Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome.

Gould syndrome is a rare multisystem disorder resulting from autosomal dominant mutations in the collagen-encoding genes COL4A1 and COL4A2. Human patients and Col4a1 mutant mice display brain pathology that typifies cerebral small vessel diseases (cSVDs), including white matter hyperintensities, dilated perivascular spaces, lacunar infarcts, microbleeds, and spontaneous intracerebral hemorrhage. The underlying pathogenic mechanisms are unknown. Using the Col4a1+/G394V mouse model, we found that vasoconstriction in response to internal pressure-the vascular myogenic response-is blunted in cerebral arteries from middle-aged (12 mo old) but not young adult (3 mo old) animals, revealing age-dependent cerebral vascular dysfunction. The defect in the myogenic response was associated with a significant decrease in depolarizing cation currents conducted by TRPM4 (transient receptor potential melastatin 4) channels in native cerebral artery smooth muscle cells (SMCs) isolated from mutant mice. The minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) is necessary for TRPM4 activity. Dialyzing SMCs with PIP2 and selective blockade of phosphoinositide 3-kinase (PI3K), an enzyme that converts PIP2 to phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3), restored TRPM4 currents. Acute inhibition of PI3K activity and blockade of transforming growth factor-beta (TGF-ß) receptors also rescued the myogenic response, suggesting that hyperactivity of TGF-ß signaling pathways stimulates PI3K to deplete PIP2 and impair TRPM4 channels. We conclude that age-related cerebral vascular dysfunction in Col4a1+/G394V mice is caused by the loss of depolarizing TRPM4 currents due to PIP2 depletion, revealing an age-dependent mechanism of cSVD.

New Approaches for Inferring Phylogenies in the Presence of Paralogs.

The availability of whole genome sequences was expected to supply essentially unlimited data for phylogenetics. However, strict reliance on single-copy genes for this purpose has drastically limited the amount of data that can be used. Here, we review several approaches for increasing the amount of data used for phylogenetic inference, focusing on methods that allow for the inclusion of duplicated genes (paralogs). Recently developed methods that are robust to high levels of incomplete lineage sorting also appear to be robust to the inclusion of paralogs, suggesting a promising way to take full advantage of genomic data. We discuss the pitfalls of these approaches, as well as further avenues for research.

Phylogenetic inference using generative adversarial networks.

MOTIVATION: The application of machine learning approaches in phylogenetics has been impeded by the vast model space associated with inference. Supervised machine learning approaches require data from across this space to train models. Because of this, previous approaches have typically been limited to inferring relationships among unrooted quartets of taxa, where there are only three possible topologies. Here, we explore the potential of generative adversarial networks (GANs) to address this limitation. GANs consist of a generator and a discriminator: at each step, the generator aims to create data that is similar to real data, while the discriminator attempts to distinguish generated and real data. By using an evolutionary model as the generator, we use GANs to make evolutionary inferences. Since a new model can be considered at each iteration, heuristic searches of complex model spaces are possible. Thus, GANs offer a potential solution to the challenges of applying machine learning in phylogenetics. RESULTS: We developed phyloGAN, a GAN that infers phylogenetic relationships among species. phyloGAN takes as input a concatenated alignment, or a set of gene alignments, and infers a phylogenetic tree either considering or ignoring gene tree heterogeneity. We explored the performance of phyloGAN for up to 15 taxa in the concatenation case and 6 taxa when considering gene tree heterogeneity. Error rates are relatively low in these simple cases. However, run times are slow and performance metrics suggest issues during training. Future work should explore novel architectures that may result in more stable and efficient GANs for phylogenetics. AVAILABILITY AND IMPLEMENTATION: phyloGAN is available on github: https://github.com/meganlsmith/phyloGAN/.

Applications of machine learning in phylogenetics.

Machine learning has increasingly been applied to a wide range of questions in phylogenetic inference. Supervised machine learning approaches that rely on simulated training data have been used to infer tree topologies and branch lengths, to select substitution models, and to perform downstream inferences of introgression and diversification. Here, we review how researchers have used several promising machine learning approaches to make phylogenetic inferences. Despite the promise of these methods, several barriers prevent supervised machine learning from reaching its full potential in phylogenetics. We discuss these barriers and potential paths forward. In the future, we expect that the application of careful network designs and data encodings will allow supervised machine learning to accommodate the complex processes that continue to confound traditional phylogenetic methods.

Inhibitory control in children with agenesis of the corpus callosum compared with typically developing children.

OBJECTIVES: The developmental absence (agenesis) of the corpus callosum (AgCC) is a congenital brain malformation associated with risk for a range of neuropsychological difficulties. Inhibitory control outcomes, including interference control and response inhibition, in children with AgCC are unclear. This study examined interference control and response inhibition: 1) in children with AgCC compared with typically developing (TD) children, 2) in children with different anatomical features of AgCC (complete vs. partial, isolated vs. complex), and 3) associations with white matter volume and microstructure of the anterior (AC) and posterior commissures (PC) and any remnant corpus callosum (CC). METHODS: Participants were 27 children with AgCC and 32 TD children 8-16 years who completed inhibitory control assessments and brain MRI to define AgCC anatomical features and measure white matter volume and microstructure. RESULTS: The AgCC cohort had poorer performance and higher rates of below average performance on inhibitory control measures than TD children. Children with complex AgCC had poorer response inhibition performance than children with isolated AgCC. While not statistically significant, there were select medium to large effect sizes for better inhibitory control associated with greater volume and microstructure of the AC and PC, and with reduced volume and microstructure of the remnant CC in partial AgCC. CONCLUSIONS: This study provides evidence of inhibitory control difficulties in children with AgCC. While the sample was small, the study found preliminary evidence that the AC (f2=.18) and PC (f2=.30) may play a compensatory role for inhibitory control outcomes in the absence of the CC.

The use of Lentilactobacillus buchneri PJB1 and Lactiplantibacillus plantarum MTD1 on the ensiling of whole-plant corn silage, snaplage, and high-moisture corn.

Experiments were conducted over a 3-yr period to evaluate the effects of bacterial inoculants on the fermentation profile and aerobic stability of whole-plant corn silage (WPC), snaplage (SNA), and high-moisture corn (HMC). Whole-plant corn was inoculated with Lentilactobacillus buchneri PJB1 in combination with Lactiplantibacillus plantarum MTD1 or with Lpb. plantarum alone (experiments 1 and 2). Snaplage (experiment 3) and HMC (experiments 4 and 5) were inoculated with Len. buchneri in combination with Lpb. plantarum or with Len. buchneri alone. After inoculation, the feedstuffs were ensiled in 7.57-L silos and stored at 21 ± 2°C for 30 or 90 d. In experiment 5, silage was subjected to air stress for 2 h every 2 wk through 42 d and then for 2 h/wk until 90 d and had samples analyzed for their bacterial community composition by metagenomics. Overall, in all experiments, silages inoculated with Len. buchneri alone or in combination with Lpb. plantarum had more acetic acid and 1,2-propanediol and fewer yeasts than uninoculated silages. After 30 d of ensiling, inoculation with Len. buchneri alone or in combination with Lpb. plantarum did not affect the aerobic stability of SNA, but it slightly increased the stability of WPC and markedly improved the stability of HMC. After 90 d of ensiling, inoculation with Len. buchneri alone or in combination with Lpb. plantarum markedly improved the aerobic stability of WPC, SNA, and HMC. In experiment 5, inoculation increased the relative abundance (RA) of Lactobacillaceae and reduced the RA of Enterobacteriaceae and Leuconostocaceae in HMC at 30 and 90 d and the RA of Clostridiaceae in non-air-stressed HMC at 90 d. Air-stressed HMC inoculated with Len. buchneri had less lactic acid, more acetic acid and 1,2-propanediol, and markedly greater aerobic stability than uninoculated air-stressed HMC at 90 d. In conclusion, inoculation with Len. buchneri PJB1 alone or in combination with Lpb. plantarum MTD1 increased the production of acetic acid and 1,2-propanediol, inhibited yeasts development, and improved the aerobic stability of WPC, SNA, and HMC. In HMC, inoculation markedly improved aerobic stability as soon as after 30 d of ensiling, and after 90 d, inoculation improved stability even under air stress conditions.

Implementation of In-Hospital Postpartum Glucose Tolerance Testing for People with Gestational Diabetes.

OBJECTIVE: We aimed to evaluate uptake of the glucose tolerance test performed during delivery hospitalization as part of routine clinical care. STUDY DESIGN: This is a retrospective cohort study of people with GDM at a tertiary center. We collected 9 months of postimplementation data after the in-hospital ("early") glucose tolerance test was adopted as a routine screening option. Adherence was compared between those who elected early glucose tolerance testing versus those who deferred testing to the standard postpartum period. Bivariable statistics including demographics, care team, and postpartum testing/visit attendance were compared between those who received early testing and those who did not using chi-square, Fisher's exact, and t-tests. RESULTS: A total of 681 patients with GDM delivered during the study period. Of those who had an early glucose tolerance test ordered (n = 408), 340 (83.3%) completed the test. Among those who did not complete an early glucose tolerance test (ordered and not completed or never ordered), only 104/341 (30.5%) completed any postpartum glucose testing in the first 12 months of postpartum. There were significant differences in characteristics in terms of race/ethnicity, insurance, type of gestational diabetes (A1GDM vs. A2GDM), diabetes medications, obstetric care provider, and delivery mode. Among those who completed early testing, 43.7% of participants had impaired glucose metabolism and 6.5% had values concerning for overt diabetes mellitus. Among those who deferred testing to the standard 6- to 12-week period, 24.0% had impaired glucose metabolism and none had overt diabetes. Those who completed an early glucose tolerance test had a lower rate of postpartum visit attendance compared with those who deferred (75.6 vs. 91.5%, p < 0.01). CONCLUSION: In this cohort, when the early glucose tolerance test is offered in clinical practice, adherence rates are higher than when the test is deferred until the postpartum visit. KEY POINTS: · Adherence rates with the early glucose tolerance test (GTT) are higher than if the testing is deferred.. · Those who completed an early GTT had a lower rate of postpartum visit attendance compared with those who deferred.. · Offering an in-hospital postpartum GTT can help address low rates of glucose testing postpartum..

The transition zone in Hirschsprung's bowel contains abnormal hybrid ganglia with characteristics of extrinsic nerves.

The aganglionic bowel in short-segment Hirschsprung's disease is characterized both by the absence of enteric ganglia and the presence of extrinsic thickened nerve bundles (TNBs). The relationship between the TNBs and the loss of enteric ganglia is unknown. Previous studies have described decreasing numbers of ganglia with increasing density of TNBs within the transition zone (TZ) between ganglionic and aganglionic gut, and there is some evidence of spatial contact between them in this region. To determine the cellular interactions involved, we have analysed the expression of perineurial markers of TNBs and enteric ganglionic markers for both neural cells and their ensheathing telocytes across four cranio-caudal segments consisting of most proximal ganglionic to most distal aganglionic from pull-through resected colon. We show that in the TZ, enteric ganglia are abnormal, being surrounded by perineurium cells characteristic of TNBs. Furthermore, short processes of ganglionic neurons extend caudally towards the aganglionic region, where telocytes in the TNB are located between the perineurium and nerve fibres into which they project telopodes. Thus, enteric ganglia within the TZ have abnormal structural characteristics, the cellular relationships of which are shared by the TNBs. These findings will help towards elucidation of the cellular mechanisms involved in the aetiology of Hirschsprung's disease.

Using all Gene Families Vastly Expands Data Available for Phylogenomic Inference.

Traditionally, single-copy orthologs have been the gold standard in phylogenomics. Most phylogenomic studies identify putative single-copy orthologs using clustering approaches and retain families with a single sequence per species. This limits the amount of data available by excluding larger families. Recent advances have suggested several ways to include data from larger families. For instance, tree-based decomposition methods facilitate the extraction of orthologs from large families. Additionally, several methods for species tree inference are robust to the inclusion of paralogs and could use all of the data from larger families. Here, we explore the effects of using all families for phylogenetic inference by examining relationships among 26 primate species in detail and by analyzing five additional data sets. We compare single-copy families, orthologs extracted using tree-based decomposition approaches, and all families with all data. We explore several species tree inference methods, finding that identical trees are returned across nearly all subsets of the data and methods for primates. The relationships among Platyrrhini remain contentious; however, the species tree inference method matters more than the subset of data used. Using data from larger gene families drastically increases the number of genes available and leads to consistent estimates of branch lengths, nodal certainty and concordance, and inferences of introgression in primates. For the other data sets, topological inferences are consistent whether single-copy families or orthologs extracted using decomposition approaches are analyzed. Using larger gene families is a promising approach to include more data in phylogenomics without sacrificing accuracy, at least when high-quality genomes are available.

Species limits and diversification of the Dendropsophus rubicundulus subgroup (Anura, Hylidae) in Neotropical savannas.

Understanding the processes that generate and maintain biodiversity at and below the species level is a central goal of evolutionary biology. Here we explore the spatial and temporal drivers of diversification of the treefrog subgroup Dendropsophus rubicundulus, a subgroup of the D. microcephalus species group, over periods of pronounced geological and climatic changes in the Neotropical savannas that they inhabit. This subgroup currently comprises 11 recognized species distributed across the Brazilian and Bolivian savannas, but the taxonomy has been in a state of flux, necessitating reexamination. Using newly generated single nucleotide polymorphism (SNP) data from restriction-site associated DNA sequencing (RADseq) and mitochondrial 16S sequence data for ∼150 specimens, we inferred phylogenetic relationships, tested species limits using a model-based approach, and estimated divergence times to gain insights into the geographic and climatic events that affected the diversification of this subgroup. Our results recognized at least nine species: D. anataliasiasi, D. araguaya, D. cerradensis, D. elianeae, D. jimi, D. rubicundulus, D. tritaeniatus, D. rozenmani, and D. sanborni. Although we did not collect SNP data for the latter two species, they are likely distinct based on mitochondrial data. In addition, we found genetic structure within the widespread species D. rubicundulus, which comprises three allopatric lineages connected by gene flow upon secondary contact. We also found evidence of population structure and perhaps undescribed diversity in D. elianeae, which warrants further study. The D. rubicundulus subgroup is estimated to have originated in the Late Miocene (∼5.45 million years ago), with diversification continuing through the Pliocene and Early Pleistocene, followed by the most recent divergence of D. rubicundulus lineages in the Middle Pleistocene. The epeirogenic uplift followed by erosion and denudation of the central Brazilian plateau throughout the Pliocene and Pleistocene, in combination with the increasing frequency and amplitude of climatic fluctuations during the Pleistocene, was important for generating and structuring diversity at or below the species level in the D. rubicundulus subgroup.

The Frequency and Topology of Pseudoorthologs.

Phylogenetics has long relied on the use of orthologs, or genes related through speciation events, to infer species relationships. However, identifying orthologs is difficult because gene duplication can obscure relationships among genes. Researchers have been particularly concerned with the insidious effects of pseudoorthologs-duplicated genes that are mistaken for orthologs because they are present in a single copy in each sampled species. Because gene tree topologies of pseudoorthologs may differ from the species tree topology, they have often been invoked as the cause of counterintuitive results in phylogenetics. Despite these perceived problems, no previous work has calculated the probabilities of pseudoortholog topologies or has been able to circumscribe the regions of parameter space in which pseudoorthologs are most likely to occur. Here, we introduce a model for calculating the probabilities and branch lengths of orthologs and pseudoorthologs, including concordant and discordant pseudoortholog topologies, on a rooted three-taxon species tree. We show that the probability of orthologs is high relative to the probability of pseudoorthologs across reasonable regions of parameter space. Furthermore, the probabilities of the two discordant topologies are equal and never exceed that of the concordant topology, generally being much lower. We describe the species tree topologies most prone to generating pseudoorthologs, finding that they are likely to present problems to phylogenetic inference irrespective of the presence of pseudoorthologs. Overall, our results suggest that pseudoorthologs are unlikely to mislead inferences of species relationships under the biological scenarios considered here.[Birth-death model; orthologs; paralogs; phylogenetics.].

Species Tree Inference Methods Intended to Deal with Incomplete Lineage Sorting Are Robust to the Presence of Paralogs.

Many recent phylogenetic methods have focused on accurately inferring species trees when there is gene tree discordance due to incomplete lineage sorting (ILS). For almost all of these methods, and for phylogenetic methods in general, the data for each locus are assumed to consist of orthologous, single-copy sequences. Loci that are present in more than a single copy in any of the studied genomes are excluded from the data. These steps greatly reduce the number of loci available for analysis. The question we seek to answer in this study is: what happens if one runs such species tree inference methods on data where paralogy is present, in addition to or without ILS being present? Through simulation studies and analyses of two large biological data sets, we show that running such methods on data with paralogs can still provide accurate results. We use multiple different methods, some of which are based directly on the multispecies coalescent model, and some of which have been proven to be statistically consistent under it. We also treat the paralogous loci in multiple ways: from explicitly denoting them as paralogs, to randomly selecting one copy per species. In all cases, the inferred species trees are as accurate as equivalent analyses using single-copy orthologs. Our results have significant implications for the use of ILS-aware phylogenomic analyses, demonstrating that they do not have to be restricted to single-copy loci. This will greatly increase the amount of data that can be used for phylogenetic inference.[Gene duplication and loss; incomplete lineage sorting; multispecies coalescent; orthology; paralogy.].

Episodic and prospective memory difficulties in 13-year-old children born very preterm.

OBJECTIVES: Children born very preterm (VP) are susceptible to a range of cognitive impairments, yet the effects of VP birth on long-term, episodic, and prospective memory remains unclear. This study examined episodic and prospective memory functioning in children born VP compared with their term-born counterparts at 13 years. METHOD: VP (n = 81: born <30 weeks' gestation) and term (n = 26) groups were aged between 12 and 14 years. Children completed: (i) standardized verbal and visuospatial episodic memory tests; and (ii) an experimental time- and event-based prospective memory test that included short-term (within assessment session) and long-term (up to 1-week post-session) tasks. Parents completed a questionnaire assessing memory functions in everyday life. RESULTS: The VP group performed worse on all measures of verbal and visuospatial episodic memory than the term group. While there were no group differences in event-based or long-term prospective memory, the VP group performed worse on time-based and short-term prospective memory tasks than term-born counterparts. Parents of children born VP reported more everyday memory difficulties than parents of children born at term, with parent-ratings indicating significantly elevated rates of everyday memory challenges in children born VP. CONCLUSIONS: Children born VP warrant long-term surveillance, as challenges associated with VP birth include memory difficulties at 13 years. This study highlights the need for greater research and clinical attention into childhood functional memory outcomes.

An education resource for human papillomavirus oropharyngeal cancer patients: think-aloud interviews.

PURPOSE: The human papillomavirus (HPV) is well recognised as a factor in developing oropharyngeal cancer (OPC). A booklet for HPV-OPC patients aimed to deliver evidence-based messages in everyday language, in a way to minimise negative psychological impacts on patients. Our study explored the suitability of the booklet for use. METHODS: Participants were recruited through social media and interviewed via Zoom. Participants were shown the booklet and a think-aloud method elicited real-time reactions to the content. Responses were analysed for each section and coded as either for or against for content, with other responses thematically analysed using NVivo. RESULTS: The sample comprised 24 participants: patients (n = 19) who completed treatment for HPV-OPC and partners of survivors of HPV-OPC (n = 5). All participants found the booklet useful, and most wished the resource had been available previously. Some indicated the information was new to them. The majority agreed the booklet would be best delivered by their specialist at point of diagnosis and would be a useful resource for friends and family. Most participants gave feedback on improvements to the booklet in terms of comprehension and design. Overall, participants found the content easy to understand. Most participants found that it helped to reduce shame and stigma associated with HPV as a sexually transmitted infection. CONCLUSION: An evidence-based booklet for HPV-OPC patients and their partners is acceptable. Implementation may be feasible in routine clinical practice, specifically at time of diagnosis. Adapting the content will help optimise the efficacy of the booklet in facilitating communication between all stakeholders.

Associations between PM2.5 and O3 exposures and new onset type 2 diabetes in regional and national samples in the United States.

BACKGROUND: Exposure to particulate matter ≤2.5 µm in diameter (PM2.5) and ozone (O3) has been linked to numerous harmful health outcomes. While epidemiologic evidence has suggested a positive association with type 2 diabetes (T2D), there is heterogeneity in findings. We evaluated exposures to PM2.5 and O3 across three large samples in the US using a harmonized approach for exposure assignment and covariate adjustment. METHODS: Data were obtained from the Veterans Administration Diabetes Risk (VADR) cohort (electronic health records [EHRs]), the Reasons for Geographic and Racial Disparities in Stroke (REGARDS) cohort (primary data collection), and the Geisinger health system (EHRs), and reflect the years 2003-2016 (REGARDS) and 2008-2016 (VADR and Geisinger). New onset T2D was ascertained using EHR information on medication orders, laboratory results, and T2D diagnoses (VADR and Geisinger) or report of T2D medication or diagnosis and/or elevated blood glucose levels (REGARDS). Exposure was assigned using pollutant annual averages from the Downscaler model. Models stratified by community type (higher density urban, lower density urban, suburban/small town, or rural census tracts) evaluated likelihood of new onset T2D in each study sample in single- and two-pollutant models of PM2.5 and O3. RESULTS: In two pollutant models, associations of PM2.5, and new onset T2D were null in the REGARDS cohort except for in suburban/small town community types in models that also adjusted for NSEE, with an odds ratio (95% CI) of 1.51 (1.01, 2.25) per 5 µg/m3 of PM2.5. Results in the Geisinger sample were null. VADR sample results evidenced nonlinear associations for both pollutants; the shape of the association was dependent on community type. CONCLUSIONS: Associations between PM2.5, O3 and new onset T2D differed across three large study samples in the US. None of the results from any of the three study populations found strong and clear positive associations.

Parental Mental Health and Parenting Behaviors Following Very Preterm Birth: Associations in Mothers and Fathers and Implications for Child Cognitive Outcome.

OBJECTIVES: To investigate the longitudinal associations between parental mental health symptoms within 4 weeks of birth, parenting behaviors at 1 year, and child general cognitive ability at 4.5-5 years in a sample of children born very preterm (VP). This study also examined whether these associations differed based on level of family social risk. METHODS: Participants were 143 children born <30 weeks' gestation and their parents. Within 4 weeks of birth, mothers' and fathers' depressive and anxiety symptoms were assessed using the Center for Epidemiologic Studies Depression Scale and Hospital Anxiety Depression Scale-Anxiety Subscale. Parents' sensitive and structuring parenting behaviors were assessed at 1 year using the Emotional Availability Scales. Child general cognitive ability was assessed at 4.5-5 years using the Wechsler Preschool & Primary Scale of Intelligence-Fourth Edition. RESULTS: Higher maternal depressive symptoms were associated with lower levels of sensitive and structuring parenting behavior, while higher maternal anxiety symptoms were associated with higher levels of structuring parenting behavior. There was weak evidence for positive associations between mothers' sensitive parenting behavior and fathers' structuring parenting behavior and child general cognitive ability. There was also weak evidence for stronger associations between mothers' mental health symptoms, parenting behaviors, and child general cognitive ability, in families of higher compared with lower social risk. CONCLUSIONS: Depressive and anxiety symptoms experienced by mothers in the initial weeks following VP birth can have long-term effects on their parenting behaviors. Enquiring about parents' mental health during their child's hospitalization in the neonatal intensive care unit is crucial.

Single-staged retromuscular abdominal wall reconstruction with mesh at the time of ostomy reversal: are we crossing the line? An ACHQC Analysis.

INTRODUCTION: The most appropriate method of reconstructing the abdominal wall at the site of a simultaneous stoma takedown is controversial. The contaminated field, concomitant GI procedure being performed and presence of a hernia all complicate decision-making. We sought to describe the surgical approaches, mesh type and outcomes of concomitant abdominal wall reconstruction during stoma takedown in a large hernia registry. METHODS AND PROCEDURES: All patients who underwent stoma takedown with simultaneous hernia repair with retromuscular mesh placement from January 2014 to May 2022 were identified within the Abdominal Core Health Quality Collaborative (ACHQC). Patients were stratified by mesh type including permanent synthetic (PS), resorbable synthetic (RS) and biologic mesh. Association of mesh type with 30-day wound events and other complications and 1-year outcomes were evaluated. RESULTS: There were 368 patients who met inclusion criteria. Eighty-nine patients had ileostomies, 276 colostomies and 3 had both. Two hundred and seventy-nine (75.8%) patients received PS mesh, 46 (12.5%) biologic, and 43 (11.7%) RS. Seventy percent (259/368) had a parastomal hernia, 75% (285/368) had a midline incisional hernia, and 48% (178/368) had both. All groups had similar preoperative comorbidities and the majority had a transversus abdominus release. All mesh groups had similar thirty-day SSI (13.2-14.3%), SSO (10.5-17.8%) and SSOPI (7.9-14.1%), p = 0.6. Three patients with PS mesh developed infected synthetic mesh and one PS mesh required excision. Four patients with PS developed an enterocutaneous fistula. Of these, only one patient was recorded as having both an enterocutaneous fistula and mesh infection. Thirty-day reoperation and readmission were similar across all mesh groups. Recurrence at 1-year was similar between mesh groups. Quality of life measured using HerQLes scores were higher at one year compared to baseline in all groups indicating improvement in hernia-specific quality of life. CONCLUSION: Early complication rates associated with simultaneous stoma takedown and abdominal wall reconstruction are significant, regardless of mesh type utilized. Concomitant surgery should be weighed heavily and tailored to individual patients.

Feasibility, acceptability and practicality of transcranial stimulation in obsessive compulsive symptoms (FEATSOCS): A randomised controlled crossover trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive form of neurostimulation with potential for development as a self-administered intervention. It has shown promise as a safe and effective treatment for obsessive compulsive disorder (OCD) in a small number of studies. The two most favourable stimulation targets appear to be the left orbitofrontal cortex (L-OFC) and the supplementary motor area (SMA). We report the first study to test these targets head-to-head within a randomised sham-controlled trial. Our aim was to inform the design of future clinical research studies, by focussing on the acceptability and safety of the intervention, feasibility of recruitment, adherence to and tolerability of tDCS, and the size of any treatment-effect. METHODS: FEATSOCS was a randomised, double-blind, sham-controlled, cross-over, multicentre study. Twenty adults with DSM-5-defined OCD were randomised to treatment, comprising three courses of clinic-based tDCS (SMA, L-OFC, Sham), randomly allocated and delivered in counterbalanced order. Each course comprised four 20-min 2 mA stimulations, delivered over two consecutive days, separated by a 'washout' period of at least four weeks. Assessments were carried out by raters who were blind to stimulation-type. Clinical outcomes were assessed before, during, and up to four weeks after stimulation. Patient representatives with lived experience of OCD were actively involved at all stages. RESULTS: Clinicians showed willingness to recruit participants and recruitment to target was achieved. Adherence to treatment and study interventions was generally good, with only two dropouts. There were no serious adverse events, and adverse effects which did occur were transient and mostly mild in intensity. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores were numerically improved from baseline to 24 h after the final stimulation across all intervention groups but tended to worsen thereafter. The greatest effect size was seen in the L-OFC arm, (Cohen's d = -0.5 [95% CI -1.2 to 0.2] versus Sham), suggesting this stimulation site should be pursued in further studies. Additional significant sham referenced improvements in secondary outcomes occurred in the L-OFC arm, and to a lesser extent with SMA stimulation. CONCLUSIONS: tDCS was acceptable, practicable to apply, well-tolerated and appears a promising potential treatment for OCD. The L-OFC represents the most promising target based on clinical changes, though the effects on OCD symptoms were not statistically significant compared to sham. SMA stimulation showed lesser signs of promise. Further investigation of tDCS in OCD is warranted, to determine the optimal stimulation protocol (current, frequency, duration), longer-term effectiveness and brain-based mechanisms of effect. If efficacy is substantiated, consideration of home-based approaches represents a rational next step. TRIAL REGISTRATION: ISRCTN17937049. https://doi.org/10.1186/ISRCTN17937049.

Against the use of the Strengths and Difficulties Questionnaire for Aboriginal and Torres Strait Islander children aged 2-15 years.

OBJECTIVE: The Strengths and Difficulties Questionnaire is a widely used screening tool for emotional and behavioural problems in children. Recent quantitative analyses have raised concerns regarding its structural validity in Aboriginal and Torres Strait Islander communities. This paper aims to extend upon existing findings by analysing the factor structure of both the parent- and teacher-reported Strengths and Difficulties Questionnaire in this population across a broader age range than in previous studies. METHODS: Participants were the caregivers and teachers of 1624 Aboriginal and Torres Strait Islander children (820 male, 804 female) aged 2-15 years from Waves 2-11 of the Longitudinal Study of Indigenous Children. The majority of children were Aboriginal living in major cities and inner regional areas. Internal consistency was estimated with McDonald's Omega. Exploratory structural equation modelling was conducted to investigate the factor structure of the parent-reported and teacher-reported versions of the Strengths and Difficulties Questionnaire. RESULTS: Responses from teachers demonstrated higher internal consistency than responses from parents, which was unacceptably low across most age groups. The purported five-factor structure of the Strengths and Difficulties Questionnaire failed to be replicated across both parent- and teacher-reported questionnaires. The results of bifactor and hierarchical exploratory structural equation models also failed to approximate the higher-order summary scales. These results indicate that the Strengths and Difficulties Questionnaire subscales and summary scores do not provide a valid index of emotional and behavioural problems in Aboriginal and Torres Strait Islander children. CONCLUSION: The Strengths and Difficulties Questionnaire should not be used with Aboriginal and Torres Strait Islander children.

The early impacts of primary HPV cervical screening implementation in Australia on the pathology sector: a qualitative study.

BACKGROUND: The transition of Australia's National Cervical Screening Program from cytology to a molecular test for human papillomavirus (HPV) (locally referred to as the 'Renewal'), including a longer five-year interval and older age at commencement, significantly impacted all sectors of program delivery. The Renewal had major implications for the roles and requirements of pathology laboratories providing services for the Program. This study aimed to understand the early impacts of the Renewal and its implementation on the pathology sector. METHODS: Semi-structured qualitative interviews were conducted with key stakeholders (N = 49) involved in the STakeholder Opinions of Renewal Implementation and Experiences Study (STORIES), 11-20 months after the program transition. A subset of interviews (N = 24) that discussed the pathology sector were analysed using inductive thematic analysis. RESULTS: Four overarching themes were identified: implementation enablers, challenges, missed opportunities, and possible improvements. Participants believed that the decision to transition to primary HPV screening was highly acceptable and evidence-based, but faced challenges due to impacts on laboratory infrastructure, resources, staffing, and finances. These challenges were compounded by unfamiliarity with new information technology (IT) systems and the new National Cancer Screening Register ('Register') not being fully functional by the date of the program transition. The limited availability of self-collection and lack of standardised fields in pathology forms were identified as missed opportunities to improve equity in the Program. To improve implementation processes, participants suggested increased pathology sector involvement in planning was needed, along with more timely and transparent communication from the Government, and clearer clinical management guidelines. CONCLUSION: The transition to primary HPV screening had a significant and multifaceted impact on the Australian pathology sector reflecting the magnitude and complexity of the Renewal. Strategies to support the pathology sector through effective change management, clear, timely, and transparent communication, as well as adequate funding sources will be critical for other countries planning to transition cervical screening programs.