Getting more from heterogeneous HIV-1 surveillance data in a high immigration country: estimation of incidence and undiagnosed population size using multiple biomarkers

BACKGROUND: Most HIV infections originate from individuals who are undiagnosed and unaware of their infection. Estimation of this quantity from surveillance data is hard because there is incomplete knowledge about (i) the time between infection and diagnosis (TI) for the general population, and (ii) the time between immigration and diagnosis for foreign-born persons. METHODS: We developed a new statistical method for estimating the incidence of HIV-1 and the number of undiagnosed people living with HIV (PLHIV), based on dynamic modelling of heterogeneous HIV-1 surveillance data. The methods consist of a Bayesian non-linear mixed effects model using multiple biomarkers to estimate TI of HIV-1-positive individuals, and a novel incidence estimator which distinguishes between endogenous and exogenous infections by modelling explicitly the probability that a foreign-born person was infected either before or after immigration. The incidence estimator allows for direct calculation of the number of undiagnosed persons. The new methodology is illustrated combining heterogeneous surveillance data from Sweden between 2003 and 2015. RESULTS: A leave-one-out cross-validation study showed that the multiple-biomarker model was more accurate than single biomarkers (mean absolute error 1.01 vs ≥1.95). We estimate that 816 [95% credible interval (CI) 775-865] PLHIV were undiagnosed in 2015, representing a proportion of 10.8% (95% CI 10.3-11.4%) of all PLHIV. CONCLUSIONS: The proposed methodology will enhance the utility of standard surveillance data streams and will be useful to monitor progress towards and compliance with the 90-90-90 UNAIDS target

Huntington's disease patient-derived astrocytes display electrophysiological impairments and reduced neuronal support

In Huntington’s disease (HD), while the ubiquitously expressed mutant Huntingtin (mtHTT) protein primarily compromises striatal and cortical neurons, glia also undergo disease-contributing alterations. Existing HD models using human induced pluripotent stem cells (iPSCs) have not extensively characterized the role of mtHTT in patient-derived astrocytes. Here physiologically mature astrocytes are generated from HD patient iPSCs. These human astrocytes exhibit hallmark HD phenotypes that occur in mouse models, including impaired inward rectifying K+ currents, lengthened spontaneous Ca2+ waves and reduced cell membrane capacitance. HD astrocytes in co-culture provided reduced support for the maturation of iPSC-derived neurons. In addition, neurons exposed to chronic glutamate stimulation are not protected by HD astrocytes. This iPSC-based HD model demonstrates the critical effects of mtHTT on human astrocytes, which not only broadens the understanding of disease susceptibility beyond cortical and striatal neurons but also increases potential drug targets

Determining puma habitat suitability in the Eastern USA

Pumas (Puma concolor) were eliminated from most of the eastern USA a century ago. In the past couple of decades, their recovery in the West has increased puma dispersal into the Midwest, with some individuals even traveling to the East Coast. We combined published expert opinion data and a habitat suitability index in an analysis that identified 17 areas in the Upper Midwest, Ozarks, Appalachia, and New England that could potentially host puma populations in the future. Thirteen of these were larger than 10,000 km2 and so likely to ensure a puma population’s long-term genetic health. Further, we quantified patch size, human density, livestock density, percent public land, and a sociocultural index reflecting wildlife values for comparing patches, as well as present a summary of current legislation relevant to puma management in the East. Our work may be useful in identifying suitable areas to restore pumas based not only on the quality of their biophysical habitat, but also on social values conducive to puma-human coexistence

Correction to: Determining puma habitat suitability in the Eastern USA (Biodiversity and Conservation, (2023), 10.1007/s10531-022-02529-z)

In the original article, One of the author names was incorrectly misspelled as Tom Bulter. It must be published as “Tom Butler”. The original article has been corrected

Early parenting interventions to prevent internalising problems in children and adolescents: a global systematic review and network meta-analysis

QUESTION: We compared the effectiveness of different types of parenting interventions based on an a priori taxonomy, and the impact of waitlists versus treatment as usual (TAU), in reducing child internalising problems. STUDY SELECTION AND ANALYSIS: We conducted a systematic review and network meta-analysis of published and unpublished randomised controlled trials (RCTs) until 1 October 2022 that investigated parenting interventions with children younger than 4 years. EXCLUSION CRITERIA: studies with children born preterm, with intellectual disabilities, or families receiving support for current abuse, neglect, and substance misuse. We assessed the certainty of evidence using the Confidence in Network Meta-Analysis framework. We used random-effects network meta-analysis to estimate standardised mean differences (SMDs) with 95% credible intervals (CrIs). FINDINGS: Of 20 520 citations identified, 59 RCTs (18 349 participants) were eligible for the network meta-analysis. Parenting interventions focusing on the dyadic relationship (SMD: -0.26, 95% CrI: -0.43 to -0.08) and those with mixed focus (-0.09, -0.17 to -0.02) were more effective in reducing internalising problems than TAU at the first time point available. All interventions were more effective than waitlist, which increased the risk of internalising problems compared with TAU (0.36, 0.19 to 0.52). All effects attenuated at later follow-ups. Most studies were rated as with 'high risk' or 'some concerns' using the Risk of Bias Assessment Tool V.2. There was no strong evidence of effect modification by theoretically informed components or modifiers. CONCLUSIONS: We found preliminary evidence that relationship-focused and mixed parenting interventions were effective in reducing child internalising problems, and the waitlist comparator increased internalising problems with implications for waiting times between referral and support. Considering the high risk of bias of most studies included, the findings from this meta-analysis should be interpreted with caution. PROSPERO registration number CRD42020172251

The Effectiveness of Alcohol Screening and Brief Intervention in Emergency Departments: A Multicentre Pragmatic Cluster Randomized Controlled Trial

BACKGROUND: Alcohol misuse is common in people attending emergency departments (EDs) and there is some evidence of efficacy of alcohol screening and brief interventions (SBI). This study investigated the effectiveness of SBI approaches of different intensities delivered by ED staff in nine typical EDs in England: the SIPS ED trial. METHODS AND FINDINGS: Pragmatic multicentre cluster randomized controlled trial of SBI for hazardous and harmful drinkers presenting to ED. Nine EDs were randomized to three conditions: a patient information leaflet (PIL), 5 minutes of brief advice (BA), and referral to an alcohol health worker who provided 20 minutes of brief lifestyle counseling (BLC). The primary outcome measure was the Alcohol Use Disorders Identification Test (AUDIT) status at 6 months. Of 5899 patients aged 18 or more presenting to EDs, 3737 (63·3%) were eligible to participate and 1497 (40·1%) screened positive for hazardous or harmful drinking, of whom 1204 (80·4%) gave consent to participate in the trial. Follow up rates were 72% (n?=?863) at six, and 67% (n?=?810) at 12 months. There was no evidence of any differences between intervention conditions for AUDIT status or any other outcome measures at months 6 or 12 in an intention to treat analysis. At month 6, compared to the PIL group, the odds ratio of being AUDIT negative for brief advice was 1·103 (95% CI 0·328 to 3·715). The odds ratio comparing BLC to PIL was 1·247 (95% CI 0·315 to 4·939). A per protocol analysis confirmed these findings. CONCLUSIONS: SBI is difficult to implement in typical EDs. The results do not support widespread implementation of alcohol SBI in ED beyond screening followed by simple clinical feedback and alcohol information, which is likely to be easier and less expensive to implement than more complex interventions

Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability

Background: Autism spectrum disorder (ASD) is characterised by impairments in social communication and by a pattern of repetitive behaviours, with learning disability (LD) typically seen in up to 70% of cases. A recent study using the PPL statistical framework identified a novel region of genetic linkage on chromosome 16q21 that is limited to ASD families with LD. Methods: In this study, two families with autism and/or LD are described which harbour rare >1.6 Mb microdeletions located within this linkage region. The deletion breakpoints are mapped at base-pair resolution and segregation analysis is performed using a combination of 1M single nucleotide polymorphism (SNP) technology, array comparative genomic hybridisation (CGH), long-range PCR, and Sanger sequencing. The frequency of similar genomic variants in control subjects is determined through analysis of published SNP array data. Expression of CDH8, the only gene disrupted by these microdeletions, is assessed using reverse transcriptase PCR and in situ hybridisation analysis of 9 week human embryos. Results: The deletion of chr16: 60 025 584-61 667 839 was transmitted to three of three boys with autism and LD and none of four unaffected siblings, from their unaffected mother. In a second family, an overlapping deletion of chr16: 58 724 527-60 547 472 was transmitted to an individual with severe LD from his father with moderate LD. No copy number variations (CNVs) disrupting CDH8 were observed in 5023 controls. Expression analysis indicates that the two CDH8 isoforms are present in the developing human cortex. Conclusion: Rare familial 16q21 microdeletions and expression analysis implicate CDH8 in susceptibility to autism and LD

Survival of Infants Born to HIV-Positive Mothers, by Feeding Modality, in Rakai, Uganda

Data comparing survival of formula-fed to breast-fed infants in programmatic settings are limited. We compared mortality and HIV-free of breast and formula-fed infants born to HIV-positive mothers in a program in rural, Rakai District Uganda.One hundred eighty two infants born to HIV-positive mothers were followed at one, six and twelve months postpartum. Mothers were given infant-feeding counseling and allowed to make informed choices as to whether to formula-feed or breast-feed. Eligible mothers and infants received antiretroviral therapy (ART) if indicated. Mothers and their newborns received prophylaxis for prevention of mother-to-child HIV transmission (pMTCT) if they were not receiving ART. Infant HIV infection was detected by PCR (Roche Amplicor 1.5) during the follow-up visits. Kaplan Meier time-to-event methods were used to compare mortality and HIV-free survival. The adjusted hazard ratio (Adjusted HR) of infant HIV-free survival was estimated by Cox regression. Seventy-five infants (41%) were formula-fed while 107 (59%) were breast-fed. Exclusive breast-feeding was practiced by only 25% of breast-feeding women at one month postpartum. The cumulative 12-month probability of infant mortality was 18% (95% CI = 11%–29%) among the formula-fed compared to 3% (95% CI = 1%–9%) among the breast-fed infants (unadjusted hazard ratio (HR)  = 6.1(95% CI = 1.7–21.4, P-value<0.01). There were no statistically significant differentials in HIV-free survival by feeding choice (86% in the formula-fed compared to 96% in breast-fed group (Adjusted RH = 2.8[95%CI = 0.67–11.7, P-value = 0.16]Formula-feeding was associated with a higher risk of infant mortality than breastfeeding in this rural population. Our findings suggest that formula-feeding should be discouraged in similar African settings

Early parenting interventions to prevent internalising problems in children and adolescents: a global systematic review and network meta-analysis

Question: We compared the effectiveness of different types of parenting interventions based on an a priori taxonomy, and the impact of waitlists versus treatment as usual (TAU), in reducing child internalising problems. Study selection and analysis: We conducted a systematic review and network meta‐ analysis of published and unpublished randomised controlled trials (RCTs) until 1 October 2022 that investigated parenting interventions with children younger than 4 years. Exclusion criteria: studies with children born preterm, with intellectual disabilities, or families receiving support for current abuse, neglect, and substance misuse. We assessed the certainty of evidence using the Confidence in Network Meta‐ Analysis framework. We used random‐ effects network meta‐ analysis to estimate standardised mean differences (SMDs) with 95% credible intervals (CrIs). Findings: Of 20 520 citations identified, 59 RCTs (18 349 participants) were eligible for the network meta‐ analysis. Parenting interventions focusing on the dyadic relationship (SMD: −0.26, 95% CrI: −0.43 to −0.08) and those with mixed focus (−0.09, –0.17 to −0.02) were more effective in reducing internalising problems than TAU at the first time point available. All interventions were more effective than waitlist, which increased the risk of internalising problems compared with TAU (0.36, 0.19 to 0.52). All effects attenuated at later follow‐ ups. Most studies were rated as with ’high risk’ or ’some concerns’ using the Risk of Bias Assessment Tool V.2. There was no strong evidence of effect modification by theoretically informed components or modifiers. Conclusions: We found preliminary evidence that relationship‐ focused and mixed parenting interventions were effective in reducing child internalising problems, and the waitlist comparator increased internalising problems with implications for waiting times between referral and support. Considering the high risk of bias of most studies included, the findings from this meta‐ analysis should be interpreted with caution. PROSPERO registration number CRD42020172251