Search

In 2019, the US Department of Health and Human Services launched the Ending the HIV Epidemic in the US initiative (EHE) with the goal of reducing new HIV infections by 90% by 2030. This initiative identifies 4 pillars (diagnose, treat, prevent, and respond) to address the HIV epidemic in the United States. To advance the EHE goals, the Federal Bureau of Prisons (FBOP) has implemented interventions at all points of the HIV care continuum. The FBOP has addressed the EHE pillar of prevention through implementing preexposure prophylaxis, developing a strategy to decrease the risk of new HIV infection, and providing guidance to FBOP healthcare providers. This article describes the implementation of programs to improve the HIV care continuum and end the epidemic of HIV within the FBOP including a review of methodology to implement an HIV preexposure prophylaxis program.

Aim: Indigenous Australians have higher rates of traumatic brain injury,with 74–90% of such injuries being concussion. This study explores concussion awareness and knowledge in Aboriginal Western Australians with high health literacy. Materials & methods: Participants, aged 18–65 years, engaged in research topic yarning, and thematic analysis of the qualitative data then undertaken. Results: There was awareness that direct head trauma can result in concussion, but a lack of differentiation between concussion and other head injuries. Knowledge was gained from sport, media or lived-experience. Symptom minimization and diversity of concussion symptoms prevented participants from seeking medical treatment. This was exacerbated by a mistrust of the medical system. Conclusion: Research findings highlight knowledge and service gaps where co-designed strategies can be targeted.

Background Transcatheter edge‐to‐edge repair (TEER) of mitral regurgitation is less invasive than surgery but has greater 5‐year mortality and reintervention risks, and leads to smaller improvements in physical functioning. The study objective was to quantify patient preferences for risk–benefit trade‐offs associated with TEER and surgery. Methods and Results A discrete choice experiment survey was administered to patients with mitral regurgitation. Attributes included procedure type; 30‐day mortality risk; 5‐year mortality risk and physical functioning for 5 years; number of hospitalizations in the next 5 years; and risk of additional surgery in the next 5 years. A mixed‐logit regression model was fit to estimate preference weights. Two hundred one individuals completed the survey: 63% were female and mean age was 74 years. On average, respondents preferred TEER over surgery. To undergo a less invasive procedure (ie, TEER), respondents would accept up to a 13.3% (95% CI, 8.7%–18.5%) increase in reintervention risk above a baseline of 10%, 4.6 (95% CI, 3.1–6.2) more hospitalizations above a baseline of 1, a 10.7% (95% CI, 6.5%–14.5%) increase in 5‐year mortality risk above a baseline of 20%, or more limited physical functioning representing nearly 1 New York Heart Association class (0.7 [95% CI, 0.4–1.1]) over 5 years. Conclusions Patients in general preferred TEER over surgery. When holding constant all other factors, a functional improvement from New York Heart Association class III to class I maintained over 5 years would be needed, on average, for patients to prefer surgery over TEER.

Abstract A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.

Objective The ‘Godrevy Project’ is an interventional trial designed to determine the effectiveness of immersive virtual reality (VR) on the holistic symptom control and well-being in oncology and palliative care patients. The primary objective of this study was to determine whether VR changed the revised Edmonton Symptom and Assessment System (ESAS-r) score representing an effective improvement in symptom control and well-being.Methods and analysis This study reports on 60 participants recruited from hospital inpatient oncology and palliative care lists, to participate in an unblinded, VR intervention. Participants were included aged >18 years with a diagnosis of cancer, receiving inpatient treatment of systemic anticancer therapy. Impact evaluation on symptoms was measured using the ESAS-r pre-VR and post-VR intervention. For ethical reasons, participants were not randomised.Results From the 60 inpatients recruited, 58 participants were included for analysis. Participants recruited were aged 19–84 years with female (58%) and male (42%) participation. The primary outcome of the study demonstrated significant improvement in ESAS-r scores for symptoms and well-being. Total ESAS-r scores showed an improvement of 42% compared with baseline, with well-being ESAS-r scores improving 51%. The most common side effect was drowsiness. There were no adverse events related to study participation.Conclusion The ‘Godrevy Project’ successfully demonstrates the feasible, effective use of VR on symptom control and well-being in oncology and palliative care patients. This study demonstrates VR as an effective, patient controlled, non-pharmacological intervention without significant side effects. This interventional trial is well placed to support future research and improve clinical practice.Trial registration number NCT04821466.

Abstract Tumor recurrence affects up to 70% of early-stage hepatocellular carcinoma (HCC) patients, depending on treatment option. Deep learning algorithms allow in-depth exploration of imaging data to discover imaging features that may be predictive of recurrence. This study explored the use of convolutional neural networks (CNN) to predict HCC recurrence in patients with early-stage HCC from pre-treatment magnetic resonance (MR) images. This retrospective study included 120 patients with early-stage HCC. Pre-treatment MR images were fed into a machine learning pipeline (VGG16 and XGBoost) to predict recurrence within six different time frames (range 1–6 years). Model performance was evaluated with the area under the receiver operating characteristic curves (AUC–ROC). After prediction, the model’s clinical relevance was evaluated using Kaplan–Meier analysis with recurrence-free survival (RFS) as the endpoint. Of 120 patients, 44 had disease recurrence after therapy. Six different models performed with AUC values between 0.71 to 0.85. In Kaplan–Meier analysis, five of six models obtained statistical significance when predicting RFS (log-rank p

Abstract Background Overactive bladder (OAB) is defined as urinary urgency accompanied by frequency and nocturia, with or without urge urinary incontinence (UUI). Vibegron, a selective β3-adrenergic receptor agonist approved in the US in December 2020, demonstrated efficacy in reducing symptoms of OAB and was safe and well tolerated in the 12-week EMPOWUR trial and its 40-week, double-blind extension trial. The goal of the COMPOSUR study is to evaluate vibegron in a real-world setting to assess patient treatment satisfaction, tolerability, safety, duration of treatment, and persistence. Methods This is a 12-month, prospective, observational, real-world study, with an optional 12-month extension to 24 months, in the US assessing adults ≥ 18 years old starting a new course of vibegron. Patients must be previously diagnosed with OAB with or without UUI, symptomatic for ≥ 3 months before enrollment, and receive prior treatment with an anticholinergic, with mirabegron, or with a combination of an anticholinergic and mirabegron. Enrollment is performed by the investigator following exclusion and inclusion criteria guided by US product labeling, reinforcing a real-world approach. Patients complete the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q) monthly and the OAB Questionnaire short form (OAB-q-SF) and Work Productivity and Activity Impairment Questionnaire (WPAI:US) at baseline and monthly for 12 months. Patients are followed up via phone call, in-person visits, or telehealth (ie, virtual) visits. The primary endpoint is patient treatment satisfaction as determined by the OAB-SAT-q satisfaction domain score. Secondary endpoints include percent positive responses to individual OAB-SAT-q questions, additional OAB-SAT-q domain scores, and safety. Exploratory endpoints include adherence and persistence. Discussion OAB leads to a significant decrease in quality of life, as well as impairment of work activities and productivity. Persistence with OAB treatments can be challenging, often due to lack of efficacy and adverse effects. COMPOSUR is the first study to provide long-term, prospective, pragmatic treatment data for vibegron in the US and the resultant effect on quality of life among patients with OAB in a real-world clinical setting. Trial registration ClinicalTrials.gov identifier: NCT05067478; registered: October 5, 2021.

Triple-negative breast cancer (TNBC) and its recently identified subtype, quadruple negative breast cancer (QNBC), collectively account for approximately 13% of reported breast cancer cases in the United States. These aggressive forms of breast cancer are associated with poor prognoses, limited treatment options, and lower overall survival rates. In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on TNBC cells both in vitro and in vivo and the deuterated analogs were more potent inhibitors of TNBC cells in vitro. Building upon these findings, our current study delves into the molecular mechanisms underlying this inhibitory action. Through transcriptome and proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Importantly, in direct comparison, our compounds are more effective than enzalutamide and docetaxel in achieving tumor growth inhibition/repression in the AR+ MDA-MD-453 xenograft model in mice. Collectively, our study sheds light on the involvement of SYVN1 E3 ligase in the VNLG-152R-induced degradation of MNK1/2 and the therapeutic potential of VNLG-152R and its more potent deuterated analogs as promising agents for the treatment of TNBC across diverse patient populations.

To investigate the association between enteric pathogens, fecal microbes, and child growth, we conducted a prospective cohort study of 236 children 3 pathogens in their feces. We observed larger increases in height-for-age-z-scores from baseline to the 6-month follow-up among children with Akkermansia muciniphila in their feces (coefficient 0.02 [95% CI 0.0001–0.04]; p = 0.04). Children with Cryptosporidium in their feces had larger declines in weight-for-height/length z-scores from baseline to the 6-month follow-up (coefficient –0.03 [95% CI –0.05 to –0.005]; p = 0.02). Our study showed high prevalence of enteric pathogens among this pediatric cohort and suggests A. muciniphila can potentially serve as a probiotic to improve child growth.

Abstract Background The mental health impacts of the COVID-19 pandemic have been profound. This paper outlines the study protocol for a trial that tests the efficacy of a brief group-based psychological intervention (Coping with COVID; CWC), relative to Supportive Counselling, to reduce distress associated with COVID-19 in a young adult population in Bangalore, India. Methods A single-blind, parallel, randomized controlled trial will be carried out via video conferencing in a small group format. Following informed consent, adults that screen positive for levels of psychological distress (Kessler 10 (K-10 score ≥ 20) and have access to a videoconferencing platform will be randomised to an adapted version of CWC (n = 90) or Supportive Counselling (SC) (n = 90). The primary outcome will be reduction in psychological distress including anxiety and depression at 2-months post treatment. Secondary outcomes include worry, positive wellbeing, and stress in relation to COVID-19. Discussion This treatment trial will assess whether CWC will result in reduced distress relative to Supportive Counselling in a young adult population in Bangalore, India. This study will yield important insights into the role of nonspecific factors versus the intervention’s components in impacting COVID-19 related distress. Trial registration This trial was prospectively registered on the Australian New Zealand Clinical Trials Registry (ACTRN12621001064897). Ethics and dissemination Ethics approval has been obtained from the participating institution, CHRIST University in Bangalore. Results of the trial will be submitted for publication in peer reviewed journals and findings presented at scientific conferences and to key service providers and policy makers.

Background: Few randomized controlled trials evaluate the long-term efficacy and safety of pharmacotherapy for overactive bladder (OAB). This network meta-analysis compares the long-term (52-week) efficacy and safety of vibegron, mirabegron and anticholinergics for the treatment of OAB. Methods: A systematic literature review and network meta-analysis were conducted following PRISMA guidelines using MEDLINE, Embase and Cochrane Central Register of Controlled Trials and terms related to OAB. Efficacy outcomes included change from baseline to week 48–52 in mean daily total urinary incontinence (UI) episodes, mean daily number of micturitions and volume voided/micturition. Efficacy outcomes were analysed using Bayesian models. Commonly reported adverse events (AEs) are described. Results: Of 2098 hits retrieved, 5 publications and 1 study report describing 5 unique randomized controlled trials were included in the analyses. Mean (95% credible interval) change from baseline in total UI episodes for vibegron 75 mg (–2.2; –2.9 to –1.5) showed a significantly greater reduction than mirabegron 50 mg (–1.3; –1.9 to –0.8) and tolterodine 4 mg extended release (–1.6; –2.1 to –1.1). No significant differences were observed between vibegron and comparators for daily micturitions or volume voided/micturition. Within the manuscripts, the 4 most common AEs (range) for anticholinergics included dry mouth (5.2–90.0%), constipation (7.7–65.0%), blurred vision (3.8–35.0%) and hypertension (8.6–9.6%); the 4 most commonly reported AEs for β3-adrenergic agonists included hypertension (8.8–9.2%), urinary tract infection (5.9–6.6%), headache (5.5%) and nasopharyngitis (4.8–5.2%). Conclusion: Vibegron was associated with significantly greater improvement in daily total UI episodes at 52 weeks than mirabegron and tolterodine. When reported, the most common AE for anticholinergics was dry mouth and for β3-adrenergic agonists was hypertension. Hypertension incidence was similar between drug classes.

Aims To assess the real-world evidence for flash glucose monitoring (Abbott FreeStyle Libre) for children with type 1 diabetes in terms of glucose control, secondary healthcare resources and costs.Research design and methods We conducted a controlled before and after study (approximately 12 months before and after) using routinely collected health record data on children who start using flash monitors and a control population of children with self-monitoring of blood glucose (SMBG). Our population-based sample of eligible individuals using flash monitoring (n=114) and controls (n=80) aged between 4 and 18 years was drawn from four paediatric diabetes clinics (secondary care) in the South West England. Outcome measures included: glycated hemoglobin (HbA1c), frequency of BG tests; frequency of sensor scans; time in recommended glucose range; short-term complications (hypoglycemia, diabetic ketoacidosis and related illness resulting in investigation) and secondary care costs.Results After adjustment for age, time since diagnosis, deprivation and the test modality (point of care or laboratory), the mean HbA1c reading for controls was 61.2 (mmol/mol) for the period before and 63.9 after. For individuals using flash monitoring, the adjusted mean HbA1c reading was 64.6 for the period before implementation and 63.8 after. Rates of short-term complications were low across all groups in the study. Whereas the ‘after’ flash monitoring group had substantially higher incremental costs (+£703 vs the flash monitoring ‘before’ comparison and +£841 vs contemporaneous SMBG controls), these cost differences were driven by primary care prescribing (sensor costs).Conclusions There was some indication that flash monitoring might help young people improve the control of their diabetes but for our sample, the difference between finger-prick testing and flash monitoring was not clinically significant (HbA1c improvement

BackgroundThe COVID-19 pandemic triggered a rapid scale-up of telehealth services in Australia as a means to provide continued care through periods of physical restrictions. The factors that influence engagement in telehealth remain unclear. ObjectiveThe purpose of this study is to understand the experience of Australian people who engaged in a telehealth consultation during the pandemic period (2020-2021) and the demographic factors that influence engagement. MethodsA web-based survey was distributed to Australians aged over 18 years that included 4 questions on frequency and type of clinical consultation, including with a general practitioner (GP), specialist, allied health, or nurse; 1 question on the experience of telehealth; and 2 questions on the quality of and satisfaction with telehealth. Statistical analysis included proportion of responses (of positive responses where a Likert scale was used) and regression analyses to determine the effect of demographic variables. ResultsOf the 1820 participants who completed the survey, 88.3% (1607/1820) had engaged in a health care consultation of some type in the previous 12 months, and 69.3% (1114/1607) of those had used telehealth. The most common type of consultation was with a GP (959/1114, 86.1%). Older people were more likely to have had a health care consultation but less likely to have had a telehealth consultation. There was no difference in use of telehealth between metropolitan and nonmetropolitan regions; however, people with a bachelor’s degree or above were more likely to have used telehealth and to report a positive experience. A total of 87% (977/1114) of participants agreed or strongly agreed that they had received the information they required from their consultation, 71% (797/1114) agreed or strongly agreed that the outcome of their consultation was the same as it would have been face-to-face, 84% (931/1114) agreed or strongly agreed that the doctor or health care provider made them feel comfortable, 83% (924/1114) agreed or strongly agreed that the doctor or health care provider was equally as knowledgeable as providers they have seen in person; 57% (629/1114) of respondents reported that they would not have been able to access their health consultation if it were not for telehealth; 69% (765/1114) of respondents reported that they were satisfied with their telehealth consultation, and 60% (671/1114) reported that they would choose to continue to use telehealth in the future. ConclusionsThere was a relatively high level of engagement with telehealth over the 12 months leading up to the study period, and the majority of participants reported a positive experience and satisfaction with their telehealth consultation. While there was no indication that remoteness influenced telehealth usage, there remains work to be done to improve access to older people and those with less than a bachelor’s degree.

The aim of this study was to develop the use of Machine Learning techniques as a means of multivariate analysis in studies of motor control. These studies generate a huge amount of data, the analysis of which continues to be largely univariate. We propose the use of machine learning classification and feature selection as a means of uncovering feature combinations that are altered between conditions. High dimensional electromyogram (EMG) vectors were generated as several arm and trunk muscles were recorded while subjects pointed at various angles above and below the gravity neutral horizontal plane. We used Linear Discriminant Analysis (LDA) to carry out binary classifications between the EMG vectors for pointing at a particular angle, vs. pointing at the gravity neutral direction. Classification success provided a composite index of muscular adjustments for various task constraints—in this case, pointing angles. In order to find the combination of features that were significantly altered between task conditions, we conducted a post classification feature selection i.e., investigated which combination of features had allowed for the classification. Feature selection was done by comparing the representations of each category created by LDA for the classification. In other words computing the difference between the representations of each class. We propose that this approach will help with comparing high dimensional EMG patterns in two ways; (i) quantifying the effects of the entire pattern rather than using single arbitrarily defined variables and (ii) identifying the parts of the patterns that convey the most information regarding the investigated effects.

IntroductionThe majority of studies on oxidative phosphorylation in immune cells have been performed in mouse models, necessitating human translation. To understand the impact of oxidative phosphorylation (OXPHOS) deficiency on human immunity, we studied children with primary mitochondrial disease (MtD).MethodsscRNAseq analysis of peripheral blood mononuclear cells was performed on matched children with MtD (N = 4) and controls (N = 4). To define B cell function we performed phage display immunoprecipitation sequencing on a cohort of children with MtD (N = 19) and controls (N = 16).ResultsVia scRNAseq, we found marked reductions in select populations involved in the humoral immune response, especially antigen presenting cells, B cell and plasma populations, with sparing of T cell populations. MTRNR2L8, a marker of bioenergetic stress, was significantly elevated in populations that were most depleted. mir4485, a miRNA contained in the intron of MTRNR2L8, was co-expressed. Knockdown studies of mir4485 demonstrated its role in promoting survival by modulating apoptosis. To determine the functional consequences of our findings on humoral immunity, we studied the antiviral antibody repertoire in children with MtD and controls using phage display and immunoprecipitation sequencing. Despite similar viral exposomes, MtD displayed antiviral antibodies with less robust fold changes and limited polyclonality.DiscussionOverall, we show that children with MtD display perturbations in the B cell repertoire which may impact humoral immunity and the ability to clear viral infections.

A functional set dahi (fermented milk analogous to yoghurt) with a desirable probiotic (Lactiplantibacillus plantarum A5) count of 9.36 log CFU/mL and excellent techno-functional attributes (DPPH: 41.95% RSA, firmness: 485.49 g, sensory overall acceptability: 8.51) was developed to contain 260 mg of SDG in 20 g of dahi. Twenty-four female Albino Wistar rats (3 months old, >180 g) were ovariectomized (OVX) and divided into three groups: OVX control, OVX and control dahi, and OVX and SDG-enriched dahi. The animal study found that ovariectomy decreased serum calcium, oestrogen, and bone ash calcium levels by 32.27, 30.95, and 48.46 percent, respectively, compared to the sham group (n = 8), while daily administration of SDG-enriched dahi (20 g) for eight weeks restored them. The proximal tibial metaphysis and distal femoral epiphysis micro-CT study showed that the ovariectomy lowered bone mineral density (BMD) by 11.06% and 9.18%, respectively, and lowered Trabecular thickness (Tb. Th) by 12.66% and 11.86%, respectively, while increasing Trabecular separation (Tb. Sp.) by 90.69% and 87.70%, respectively, compared to the sham control-group rats. SDG-enriched dahi improved BMD by 16.06 and 12.24% and Tb. Th by 35.32 and 19.62%, respectively, and decreased Tb. Sp by 47.04 and 47.22%, respectively, in OVX rats. The results suggest that the developed set dahi may help treat postmenopausal osteoporosis.

Abstract Background Accurate data on the types of healthcare people seek in the early stages following mild traumatic brain injury (mTBI) in Australia is lacking. We sought to investigate the types of healthcare people seek following mTBI, including seeking no care at all; ascertain the demographic, pre- and peri-injury factors, and symptom characteristics associated with the care that people access; and examine whether choice of care is associated with symptomatic recovery and quality of life. Methods An online retrospective survey of Australians aged 18 to 65 years who had experienced a self-reported ‘concussion’ (mTBI) within the previous 18 months. Types of healthcare accessed were investigated, as well as those who did not seek any care. Data were analysed using frequency and percentages, chi-squared tests and logistic regression models. Results A total of 201 respondents had experienced a self-reported ‘concussion’ but 21.4% of the respondents did not seek any care. Of the 183 respondents who sought healthcare, 52.5% attended a hospital Emergency Department, 41.0% attended a general practitioner and 6.6% accessed sports-based care. Compared to their counterparts, those who had a lower level of education (p = 0.001), had experienced previous mTBI (p = 0.045) or previous mental health issues (p = 0.009) were less likely to seek healthcare, whilst those who had experienced loss of consciousness (p = 0.014), anterograde (p = 0.044) or retrograde (p = 0.009) amnesia, and symptoms including drowsiness (p = 0.005), nausea (p = 0.040), and feeling slow (p = 0.031) were more likely to seek care. Those who did not seek care were more likely to recover within one month (AOR 4.90, 95%CI 1.51 – 15.89, p = 0.008), albeit the relatively large 95%CI warrants careful interpretation. Compared to seeking care, not seeking care was not found to be significantly associated with symptom resolution nor quality of life (p > 0.05). Conclusions This study provides unique insight into factors associated with healthcare utilisation in the early stages following mTBI, as well as outcomes associated with choice of care, including not seeking care. Delivering targeted community education on the signs and symptoms of mTBI, and the advantages of seeking care following injury is an important step forward in the management of this challenging condition.

The study titled "A Study on the knowledge and attitude of primary school teachers towards inclusive education of children with specific learning disabilities" intended to determine the level of knowledge of primary school teachers on specific learning disabilities and inclusive education, to assess the attitude of primary school teachers towards inclusive education of children with specific learning disabilities, to study the association of teachers' knowledge and their attitude towards inclusive education with selected professional variables, to compare knowledge and attitude of primary school teachers based on educational sub-districts and teaching section, to find the relationship between knowledge and attitude of primary school teachers towards inclusive education of children with specific learning disabilities. The tools used consists of a questionnaire, to collect demographic and professional profile and to assess teachers' knowledge of specific learning disabilities and inclusive education; and the teachers' attitude towards inclusive education scale (TAIS) to understand the attitude of teachers towards inclusive education. The sample consisted of 180 primary school teachers. The result shows that 63% of participants have an average level of knowledge and 51% of the participants have a positive attitude towards inclusive education of children with specific learning disabilities. The study found out that there is a significant correlation between teachers' knowledge and their attitude towards inclusive education.

Objectives Flash glucose monitoring for patients with T1 diabetes avoids frequent painful finger-prick testing, thus potentially improving frequency of glucose self-monitoring. Our study aimed to explore experiences of young people using Freestyle Libre sensors and their parents, and to identify benefits and challenges to National Health Service (NHS) staff of its adoption in their care provision.Participants Young people with T1 diabetes, their parents and healthcare professionals were interviewed between February and December 2021. Participants were recruited via social media and through NHS diabetes clinic staff.Design Semistructured interviews were conducted online and analysed using thematic methods. Staff themes were mapped onto normalisation process theory (NPT) constructs.Results Thirty-four participants were interviewed: 10 young people, 14 parents and 10 healthcare professionals. Young people reported that life was much easier since changing to flash glucose monitoring, increasing confidence and independence to manage their condition. Parents’ quality of life improved and they appreciated access to real-time data. Using the NPT concepts to understand how technology was integrated into routine care proved useful; health professionals were very enthusiastic about flash glucose monitoring and coped with the extra data load to facilitate more tailored patient support within and between clinic visits.Conclusion This technology empowers young people and their parents to understand their diabetes adherence more completely; to feel more confident about adjusting their own care between clinic appointments; and provides an improved interactive experience in clinic. Healthcare teams appear committed to delivering improving technologies, acknowledging the challenge for them to assimilate new information required to provide expert advice.

Abstract Background Stereotactic body radiation therapy (SBRT) for patients with borderline resectable and locally advanced pancreatic adenocarcinoma (BRPC/LAPC) remains controversial. Herein, we report on surgical, pathologic, and survival outcomes in BRPC/LAPC patients treated at a high‐volume institution with induction chemotherapy (CTX) followed by 5‐fraction SBRT. Methods BRPC/LAPC patients treated between 2016 and 2019 were retrospectively reviewed. Surgical and pathological outcomes were descriptively characterized. Overall survival (OS) and progression‐free survival (PFS) were analyzed using Cox proportional hazard regression. Locoregional failure and distant failure were analyzed with Fine–Gray competing risk model. Results Of 155 patients, 91 (59%) had LAPC and 64 (41%) had BRPC. Almost all were treated with induction multi‐agent CTX with either FOLFIRINOX (75%) or gemcitabine and nab‐paclitaxel (24%) for a median duration of 4.0 months (1–18 months). All received SBRT to a median dose of 33 Gy. Among 64 BRPC patients, 50 (78%) underwent resection, of whom 48 (96%) achieved margin‐negative (R0) resection. Among 91 LAPC patients, 57 (63%) underwent resection, of whom 50 (88%) achieved R0 resection. Despite the high R0 rate, 33% of patients experienced locoregional failure, which was a component of 44% of all failures. After SBRT, median OS and PFS were 18.7 and 7.7 months, respectively. After SBRT, 1‐ and 2‐year OS probabilities were 70% and 45%, whereas, from diagnosis, they were 93% and 51%. Conclusions Although a high proportion of BRPC/LAPC patients treated with induction multi‐agent CTX followed by SBRT successfully achieved R0 resection, locoregional failure remained common, highlighting the need to continue to optimize radiation delivery in this context.

Hidradenitis suppurativa (HS) is a common, debilitating inflammatory skin disease linked to immune dysregulation and abnormalities in follicular structure and function. Several studies have characterized the transcriptomic profile of affected and unaffected skin in small populations. In this study of 20 patients, RNA from lesional and matching non-lesional skin biopsies in 20 subjects were used to identify an expression-based HS disease signature. This was followed by differential expression and pathway enrichment analyses, as well as jointly reanalyzing our findings with previously published transcriptomic profiles. We establish an RNA-Seq based HS expression disease signature that is mostly consistent with previous reports. Bulk-RNA profiles from 104 subjects in 7 previously reported data sets identified a disease signature of 118 differentially regulated genes compared to three control data sets from non-lesional skin. We confirmed previously reported expression profiles and further characterized dysregulation in complement activation and host response to bacteria in disease pathogenesis. Changes in the transcriptome of lesional skin in this cohort of HS patients is consistent with smaller previously reported populations. The findings further support the significance of immune dysregulation, in particular with regard to bacterial response mechanisms. Joint analysis of this and previously reported cohorts indicate a remarkably consistent expression profile.

This study aims to elicit consumer preferences regarding telehealth and face-to-face consultations in Australia. It used a discrete choice experiment, presenting participants with a series of hypothetical choices, and based on their responses, infer what is most important to them. Data were analysed using conditional logit regression and latent class analysis. A total of 1,025 participants completed the survey, considering four different clinical scenarios. Face-to-face contacts were, on average, preferred to either telephone or video services. However, telehealth was identified as an attractive option if it prevents significant travel and can be conducted with a familiar doctor. Participants were strongly driven by cost, particularly greater than $30. Telehealth was least preferred for situations involving a new and unknown physical symptom, and relatively more preferred for surgical follow-up. The latent class analysis demonstrates only 15.9% of participants appeared unwilling to consider telehealth. The findings of this study suggest that meeting the needs of the Australian population requires a blended approach to service delivery, with telehealth being valued in a range of clinical scenarios. Price sensitivity was evident, therefore if telehealth services can be delivered with lower patient cost, then they are likely to be attractive.

Abstract Background Viral infection is a major cause of morbidity in children with mitochondrial disease (MtD). As a result, families with children with MtD are highly adherent to risk mitigation behaviours (RMBs) advised by the Centers for Disease Control and Prevention during the COVID‐19 pandemic that can modulate infection risk. Methods Deep serologic phenotyping of viral infections was performed via home‐based sampling by combining SARS‐CoV‐2 serologic testing and phage display immunoprecipitation and sequencing. Samples were collected approximately 1 year apart (October 2020 to April 2021 and October 2021 to March 2022) on households containing a child with MtD. Results In contrast to our first collection in 2020–2021, SARS‐CoV‐2 antibody profiles for all participants in 2021–2022 were marked by greater isotype diversity and the appearance of neutralizing antibodies. Besides SARS‐CoV‐2, households (N = 15) were exposed to >38 different respiratory and gastrointestinal viruses during the study, averaging five viral infections per child with MtD. Regarding clinical outcomes, children with MtD (N = 17) experienced 34 episodes of illness resulting in 6 hospitalizations, with some children experiencing multiple episodes. Neurologic events following illness were recorded in five patients. Infections were identified via clinical testing in only seven cases. Viral exposome profiles were consistent with clinical testing and even identified infections not captured by clinical testing. Conclusions Despite reported adherence to RMBs during the COVID‐19 pandemic by families with a child with MtD, viral infection was pervasive. Not all infections resulted in illness in the child with MtD, suggesting that some were subclinical or asymptomatic. However, selected children with MtD did experience neurologic events. Our studies emphasize that viral infections are inexorable, emphasizing the need for further understanding of host‐pathogen interactions through broad serologic surveillance.

Background: Significant increases in healthcare-associated infections (HAIs) including central-line associated blood stream infections (CLABSIs) have been reported during the COVID-19 pandemic. Acute-care hospitals have faced staffing and personal protective equipment shortages, increased critical care capacity, and diversion of resources from traditional HAI surveillance and prevention efforts. In this study, we characterized CLABSIs among patients with COVID-19 and compared demographics, comorbidities, and outcomes between patients diagnosed with CLABSI with and without COVID-19. Methods: This is an observational retrospective cohort study of all patients diagnosed with CLABSI as defined by NHSN at William P. Clements Jr. University Hospital from April 1, 2020, through September 30, 2021. A retrospective chart review was conducted to identify demographics, comorbidities, and outcomes of hospitalized patients diagnosed with CLABSI. Patients hospitalized with and without COVID-19 were compared using the independent-sample t test for means and the χ2 test for proportions. Results: Overall, 82 patients diagnosed with CLABSI between April 1, 2020, to September 30, 2021, among whom 31 (38%) were hospitalized with COVID-19 and 51 (62%) were not hospitalized with COVID-19. Patients hospitalized with COVID-19 were significantly more likely to be obese (58% for COVID-19 positive vs 26% for COVID-19 negative; P = .01) and to require extracorporeal membrane oxygenation (19% vs 4%; P = .04). However, COVID-19 patients were significantly less likely to have hematologic malignancy (7% vs 28%; P = .03), undergone bone marrow transplantation (0% vs 18%; P = .01), or have neutropenia (3% vs 22%; P = .03). There were no significant differences in line type or organism identified. Gram-positive pathogens were identified in 16 patients (52%) hospitalized with COVID-19. Gram-negative pathogens were identified in 3 patients (10%); fungal organisms were identified in 10 patients (32%), and 2 cases (7%) were polymicrobial. Patients with COVID-19 were significantly more likely to require an ICU stay (84% vs 43%). p Conclusions: High device utilization as well as prolonged hospitalization and line days among patients with COVID-19 along are contributing risk factors for CLABSI among patients hospitalized with COVID-19. This finding highlights the need for ongoing HAI surveillance and prevention efforts in patients hospitalized with COVID-19 given their characteristics and increased risk for CLABSI. Reinforcing infection prevention efforts by accentuating the importance of optimal line care and regular feedback are crucial, especially among patients hospitalized with COVID-19.

Abstract Background General Practitioners (GPs) may be called upon to assess patients who have sustained a concussion despite limited information being available at this assessment. Information relating to how concussion is actually being assessed and managed in General Practice is scarce. This study aimed to identify characteristics of current Western Australian (WA) GP exposure to patients with concussion, factors associated with GPs’ knowledge of concussion, confidence of GPs in diagnosing and managing patients with concussion, typical referral practices and familiarity of GPs with guidelines. Methods In this cross-sectional study, GPs in WA were recruited via the RACGP WA newsletter and shareGP and the consented GPs completed an electronic survey. Associations were performed using Chi-squared tests or Fisher’s Exact test. Results Sixty-six GPs in WA responded to the survey (response rate = 1.7%). Demographics, usual practice, knowledge, confidence, identification of prolonged recovery as well as guideline and resource awareness of GPs who practised in regional and metropolitan areas were comparable (p > 0.05). Characteristics of GPs were similar between those who identified all symptoms of concussion and distractors correctly and those who did not (p > 0.05). However, 84% of the respondents who had never heard of concussion guidelines were less likely to answer all symptoms and distractors correctly (p = 0.039). Whilst 78% of the GPs who were confident in their diagnoses had heard of guidelines (p = 0.029), confidence in managing concussion was not significantly associated with GPs exposure to guidelines. It should be noted that none of the respondents correctly identified signs of concussion and excluded the distractors. Conclusions Knowledge surrounding concussion guidelines, diagnosis and management varied across GPs in WA. Promotion of available concussion guidelines may assist GPs who lack confidence in making a diagnosis. The lack of association between GPs exposure to guidelines and confidence managing concussion highlights that concussion management may be an area where GPs could benefit from additional education and support.

There is a plethora of research assessesing the effect of background music on task performance; however, these results have largely been inconclusive and divided. Music is a powerful medium that possesses a lot of positive benefits. This paper addresses the gaps in the existing literature and attempts to explore the effect of background music on adolescents’ performance in a reading comprehension task. It also examines the role of culture in the said effect of performance, by assessing whether one’s own culture leads to a better performance when compared to both silence and music from a different culture. To this end, an experimental study was conducted on 34 adolescents between the ages of 13–14 (M = 13.50, SD = 0.50). The results indicate that a strong positive effect is achieved on task performance when background music is present, especially one that identifies with the participants’ cultural background.

Background: A challenge during the COVID-19 pandemic has been widespread adherence to risk-reducing behaviors. Individuals with mitochondrial disease (MtD) are special population with an increased risk of morbidity associated with infection. Purpose: To measure risk mitigation behaviors (RMBs) in families affected by MtD and identify factors that may influence these behaviors. Methods: An online questionnaire was distributed in April and June 2020. Individuals with MtD or their caregivers completed the survey. Results: We received 529 eligible responses with n = 312 completing all questions for our multivariate regression model. The most common RMBs were increased hand washing (96%), social distancing (94%), and avoiding public gatherings (93%). Higher numbers of recent healthcare visits (b = 0.62, p

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Abstract Background Small cell lung cancer (SCLC) is a more aggressive subtype of lung cancer that often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. Consequently, such phenotypical characteristics of SCLC set limitations on viable procedural options, making it difficult to develop both screenings and effective treatments. In this study, we examine a novel mechanistic insight in SCLC cells that could potentially provide a more sensitive therapeutic alternative for SCLC patients. Methods Biochemistry studies, including size exclusion chromatography, mass spectrometry, and western blot analysis, were conducted to determine the protein-protein interaction between additional sex combs-like protein 3 (ASXL3) and bromodomain-containing protein 4 (BRD4). Genomic studies, including chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing, and genome-wide analysis, were performed in both human and mouse SCLC cells to determine the dynamic relationship between BRD4/ASXL3/BAP1 epigenetic axis in chromatin binding and its effects on transcriptional activity. Results We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4’s extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. Genetic depletion of ASXL3 results in a genome-wide reduction of histone H3K27Ac levels and BRD4-dependent gene expression in SCLC. Pharmacologically induced inhibition with BET-specific chemical degrader (dBET6) selectively inhibits cell proliferation of a subtype of SCLC that is characterized with high expression of ASXL3. Conclusions Collectively, this study provides a mechanistic insight into the oncogenic function of BRD4/ASXL3/BAP1 epigenetic axis at active chromatin enhancers in SCLC-A subtype, as well as a potential new therapeutic option that could become more effective in treating SCLC patients with a biomarker of ASXL3-highly expressed SCLC cells.

Abstract Background Metastasis directed therapy (MDT) for patients with oligometastatic disease is associated with improvements in progression free survival (PFS) and overall survival (OS) compared to systemic therapy alone. Additionally, within a prostate-cancer-specific cohort, MDT is able to forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be safe and effective in HSOPCa, a large percentage of men will eventually have disease recurrence. Patterns of failure in HSOPCa demonstrate patients tend to have recurrence in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of MDT + radium-223 dichloride in prolonging progression free survival in men with HSOPCa. Methods Patients with HSOPCa and 3 or less metastases with at least 1 bone metastasis will be randomized 1:1 to stereotactic ablative radiation (SABR, also known as stereotactic body radiation therapy (SBRT)) alone vs SABR + radium-223 dichloride with a minimization algorithm to balance assignment by institution, primary intervention, prior hormonal therapy, and PSA doubling time. SABR is delivered in one to five fractions and patients in the SABR + radium-223 dichloride arm will receive six infusions of radium-223 dichloride at four-week intervals. The primary end point is progression free survival. The secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response. Discussion The RAVENS trial will be the first described phase II, non-blinded, randomized study to compare SABR +/− radium-223 dichloride in patients with HSOPCa and 3 or less metastases with at least one bone metastasis. The primary hypothesis is that SABR + radium-223 dichloride will increase median progression-free survival from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm. Trial registrations Clinicaltrials.gov. Identifier: NCT04037358 . Date of Registration: July 30, 2019. Date of First Participant Enrolled: August 9, 2019. Date of Last Approved Amendment: October 16, 2019. Protocol Version: Version 5.

BackgroundFly-In-Fly-Out (FIFO) workers travel to work at isolated locations, and rotate continuous workdays with leave periods at home, and such work practice is common in the offshore oil and gas and onshore mining industry worldwide. The COVID-19 pandemic and accompanying public health actions appear to have had a negative impact on several health-related behaviours among the general population. However, little is known about the impact of the COVID-19 pandemic on the health behaviours of FIFO workers, who have shown higher pre-pandemic rates of risky behaviours than the general population in Australia. This study examined the health-related behaviours of FIFO workers in the mining industry during the COVID-19 pandemic.MethodsA descriptive cross-sectional study was conducted. FIFO workers from an Australian mining company who underwent COVID-19 screening between May and November 2020 completed an online survey about their regular health-related behaviours. The independent sample t-test and Pearson's chi-square test where appropriate were conducted to examine the differences between males and females for the behavioural outcomes.ResultsA total of 768 FIFO workers (633 males and 135 females) participated in the study. Prevalence of smoking was high (32%). Males smoked more cigarettes per day than females (15.2±7.0 vs 13.1±7.1, p = .174). Most participants (74.7%) drank alcohol on more than two days per week. Compared to females, more males (20.2% vs 8.0%) consumed alcohol at short-term harmful levels (p = .010). About a third (34.4%) of the workers (33.5% of males and 38.5% of females, p = .264) engaged in inadequate moderate-vigorous exercises/physical activity. About a third (33.1%) of workers (33.7% of males and 30.4% of females; p = .699) had multiple risk behaviours.ConclusionsPrevalence of multiple risk behaviours was high. Interventions aimed at the prevention of risky health-related behaviours should target the different behavioural patterns and may require emphasis on gender-informed techniques particularly when addressing alcohol consumption.

ObjectiveTo provide a review of prediction models that have been used to measure clinical or pathological progression of chronic kidney disease (CKD).DesignScoping review.Data sourcesMedline, EMBASE, CINAHL and Scopus from the year 2011 to 17th February 2022.Study selectionAll English written studies that are published in peer-reviewed journals in any country, that developed at least a statistical or computational model that predicted the risk of CKD progression.Data extractionEligible studies for full text review were assessed on the methods that were used to predict the progression of CKD. The type of information extracted included: the author(s), title of article, year of publication, study dates, study location, number of participants, study design, predicted outcomes, type of prediction model, prediction variables used, validation assessment, limitations and implications.ResultsFrom 516 studies, 33 were included for full-text review. A qualitative analysis of the articles was compared following the extracted information. The study populations across the studies were heterogenous and data acquired by the studies were sourced from different levels and locations of healthcare systems. 31 studies implemented supervised models, and 2 studies included unsupervised models. Regardless of the model used, the predicted outcome included measurement of risk of progression towards end-stage kidney disease (ESKD) of related definitions, over given time intervals. However, there is a lack of reporting consistency on details of the development of their prediction models.ConclusionsResearchers are working towards producing an effective model to provide key insights into the progression of CKD. This review found that cox regression modelling was predominantly used among the small number of studies in the review. This made it difficult to perform a comparison between ML algorithms, more so when different validation methods were used in different cohort types. There needs to be increased investment in a more consistent and reproducible approach for future studies looking to develop risk prediction models for CKD progression.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease caused by a trinucleotide CAG repeat. SCA7 predominantly causes a loss of photoreceptors in the retina and Purkinje cells of the cerebellum. Severe infantile-onset SCA7 also causes renal and cardiac irregularities. Previous reports have shown that SCA7 results in increased susceptibility to DNA damage. Since DNA damage can lead to accumulation of senescent cells, we hypothesized that SCA7 causes an accumulation of senescent cells over the course of disease. A 140-CAG repeat SCA7 mouse model was evaluated for signs of disease-specific involvement in the kidney, heart, and cerebellum, tissues that are commonly affected in the infantile form. We found evidence of significant renal abnormality that coincided with an accumulation of senescent cells in the kidneys of SCA7140Q/5Q mice, based on histology findings in addition to RT-qPCR for the cell cycle inhibitors p16Ink4a and p21Cip1 and senescence-associated ß-galactosidase (SA-ßgal) staining, respectively. The Purkinje layer in the cerebellum of SCA7140Q/5Q mice also displayed SA-ßgal+ cells. These novel findings offer evidence that senescent cells accumulate in affected tissues and may possibly contribute to SCA7's specific phenotype.

Recently, the use of three-dimensional neural tissues cultured in vitro and called ''cerebral organoids'' has advanced recapitulation of neural development and disease modeling studies. Along with such advances, cerebral organoid research, and associated concerns call for the elucidation of two points: (1) how cerebral organoid research is currently progressing and the future directions it is likely to take, especially in functional assessment of organoids, and (2) how we should solve ethical issues of possible consciousness in cerebral organoid research. This paper aims first to explore these two issues, and then to present implications and prospects for future cerebral organoid research. : Here, Sawai et al. discuss two issues: (1) how cerebral organoid research is currently progressing and the future directions it is likely to take, especially in functional assessment of organoids, and (2) how to approach the ethical issues of possible consciousness in cerebral organoids. The paper concludes with implications and prospects for future cerebral organoid research. Keywords: neuroethics, cerebral organoids, organoids, pluripotent stem cells, consciousness, moral status, functional assessment, neural network

Abstract Background The Cholera-Hospital-Based-Intervention-for-7-Days (CHoBI7) is a handwashing with soap and water treatment intervention program delivered by a health promoter bedside in a health facility and through home visits to diarrhea patients and their household members during the 7 days after admission to a health facility. In a randomized controlled trial among cholera patient households in Bangladesh, the 7-day CHoBI7 program resulted in a significant reduction in cholera among household members of cholera patients and sustained improvements in drinking water quality and handwashing with soap practices 12 months post-intervention. In an effort to take this intervention to scale across Bangladesh in partnership with the Bangladesh Ministry of Health and Family Welfare, this study evaluates the feasibility and acceptability of mobile health (mHealth) programs as a low-cost, scalable approach for CHoBI7 program delivery. Methods Formative research for the development of the CHoBI7 mHealth intervention included 40 semi-structured interviews, 4 mHealth workshops, 2 group discussions, and a pilot study of 52 households to assess the feasibility and acceptability of the developed mHealth program. Thematic analysis of the interviews and group discussions was conducted by two individuals separately based on emergent themes, and then themes were compared and discussed. Results A theory- and evidence-based approach using qualitative research methods was implemented to design the CHoBI7 mHealth program. Semi-structured interviews with government stakeholders identified perceptions and preferences for scaling the CHoBI7 mHealth program. Group discussions and semi-structured interviews with diarrhea patients and their family members identified beneficiary perceptions of mHealth and preferences for CHoBI7 mHealth program delivery. mHealth workshops were conducted as an interactive approach to draft and refine mobile message content based on stakeholder preferences. The pilot findings indicate that the CHoBI7 mHealth program has high user acceptability and is feasible to deliver to diarrhea patients that present at health facilities for treatment in Bangladesh. Both text and voice messages were recommended for program delivery. Dr. Chobi, the sender of mHealth messages, was viewed as a credible source of information that could be shared with others. Conclusion This study presents a theory- and evidence-based approach that can be implemented for the development of future water, sanitation, and hygiene mHealth programs in low-resource settings.

For heritability estimation using a two-component random effects model, we provided formulas for the limiting distribution of the maximum likelihood estimate. These formulas are applicable even when the wrong measure of kinship is used to capture additive genetic correlation. When the model is correctly specified, we showed that the asymptotic sampling variance of heritability estimate is determined by both the study design and the extent of variation in the kinship measure that constitutes the additive genetic correlation matrix. When the correlation matrix is mis-specified, the extent of asymptotic bias depends additionally on how the fitted correlation matrix differs from the truth. In particular, we showed in a simulation study that estimating heritability using a population-based design and the classic GRM as the fitted correlation matrix can potentially contribute to the ”missing heritability” problem.

Prostate cancer (PCa) relies in part on AR-signaling for disease development and progression. Earlier, we developed drug candidate galeterone, which advanced through phase 2-clinical trials in treating castration-resistant PCa (CRPC). Subsequently, we designed, synthesized, and evaluated next-generation galeterone-analogs including VNPP433-3β which is potently efficacious against pre-clinical models of PCa. This study describes the mechanism of action of VNPP433-3β that promotes degradation of full-length AR (fAR) and its splice variant AR-V7 besides depleting MNK1/2 in in vitro and in vivo CRPC models that stably overexpresses fAR. VNPP433-3β directly engages AR within the cell and promotes proteasomal degradation of fAR and its splice variant AR-V7 by enhancing the interaction of AR with E3 ligases MDM2/CHIP but disrupting AR-HSP90 binding. Next, VNPP433-3β decreases phosphorylation of 4EBP1 and abates binding of eIF4E and eIF4G to 5′ cap of mRNA by depleting MNK1/2 with consequent depletion of phosphorylated eIF4E. Finally, RNA-seq demonstrates modulation of multiple pathways that synergistically contribute to PCa inhibition. Therefore, VNPP433-3β exerts its antitumor effect by imposing 1) transcriptional regulation of AR and AR-responsive oncogenes 2) translational regulation by disrupting mRNA-5′cap-dependent translation initiation, 3) reducing AR half-life through enhanced proteasomal degradation in vitro and AR-overexpressing tumor xenografts in vivo.

Introduction Mild traumatic brain injury (mTBI) is a complex injury with heterogeneous physical, cognitive, emotional and functional outcomes. Many who sustain mTBI recover within 2 weeks of injury; however, approximately 10%–20% of individuals experience mTBI symptoms beyond this ‘typical’ recovery timeframe, known as persistent post-concussion symptoms (PPCS). Despite increasing interest in PPCS, uncertainty remains regarding its prevalence in community-based populations and the extent to which poor recovery may be identified using early predictive markers.Objective (1) Establish a research dataset of people who have experienced mTBI and document their recovery trajectories; (2) Evaluate a broad range of novel and established prognostic factors for inclusion in a predictive model for PPCS.Methods and analysis The Concussion Recovery Study (CREST) is a prospective, longitudinal observational cohort study conducted in Perth, Western Australia. CREST is recruiting adults aged 18–65 from medical and community-based settings with acute diagnosis of mTBI. CREST will create a state-wide research dataset of mTBI cases, with data being collected in two phases. Phase I collates data on demographics, medical background, lifestyle habits, nature of injury and acute mTBI symptomatology. In Phase II, participants undergo neuropsychological evaluation, exercise tolerance and vestibular/ocular motor screening, MRI, quantitative electroencephalography and blood-based biomarker assessment. Follow-up is conducted via telephone interview at 1, 3, 6 and 12 months after injury. Primary outcome measures are presence of PPCS and quality of life, as measured by the Post-Concussion Symptom Scale and the Quality of Life after Brain Injury questionnaires, respectively. Multivariate modelling will examine the prognostic value of promising factors.Ethics and dissemination Human Research Ethics Committees of Royal Perth Hospital (#RGS0000003024), Curtin University (HRE2019-0209), Ramsay Health Care (#2009) and St John of God Health Care (#1628) have approved this study protocol. Findings will be published in peer-reviewed journals and presented at scientific conferences.Trial registration number ACTRN12619001226190.

Summary: Background: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years. Methods: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus–associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths. Findings: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries. Interpretation: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries. Funding: Bill & Melinda Gates Foundation.

Pseudocercospora fijiensis is the causal agent of the highly destructive black Sigatoka disease of banana. Previous research has focused on polyketide synthase gene clusters in the fungus, given the importance of polyketide pathways in related plant pathogenic fungi. A time course study of expression of the previously identified PKS7-1, PKS8-2, and PKS10-2 gene clusters showed high expression of all three PKS genes and the associated clustered genes in infected banana plants from 2 weeks post-inoculation through 9 weeks. Engineered transformants silenced for PKS8-2 and PKS10-2 were developed and tested for pathogenicity. Inoculation of banana plants with silencing transformants for PKS10-2 showed significant reduction in disease symptoms and severity that correlated with the degree of silencing in the conidia used for inoculation, supporting a critical role for PKS10-2 in disease development. Unlike PKS10-2, a clear role for PKS8-2 could not be determined. Two of four PKS8-2 silencing transformants showed reduced disease development, but disease did not correlate with the degree of PKS8-2 silencing in the transformants. Overall, the degree of silencing obtained for the PKS8-2 transformants was less than that obtained for the PKS10-2 transformants, which may have limited the utility of the silencing strategy to identify a role for PKS8-2 in disease. Orthologous PKS10-2 clusters had previously been identified in the related banana pathogens Pseudocercospora musae and Pseudocercospora eumusae. Genome analysis identified orthologous gene clusters to that of PKS10-2 in the newly sequenced genomes of Pseudocercospora fuligena and Pseudocercospora cruenta, pathogens of tomato and cowpea, respectively. Our results support an important role for the PKS10-2 polyketide pathway in pathogenicity of Pseudocercospora fijiensis, and suggest a possible role for this pathway in disease development by other Pseudocercospora species.

The international importance of banana and severity of black Sigatoka disease have led to extensive investigations into the genetic characteristics and metabolic interactions between the Dothideomycete Pseudocercospora fijiensis and its banana host. P. fijiensis was shown to have a greatly expanded genome compared to other Dothideomycetes, due to the proliferation of retrotransposons. Genome analysis suggests the presence of dispensable chromosomes that may aid in fungal adaptation as well as pathogenicity. Genomic research has led to the characterization of genes and metabolic pathways involved in pathogenicity, including: secondary metabolism genes such as PKS10-2, genes for mitogen-activated protein kinases such as Fus3 and Slt2, and genes for cell wall proteins such as glucosyl phosphatidylinositol (GPI) and glycophospholipid surface (Gas) proteins. Studies conducted on resistance mechanisms in banana have documented the role of jasmonic acid and ethylene pathways. With the development of banana transformation protocols, strategies for engineering resistance include transgenes expressing antimicrobial peptides or hydrolytic enzymes as well as host-induced gene silencing (HIGS) targeting pathogenicity genes. Pseudocercospora fijiensis has been identified as having high evolutionary potential, given its large genome size, ability to reproduce both sexually and asexually, and long-distance spore dispersal. Thus, multiple control measures are needed for the sustainable control of black Sigatoka disease.