including reason for referral or multiple-opinion, primary allergic concerns, and others, from referral forms and consult notes were accessed through local Electronic Medical Records and subsequently analyzed for trends in categorical variables to assess the rationale for and impact of multiple-opinion referrals to our clinic., Results: Of 1029 new referrals received, 210 (20.4%) were multiple-opinion referrals. Food allergy was the predominant allergic concern prompting further opinion (75.7%). The main rationale for seeking further opinions was wanting an assessment by a certified allergist in cases where prior consultation was performed by non-allergist specialist, primary care provider, or alternative health care provider. Of second-opinion referrals generated, 70 (33.3%) initial consultations were performed by an Allergist, whereas 140 (66.7%) were performed by a non-allergist., Conclusions: Many new consults at the BCCH Allergy Clinic are multiple-opinion assessments, contributing to long waitlists. Advocacy at the systems level through standardized referral guidelines, centralized triaging systems, and stronger support for Primary Care Providers is needed to provide better access in Canada for children needing a specialized Allergist. Trial registration UBC/BCCH Research Ethics Board., (© 2023. The Author(s).)

Objective: The objective of this study was to compare the occurrence of post-operative complications and survival to discharge in horses with ileal impactions resolved by manual decompression compared with jejunal enterotomy., Animals: A total of 121 client-owned horses undergoing surgical correction of an ileal impaction at three teaching hospitals., Materials and Methods: Data from the medical records of horses undergoing surgical correction of an ileal impaction was retrospectively collected. Post-operative complications, survival to discharge, or post-operative reflux present were evaluated as dependent variables and pre-operative PCV, surgery duration, pre-operative reflux, and type of surgery were evaluated as independent variables. Type of surgery was divided into manual decompression ( n  = 88) and jejunal enterotomy ( n  = 33)., Results: There were no significant differences in development of minor complications, development of major complications, presence of post-operative reflux, amount of post-operative reflux, and survival to discharge between horses that were treated with manual decompression and those treated with distal jejunal enterotomy. Pre-operative PCV and surgery duration were significant predictors of survival to discharge., Conclusions and Clinical Relevance: This study showed that there are no significant differences in post-operative complications and survival to discharge in horses undergoing distal jejunal enterotomy versus manual decompression for correction of ileal impaction. Pre-operative PCV and duration of surgery were found to be the only predictive factors of survival to discharge. Based on these findings, distal jejunal enterotomy should be considered earlier in horses with moderate to severe ileal impactions identified at surgery., 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., (Copyright © 2023 Ruff, Zetterstrom, Boone, Hofmeister, Smith, Epstein, Blikslager, Fogle and Burke.)

Disclosure to children living with HIV (CLHIV) about their own status is associated with positive outcomes such as treatment adherence, but prior cross-sectional studies in sub-Saharan Africa report disclosure rates of <50%. This study aims to assess pediatric disclosure over time. 548 CLHIV were followed from 2/2013-4/2018 in Johannesburg, South Africa. Cumulative incidence of disclosure was calculated with Kaplan-Meier analysis, and disclosure characteristics assessed with a Cox model. By end of follow-up, cumulative disclosure was 70.3% (95% confidence interval: 60.0-79.9). Median age at disclosure was 9 years (range: 3-13). Baseline predictors of disclosure included older child age and the child having a history of going hungry. Prior to disclosure, 98.0% of caregivers who disclosed had conversed with their child about their illness or an HIV-related topic, or their child had asked about HIV, versus 88.6% of caregivers who never disclosed. While many children did not receive disclosure during this relatively large, longitudinal study of South African CLHIV, caregivers who had not yet disclosed may have been preparing to do so by discussing their child's health or HIV generally with their child. This highlights the need for clinicians to consistently support caregivers throughout the incremental disclosure process.

Background: SARS-CoV-2 infection in pregnant women has been associated with severe illness in the women and higher rates of premature delivery. There is, however, paucity of data on the impact of the timing of SARS-CoV-2 infection and on symptomatic or asymptomatic infections on birth outcomes. Data from low-middle income settings is also lacking., Methods: We conducted a longitudinal study from April 2020 to March 2021, in South Africa, where symptomatic or asymptomatic pregnant women were investigated for SARS-CoV-2 infection during the antepartum period. We aimed to evaluate if there was an association between antepartum SARS-CoV-2 infection on birth outcomes. SARS-CoV-2 infection was investigated by nucleic acid amplification test (NAAT), histological examination was performed in a sub-set of placentas., Results: Overall, 793 women were tested for SARS-CoV-2 antenatally, including 275 (35%) who were symptomatic. SARS-CoV-2 infection was identified in 138 (17%) women, of whom 119 had symptoms (COVID-19 group) and 19 were asymptomatic. The 493 women who were asymptomatic and had a negative SARS-CoV-2 NAAT were used as the referent comparator group for outcomes evaluation. Women with COVID-19 compared with the referent group were 1.66-times (95% confidence interval (CI) = 1.02-2.71) more likely to have a low-birthweight newborn (30% vs 21%) and 3.25-times more likely to deliver a very low-birthweight newborn (5% vs 2%). Similar results for low-birthweight were obtained comparing women with SARS-CoV-2 confirmed infection (30%) with those who had a negative NAAT result (22%) independent of symptoms presentation. The placentas from women with antenatal SARS-CoV-2 infection had higher percentage of chorangiosis (odds ratio (OR) = 3.40, 95% CI = 1.18-.84), while maternal vascular malperfusion was more frequently identified in women who tested negative for SARS-CoV-2 (aOR = 0.28, 95% CI = 0.09-0.89)., Conclusions: Our study demonstrates that in a setting with high HIV infection prevalence and other comorbidities antenatal SARS-CoV-2 infection was associated with low-birthweight delivery., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form. MCN reports grants to her institution from the Bill & Melinda Gates Foundation, European & Developing Countries Clinical Trials Partnership, Pfizer, AstraZeneca and Sanofi. Personal honoraria received from Pfizer and Sanofi unrelated to the manuscript. SAM reports grants to his institution related to COVID-19 epidemiology and vaccine studies from the Bill & Melinda Gates Foundation, South African Medical Research Council, Novavax, Pfizer, Gritstone (PATH), Providence, Johnson and Johnson, AstraZeneca and European & Developing Countries Clinical Trials Partnership. Additional non-COVID-19 grants to the institution also received from GSK and Minervax. Personal honoraria received from Bill & Melinda Gates Foundation unrelated to the manuscript. Other authors disclose no relevant interests., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

Objective: Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection during pregnancy has been associated with poor pregnancy outcomes. There is, however, not much information on the impact of the timing of SARS-CoV-2 infection on pregnancy outcomes, and studies from low-middle income settings are also scarce., Study Design: We conducted a cross-sectional study from April to December 2020, in South Africa, to assess the association of SARS-CoV-2 infection on a nasal swab at the time of labor with fetal death, preterm birth, low birth weight, or pregnancy-induced complications. When possible, maternal blood, cord blood, and placenta were collected. SARS-CoV-2 infection was investigated by a nucleic acid amplification test (NAAT)., Results: Overall, 3,117 women were tested for SARS-CoV-2 on a nasal swab, including 1,562 (50%) healthy women with uncomplicated term delivery. A positive NAAT was detected among 132 (4%) women. Adverse birth outcomes or pregnancy-related complications were not associated with SARS-CoV-2 infection at the time of labor. Among SARS-CoV-2-infected women, an NAAT-positive result was also obtained from 6 out of 98 (6%) maternal blood samples, 8 out of 93 (9%) cord-blood samples, 14 out of 54 (26%) placentas, and 3 out of 22 (14%) nasopharyngeal swabs from newborns collected within 72 hours of birth. Histological assessment of placental tissue revealed that women with SARS-CoV-2 nasal infection had a higher odds (3.82, 95% confidence interval: 1.20, 12.19) of chronic chorioamnionitis compared with those without SARS-CoV-2 infection., Conclusion: Our study demonstrates that intrapartum, SARS-CoV-2 infection was not associated with evaluated poor outcomes. In utero fetal and placental infections and possible vertical and/or horizontal viral transfer to the newborn were detected among women with nasal SARS-CoV-2 infection., Key Points: · Intrapartum SARS-CoV-2 infection was not associated with evaluated poor outcomes.. · In utero fetal and placental infections were detected among women with nasal SARS-CoV-2 infection.. · Women with SARS-CoV-2 nasal infection had a higher odds of chronic chorioamnionitis.., Competing Interests: None declared., (Thieme. All rights reserved.)

Rationale and Objective: Deprivation of social interaction promotes social reward seeking in rodents, assessed primarily by the conditioned place preference procedure. Here, we used an operant social procedure in rats and examined the effect of the housing condition (pair-housing vs. single-housing) during or after social self-administration on social reward seeking., Methods: We first trained paired-housed or single-housed rats to gain access to an age- and sex-matched novel peer. On post-training day 1 (PTD1), we tested both groups for social seeking without the presence of the novel peer. Next, we divided each group into pair-housing or single-housing conditions and tested all four groups (pair-pair, pair-single, single-pair, and single-single) for social seeking on post-training day 12 (PTD12). Finally, we analyzed Fos expression in the striatum associated with social seeking on PTD12., Result: Single-housed rats earned more social rewards during social self-administration than pair-housed rats. Social isolation during social self-administration also promoted social seeking on PTD1 and PTD12, regardless of their housing conditions after social self-administration training. Additionally, in pair-housed rats, social isolation during the post-training period led to a time-dependent increase of social seeking on PTD12 compared with PTD1. Finally, the Fos analyses revealed an increase of Fos expression in NAc shell of single-single rats after social seeking test on PTD12 compared with pair-pair rats., Conclusion: Our data suggest that social isolation promotes operant social self-administration and social seeking. In addition, neuronal activation of NAc shell is associated with social seeking after social isolation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In pregnant women, antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein cross the placenta and can be detected in cord-blood at the time of delivery. We measured SARS-CoV-2 full-length antispike IgG in blood samples collected from women living with HIV (WLWHIV) and without HIV when presenting for labour, and from paired cord-blood samples. Antispike IgG was measured in maternal blood at delivery on the Luminex platform. Cord-blood samples from newborns of women in with detectable antispike IgG were analysed. The IgG geometric mean concentrations (GMCs) and the percentage of cord-blood samples with detectable antispike IgG were compared between WLWHIV and without HIV. A total of 184 maternal and cord-blood pairs were analysed, including 47 WLWHIV and 137 without HIV. There was no difference in antispike GMCs between WLWHIV and without HIV [157 binding antibody units (BAU)/ml vs. 187 BAU/ml; P  = 0.17)]. Cord-blood samples from newborns of WLWHIV had lower GMCs compared with those without HIV (143 vs. 205 BAU/ml; P  = 0.033). Cord-to-maternal blood antibody ratio was 1.0 and similar between the two HIV groups. In WLWHIV, those who were 30 years old or less had lower cord-to-maternal blood antibody ratio (0.75 vs. 1.10; P  = 0.037) and their newborns had lower cord-blood GMCs (94 vs. 194 BAU/ml; P  = 0.04) compared with the older women. Independently of maternal HIV infection status, there was efficient transplacental transfer of antispike antibodies. The GMCs in cord-blood from newborns of WLWHIV were lower than those in HIV-unexposed newborns., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We evaluated longitudinal trends and associations between bone mass, bone turnover and inflammatory markers among South African children living with HIV (CLHIV) and controls., Design: We previously reported decreased bone mass among CLHIV independent of marked inflammation and increased bone turnover. The goal of this study was to evaluate longitudinal changes in bone mass, bone turnover and inflammation over 2 years., Methods: Longitudinal analyses were conducted among 220 CLHIV and 220 controls. Anthropometric measurements, physical activity, antiretroviral regimen, virologic and immunologic status, whole body (WB) and lumbar spine (LS) bone mineral content (BMC) and bone mineral density (BMD) were collected (enrollment, 12 and 24 months). Bone turnover markers including C-telopeptide of type I collagen (CTx) and procollagen type I N-terminal propeptide (P1NP) and inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble CD14 and high-sensitivity C-reactive protein (hsCRP) were collected at enrollment and 24 months., Results: Compared with controls, CLHIV had significantly lower mean WB-BMC, WB-BMD, WB-BMC z scores, LS-BMC and LS-BMD as well as lower bone formation (P1NP) and resorption (CTx), and higher hsCRP and soluble CD14 over 24 months. CLHIV on efavirenz (EFV) had consistently lower TNF-alpha and IL-6 compared with those on ritonavir-boosted lopinavir (LPV/r) at all time points., Conclusion: Over 2 years of follow-up, South African CLHIV had persistently lower bone mass, bone turnover, and macrophage activation. Lower bone mass and higher pro-inflammatory cytokine profiles were consistently observed among those on LPV/r-based compared with EFV-based regimens., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: With expansion of antiretroviral therapy (ART) programs, transmission rates are low but new infant infections still occur. We investigated predictors of pre-ART viral load (VL) and CD4+ T-cell counts and percentages in infants diagnosed with HIV at birth in a setting with high coverage of maternal ART and infant prophylaxis., Methods: As part of an early treatment study, 97 infants with confirmed HIV-infection were identified at a hospital in Johannesburg, South Africa. Infant VL and CD4+ T-cell parameters were measured before ART initiation. Data were collected on maternal characteristics, including VL, CD4+ T-cell counts and ART, and infant characteristics, including sex, birth weight, and mode of delivery., Results: Pre-ART, median infant VL was 28,405 copies/mL [interquartile range (IQR): 2515-218,150], CD4+ T-cell count 1914 cells/mm (IQR: 1474-2639) and percentage 40.8% (IQR: 32.2-51.2). Most (80.4%) infants were born to mothers who received ART during pregnancy and 97.9% of infants received daily nevirapine prophylaxis until ART initiation at median of 2 days of age (IQR: 1-7). Infant pre-ART VL was more likely to be ≥1000 copies/mL when their mothers had VL ≥1000 copies/mL [Odds Ratio (OR): 6.88, 95% confidence interval (CI): 2.32-20.41] and was higher in boys than girls (OR: 3.29, 95% CI: 1.07-9.95). Lower maternal CD4+ T-cell count (<350 cells/mm) was associated with lower infant CD4+ T-cell count (<1500 cells/mm) (OR: 3.59, 95% CI: 1.24-10.43)., Conclusions: Pre-ART VL and CD4+ T-cell parameters of intrauterine-infected infants were associated with VL and CD4+ T-cell counts of their mothers. Maternal ART during pregnancy may begin treatment of intrauterine infection and may mask the severity of disease in infected infants identified in the current era with high-maternal ART coverage.

Objectives: Children with HIV (CHIV) have lifetime exposure to antiretrovirals (ART); therefore, optimizing their regimens to have the least impact on fat redistribution is a priority., Methods: This is a cross-sectional study of 219 perinatally infected CHIV and 219 HIV-uninfected controls from similar socioeconomic backgrounds in Johannesburg, South Africa. We compared total body and regional fat distribution in CHIV on suppressive ART regimens with controls and, among CHIV, between ritonavir-boosted lopinavir (LPV/r)-based and efavirenz (EFV)-based regimens., Results: The mean age of the 219 uninfected children (45% girls) and the 219 CHIV (48% girls) was 7.0 and 6.4 years, respectively. CHIV had lower adjusted total body fat (P = 0.005) and lower percentage fat at the trunk (P = 0.020), arms (P = 0.001), and legs (P < 0.001) than uninfected children. CHIV on LPV/r had similar body composition as those on EFV, except for arm fat mass (P = 0.030). When stratified by sex, girls with HIV on LPV/r had lower adjusted total (P = 0.007), trunk (P = 0.002), arms (P = 0.008), legs (P = 0.048) fat mass; trunk-to-total body fat (P = 0.044); and higher legs-to-total body fat (P = 0.011) than those on EFV., Conclusions: South African CHIV receiving ART had lower global and partial fat mass and percentage fat than healthy controls. In girls with HIV with sustained virologic suppression on ART, switching from LPV/r to EFV could attenuate fat mass loss, indicating that EFV-based regimen may be a better option in this group of individuals., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.

Purpose of Review: Postmastectomy pain syndrome (PMPS) remains poorly defined, although it is applied to chronic neuropathic pain following surgical procedures of the breast, including mastectomy and lumpectomy in breast-conserving surgery. It is characterized by persistent pain affecting the anterior thorax, axilla, and/or medial upper arm following mastectomy or lumpectomy. Though the onset of pain is most likely to occur after surgery, there may also be a new onset of symptoms following adjuvant therapy, including chemotherapy or radiation therapy., Recent Findings: The underlying pathophysiology is likely multifactorial, although exact mechanisms have yet to be elucidated. In this regard, neuralgia of the intercostobrachial nerve is currently implicated as the most common cause of PMPS. Numerous pharmacological options are available in the treatment of PMPS, including gabapentinoids, tricyclic antidepressants, selective serotonin reuptake inhibitors, NMDA receptor antagonists, and nefopam (a non-opioid, non-steroidal benzoxazocine analgesic). Minimally invasive interventional treatment including injection therapy, regional anesthesia, botulinum toxin, and neuromodulation has been demonstrated to have some beneficial effect. A comprehensive update highlighting current perspectives on the treatment of postmastectomy pain syndrome is presented with emphasis on treatments currently available and newer therapeutics currently being evaluated to alleviate this complex and multifactorial condition.

Background: Prompt initiation of antiretroviral therapy (ART) for HIV-infected infants is strongly recommended but diagnostic confirmation is important as committing children to life-long ART carries serious health and social implications., Methods: Two HIV-exposed infants in Johannesburg, South Africa were identified presenting with unusual trajectories of diagnostic nucleic acid amplification tests (NAAT) and viral load results., Results: Case 1 had repeat indeterminate NAAT results during the first 3 weeks of life; repeat testing thereafter was negative with undetectable viral load including after daily nevirapine prophylaxis ended. ART was not initiated at this time. Case 2 had a single positive NAAT result at 1 month of age that prompted initiation of ART. Subsequent results were negative and ART was discontinued. Repeat negative NAAT with viral load below the limit of quantification or undetectable continued to be obtained. Shortly after and around weaning, positive NAAT results with high viral load (7.1 and 6.03 log10 copies/ml for Cases 1 and 2, respectively) were observed in both children. Both mothers were treated with tenofovir, emtricitabine and efavirenz during breastfeeding. Testing with ultrasensitive assays on early samples conclusively revealed HIV-1 proviral DNA in Case 1. Testing with ultrasensitive assays after the early period but prior to weaning did not detect HIV in either infant., Conclusion: We hypothesize that breast milk from the mothers of these two rare cases had HIV-specific or nonspecific factors that led to the undetectable results in already infected infants until breastfeeding ended. Our results raise the importance of repeat testing of HIV-exposed breast-fed infants after complete cessation of all breastfeeding.

The current study focuses on the short-term effect of MARIO, a social robot, on quality of life, depression, and perceived social support in persons with dementia (PWD) and evaluates their acceptability of MARIO. Ten PWD in one nursing home took part in a 4-week pilot study, where each participant had up to 12 sessions with MARIO. Sessions comprised engagement in music, news, reminiscence, games, and calendar applications. Standardized questionnaires were administered before and after the 4-week period. Participants had a sustained interest in MARIO during their interactions and an acceptance of MARIO's appearance, sound, and applications. Consequently, participants spent more time socially engaged. No statistically significant differences were found in quality of life, depression, and perceived social support. PWD can engage with a social robot in a real-world nursing home. Future research should incorporate a larger sample and longer intervention period. [Journal of Gerontological Nursing, 45(7), 36-45.]., (Copyright 2019, SLACK Incorporated.)

Background: Initiation of antiretroviral therapy (ART) following diagnosis of HIV infection at birth is an emerging area of paediatric HIV care. We present outcomes of HIV-infected infants identified at birth at Rahima Moosa Mother and Child Hospital in Johannesburg, South Africa., Methods: From September, 2013 (era 1), only high-risk HIV-exposed infants were offered diagnostic HIV PCR tests at birth. From June, 2014 (era 2), all HIV-exposed infants were offered laboratory-based diagnostic PCR tests. From October, 2014 (era 3), point of care (POC) diagnostic PCR tests were also done if staff availability allowed. We describe time to ART initiation, mortality, retention in care, and viral suppression among the HIV-infected infants identified across these eras., Findings: We tested 5449 HIV-exposed infants who were born between Sept 1, 2013, and June 30, 2016. 88 neonates with confirmed HIV infection were identified and included in the study, of which 86 (98%) started ART. Median age at ART initiation decreased from 9 days (IQR 6-25) in eras 1 and 2 to 2 days (1-8) in era 3. In era 3, more neonates who were co-tested with POC testing started ART within 48 h of birth (29 [83%] of 35; median 1 day [IQR 1-2]) than infants who were not co-tested (one [4%] of 29; median 6 days [5-10]). The probability of mortality by 12 months across the eras was 14% (95% CI 8-24) and did not differ by era. Of the 72 infants who survived and initiated ART at the site, 56 (78%) were retained at 12 months. Of the 56 infants retained in care, 40 (71%) had a viral load less than 400 copies per mL at 12 months, with no differences between eras (p=0·23)., Interpretation: HIV-infected infants can be identified at birth and ART can be initiated within hours to days. Although most infants in our cohort started ART, mortality remained unacceptably high with suboptimal retention and viral suppression. Reducing mortality and improving retention and viral suppression remain urgent priorities., Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institute of Allergy and Infectious Disease, National Institutes of Health, USAID/PEPfAR, and the South African National HIV Programme., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Evaluate the analgesic properties and pharmacokinetics of transdermal fentanyl patches (TFPs) in goats., Design: Prospective, randomized study., Setting: Preclinical Testing Facility at a University Teaching Hospital., Animals: Thirty-four adult female Boer-cross goats., Interventions: Goats underwent surgery as part of a concurrent orthopedic research study. Twelve hours prior to surgery, each goat received a TFP (target dosage of 2.5 μg/kg/h), or a placebo patch with analgesia provided by buprenorphine (0.01 mg/kg, IM, q 6 h). Patches were removed after 72 hours. Blood was sampled at specified intervals, up to 84 hours following TFP placement. Plasma concentrations of fentanyl (FEN) were determined using liquid chromatography-mass spectrometry. Postoperative pain assessments were performed by two independent blinded observers., Measurements and Main Results: TFPs were applied at a mean (± standard deviation, SD) dose of 2.54 ± 0.36 μg/kg/h. No adverse events occurred. Pain scores between TFP and BUP groups were not significantly different at any time point. Mean plasma FEN concentration (± SD) 2 hours following patch application was 1.06 ± 0.85 ng/mL, and remained above 0.5 ng/mL for 40 hours. Maximum mean plasma FEN concentration (C max ) was 1.84 (ranging from 0.81 to 3.35) ng/mL with average time to maximum concentration (T max ) of 12 hours after patch application., Conclusions: TFP resulted in consistent FEN absorption and plasma concentrations within the human and ovine therapeutic ranges. Pain scores for goats administered TFP were not different than those administered buprenorphine. Ease of administration, duration of analgesia, and decreased dosing frequency make TFPs an attractive option for pain management in goats., (© Veterinary Emergency and Critical Care Society 2017.)

Background: Fetal alcohol spectrum disorder (FASD) is the leading cause of preventable intellectual disabilities in the United States and a significant public health issue., Objectives: The purpose of this study is to evaluate the knowledge and screening practices of pre-clinical medical students and clinical providers on FAS, FASD, and alcohol consumption., Methods: A short survey sent to medical students and residents on the campus of a large medical school and university hospital., Results: On the survey of clinical providers, 38% of respondents stated they always survey pregnant women about their alcohol consumption, 34% stated they always screen patients planning to get pregnant, and 9% screen women of childbearing age. There were a significant percentage of providers who never screen women. When questioned regarding safe amounts of alcohol consumption during pregnancy, 69% of pre-clinical medical students and 67% of clinical providers stated there is no safe amount of alcohol consumption. Clinical providers were much more likely to correctly select the facial features necessary for the diagnosis (p-value < 0.01)., Conclusions: Significant differences exist in the knowledge and screening practices of these different healthcare providers and trainees. Future interventions should seek to improve knowledge on FAS, FASD, and alcohol consumption, in order for practitioners to be more consistent with national guidelines and the Surgeon General recommendations.

Mercury (Hg) stored in vegetation and soils is known to be released to the atmosphere during wildfires, increasing atmospheric stores and altering terrestrial budgets. Increased erosion and transport of sediments is well-documented in burned watersheds, both immediately post-fire and as the watershed recovers; however, understanding post-fire mobilization of soil Hg within burned watersheds remains elusive. The goal of the current study is to better understand the impact of wildfire on soil-bound Hg during the immediate post-fire period as well as during recovery, in order to assess the potential for sediment-driven transport to and within surface waters in burned watersheds. Soils were collected from three southern California watersheds of similar vegetation and soil characteristics that experienced wildfire. Sampling in one of these watersheds was extended for several seasons (1.5 years) in order to investigate temporal changes in soil Hg concentrations. Laboratory analysis included bulk soil total Hg concentrations and total organic carbon of burned and unburned samples. Soils were also fractionated into a subset of grain sizes with analysis of Hg on each fraction. Low Hg concentrations were observed in surface soils immediately post-fire. Accumulation of Hg coincident with moderate vegetative recovery was observed in the burned surface soils 1 year following the fire, and mobilization was also noted during the second winter (rainy) season. Hg concentrations were highest in the fine-grained fraction of unburned soils; however, in the burned soils, the distribution of soil-bound Hg was less influenced by grain size. The accelerated accumulation of Hg observed in the burned soils, along with the elevated risk of erosion, could result in increased delivery of organic- or particulate-bound Hg to surface waters in post-fire systems.