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PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.

We aimed to evaluate the performance of Oxford Nanopore Technologies (ONT) sequencing from positive blood culture (BC) broths for bacterial identification and antimicrobial susceptibility prediction. Patients with suspected sepsis in four intensive care units were prospectively enrolled. Human-depleted DNA was extracted from positive BC broths and sequenced using ONT (MinION). Species abundance was estimated using Kraken2, and a cloud-based system (AREScloud) provided in silico predictive antimicrobial susceptibility testing (AST) from assembled contigs. Results were compared to conventional identification and phenotypic AST. Species-level agreement between conventional methods and AST predicted from sequencing was 94.2% (49/52), increasing to 100% in monomicrobial infections. In 262 high-quality AREScloud AST predictions across 24 samples, categorical agreement (CA) was 89.3%, with major error (ME) and very major error (VME) rates of 10.5% and 12.1%, respectively. Over 90% CA was achieved for some taxa (e.g., Staphylococcus aureus) but was suboptimal for Pseudomonas aeruginosa. In 470 AST predictions across 42 samples, with both high quality and exploratory-only predictions, overall CA, ME, and VME rates were 87.7%, 8.3%, and 28.4%. VME rates were inflated by false susceptibility calls in a small number of species/antibiotic combinations with few representative resistant isolates. Time to reporting from sequencing could be achieved within 8-16 h from BC positivity. Direct sequencing from positive BC broths is feasible and can provide accurate predictive AST for some species. ONT-based approaches may be faster but significant improvements in accuracy are required before it can be considered for clinical use.IMPORTANCESepsis and bloodstream infections carry a high risk of morbidity and mortality. Rapid identification and susceptibility prediction of causative pathogens, using Nanopore sequencing direct from blood cultures, may offer clinical benefit. We assessed this

BACKGROUND: Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection. METHODS: This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI. FINDINGS: Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease

Background: Talimogene laherparepvec (T-VEC), a first-in-class oncolytic viral immunotherapy, enhances tumor-specific immune activation. T-VEC combined with atezolizumab, which blocks inhibitor T-cell checkpoints, could provide greater benefit than either agent alone. Safety/efficacy of the combination was explored in patients with triple negative breast cancer (TNBC) or colorectal cancer (CRC) with liver metastases.ncidence, and secondary endpoints included efficacy and AEs. Methods: In this phase Ib, multicenter, open-label, parallel cohort study of adults with TNBC or CRC with liver metastases, T-VEC (106 then 108 PFU/ml; ≤ 4 ml) was administered into hepatic lesions via image-guided injection every 21 (±3) days. Atezolizumab 1200 mg was given on day 1 and every 21 (±3) days thereafter. Treatment continued until patients experienced dose-limiting toxicity (DLT), had complete response, progressive disease, needed alternative anticancer treatment, or withdrew due to an adverse event (AE). The primary endpoint was DLT incidence, and secondary endpoints included efficacy and AEs. Results: Between 19 March 2018 and 6 November 2020, 11 patients with TNBC were enrolled (safety analysis set: n = 10); between 19 March 2018 and 16 October 2019, 25 patients with CRC were enrolled (safety analysis set: n = 24). For the 5 patients in the TNBC DLT analysis set, no patient had DLT; for the 18 patients in the CRC DLT analysis set, 3 (17%) had DLT, all serious AEs. AEs were reported by 9 (90%) TNBC and 23 (96%) CRC patients, the majority with grade ≥ 3 [TNBC, 7 (70%); CRC, 13 (54%)], and 1 was fatal [CRC, 1 (4%)]. Evidence of efficacy was limited. Overall response rate was 10% (95% confidence interval 0.3-44.5) for TNBC; one (10%) patient had a partial response. For CRC, no patients had a response; 14 (58%) were unassessable. Conclusions: The safety profile reflected known risks with T-VEC including risks of intrahepatic injection; no unexpected safety findings from addition of a

Purpose/objective(s)Radiographic MRI response following prostate radiotherapy, particularly stereotactic body radiotherapy (SBRT), remains poorly understood. Our objective was to describe radiographic changes to the prostate gland and prostate tumor following SBRT of men treated on a prospective, randomized trial.Materials/methodsMIRAGE (NCT04384770) is a single center, randomized phase III trial of patients receiving either CT or MRI guided SBRT for localized prostate cancer. Patients underwent pre-treatment and annual post-treatment MRIs, in addition to routine PSA surveillance. Outcomes reported include percent gland shrinkage, percent PSA response at one year, and presence of residual tumor based on radiographic interpretation. Patient characteristics were compared via two-sample t-test or Fischer's exact test. Both univariate and multivariable logistical analysis were employed to identify potential clinical predictors of residual tumor on 1-year follow up MRI.ResultsThis study cohort included 94 eligible patients with baseline characteristics in Table 1. Residual lesions were seen in 13 patients (14%), 5/27 (18.5%) treated without ADT and 8/67 (12%) with ADT. PSA ablation was deep, with a 79% median decrease without ADT and 98% median decrease with ADT. Patients receiving ADT showed more gland shrinkage (17% vs. 34% shrinkage, p = 0.0001), while radiographic non-responders and responders experienced similar gland shrinkage (median 21% vs 29% shrinkage, p > 0.05). No significant clinical predictors of residual tumor were identified on univariate and multivariate analysis. No patient had any clinical or biochemical evidence of failure.ConclusionA total of 14% of patients were found to have residual tumor detected on MRI one year after SBRT. These data highlight the protracted nature of radiographic tumor response to radiation therapy, even with ablative radiation techniques. The analysis is limited by the lack of biopsy data to quantify whether visualized resi

Financial counselling and income-maximisation services have the potential to reduce financial hardship and its associated burdens on health and wellbeing in High Income Countries. However, referrals to financial counselling services are not systematically integrated into existing health service platforms, thus limiting our ability to identify and link families who might be experiencing financial hardship. Review evidence on this is scarce. The purpose of this study is to review "healthcare-income maximisation" models of care in high-income countries for families of children aged between 0 and 5 years experiencing financial difficulties, and their impacts on family finances and the health and wellbeing of parent(s)/caregiver(s) or children. A systematic review of the MEDLINE, EMBase, PsycInfo, CINAHL, ProQuest, Family & Society Studies Worldwide, Cochrane Library, and Informit Online databases was conducted according to the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement. A total of six studies (five unique samples) met inclusion criteria, which reported a total of 11,603 families exposed to a healthcare-income maximisation model. An average annual gain per person of £1661 and £1919 was reported in two studies reporting one Scottish before-after study, whereby health visitors/midwives referred 4805 clients to money advice services. In another UK before-after study, financial counsellors were attached to urban primary healthcare centres and reported an average annual gain per person of £1058. The randomized controlled trial included in the review reported no evidence of impacts on financial or non-financial outcomes, or maternal health outcomes, but did observe small to moderate effects on child health and well-being. Small to moderate benefits were seen in areas relating to child health, preschool education, parenting, child abuse, and early behavioral adjustment. There was a high level of bias in most studies, and insufficient evi

Extracorporeal membrane oxygenation (ECMO) may be a viable salvage therapy in selected patients with septic shock. As ECMO use increases, we studied left ventricular (LV) performance during sepsis with and without ECMO using a pressure-volume (PV) loop in a murine model and aimed to understand LV hemodynamics in septic shock with ECMO. The rats were divided into Group 1 (ECMO applied to healthy rats), Group 2 (ECMO for septic rats), Group 3 (Controls, n = 20) and Group 4 (Sepsis induction only, n = 20). The cardiac parameters include end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and end-systolic pressure (ESP), ejection fraction (EF), end-systolic elastance (Ees), diastolic time constant (Tau) index, arterial elastance (Ea), pressure-volume area (PVA), stroke work (SW), and potential energy (PE). We compared the changes of parameters in all groups. A total of 74 rats were included in the analyses. After 2 h on ECMO, Group 2 was associated with significant increases in ESP, EDV, ESV, PVA, PE, and SW. The difference ratio of PE and PVA was significantly higher in Group 2 compared to Group 1 (P < 0.01). In conclusion, myocardial oxygen consumption was higher in septic shock with ECMO than in controls.

Background : Housing is a social determinant of health that impacts the health and wellbeing of families and children. Screening and referral to address social determinants of health in healthcare and social service settings has been proposed to support families with housing problems. A systematic review was conducted to catalogue housing screening questions asked of families in healthcare and social service settings, determine if any validated screening tools exist and extract information about any recommendations for action after screening. Methods: The electronic databases MEDLINE, PsycINFO, EMBASE, Ovid Emcare, Scopus and CINAHL were searched from 2009 to 2019. Inclusion criteria were peerreviewed literature that included questions about housing being asked of children or young people aged 0-18 years old and their families accessing any health or social service. We extracted data on the housing questions asked, source of housing questions, validity of questions and tools, descriptions of actions to address housing issues. Findings: Twenty-three peer-reviewed papers met the inclusion criteria. The housing questions in social screening tools vary widely. There are no standard housing-related questions that healthcare and social service providers ask families. Nine screening tools were validated. An action was included as part of 10 social screening tools. Actions for identified housing problems included provision of a community resource guide, referral to a social worker or social service agency, or referral to a housing and child welfare demonstration project. Conclusion : This review provides a catalogue of housing questions and subsequent referral and actions that healthcare and/or social service providers can ask families who may be experiencing housing problems.

Objective: Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. Design Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. Results: neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1(+) dendritic cell activation and CD8(+) T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8(+) T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8(+) T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. Conclusion: CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC., Cancer Research UK (CRUK); Newcastle Experimental Cancer Medicine Centre; Accelerator Award; Fondazione AIRC; MRC program; AstraZeneca; Wellcome Trust; Newcatle University Faculty of Medical Sciences; WE Harker Foundation; Ministry of Economy and Competitiveness (MINECO) (MICINN); Fundació Universitària Agustí Pedro i Pons; Instituto de Salud Carlos III (ISCIII); European Union (EU); European Social Fund; German Research Foundation (DFG); Fulbright España; National Institutes of Health (NIH); Samuel Waxman Cancer Research Foundation; Spanish National Health Institute; Fundación Científica de la Asociación Española Contra el Cáncer; Generalitat de Catalunya; Sara Borrell Fellowship

Background: The COVID-19 pandemic and the associated economic recession has increased parental psychosocial stress and mental health challenges. This has adversely impacted child development and wellbeing, particularly for children from priority populations (culturally and linguistically diverse (CALD) and rural/regional communities) who are at an already increased risk of health inequality. The increased mental health and psychosocial needs were compounded by the closure of in-person preventive and health promotion programs resulting in health organisations embracing technology and online services. Watch Me Grow- Electronic (WMG-E) – developmental surveillance platform- exemplifies one such service. WMG-E was developed to monitor child development and guide parents towards more detailed assessments when risk is identified. This Randomised Controlled Trial (RCT) aims to expand WMG-E as a digital navigation tool by also incorporating parents’ mental health and psychosocial needs. Children and families needing additional assessments and supports will be electronically directed to relevant resources in the ‘care-as-usual’ group. In contrast, the intervention group will receive continuity of care, with additional in-person assessment and ‘warm hand over’ by a ‘service navigator’ to ensure their needs are met. Methods: Using an RCT we will determine: (1) parental engagement with developmental surveillance; (2) access to services for those with mental health and social care needs; and (3) uptake of service recommendations. Three hundred parents/carers of children aged 6 months to 3 years (recruited from a culturally diverse, or rural/regional site) will be randomly allocated to the ‘care-as-usual’ or ‘intervention’ group. A mixed methods implementation evaluation will be completed, with semi-structured interviews to ascertain the acceptability, feasibility and impact of the WMG-E platform and service navigator. Conclusions: Using WMG-E is expected to: normalise and de-sti

Introduction Poverty and deprivation can harm children's future health, learning, economic productivity and societal participation. The Australian Healthier Wealthier Families project seeks to reduce the childhood inequities caused by poverty and deprivation by creating a systematic referral pathway between two free, community-based services: Universal, well-child nursing services, which provide health and development support to families with children from birth to school entry, and financial counselling. By adapting the successful Scottish 'Healthier Wealthier Children' model, the objectives of this Australian pilot are to test the (1) feasibility of systematising the referral pathway, and (2) short-term impacts on household finances, caregiver health, parenting efficacy and financial service use. Methods and analysis This pilot randomised controlled trial will run in three sites across two Australian states (Victoria and New South Wales), recruiting a total of 180 participants. Nurses identify eligible caregivers with a 6-item, study-designed screening survey for financial hardship. Caregivers who report one or more risk factors and consent are randomised. The intervention is financial counselling. The comparator is usual care plus information from a government money advice website. Feasibility will be evaluated using the number/proportion of caregivers who complete screening, consent and research measures, and access financial counselling. Though powered to assess feasibility, impacts will be measured 6 months post-enrolment with qualitative interviews and questionnaires about caregiver-reported income, loans and costs (adapted from national surveys, for example, the Household, Income and Labour Dynamics in Australia Survey); health (General Health Questionnaire 1, EuroQol five-dimensional questionnaire, Depression, Anxiety, Stress Scale short-form); efficacy (from the Longitudinal Study of Australian Children); and financial service use (study-designed) compared

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Introduction: Septic shock remains amongst the leading causes of childhood mortality. Therapeutic options to support children with septic shock refractory to initial resuscitation with fluids and inotropes are limited. Recently, the combination of intravenous hydrocortisone with high dose ascorbic acid and thiamine (HAT therapy), postulated to reduce sepsis-related organ dysfunction, has been proposed as a safe approach with potential for mortality benefit, but randomized trials in paediatric patients are lacking. We hypothesize that protocolised early use of HAT therapy ("metabolic resuscitation") in children with septic shock is feasible and will lead to earlier resolution of organ dysfunction. Here, we describe the protocol of the Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation-A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU). Methods and Analysis: The RESPOND PICU study is an open label randomized-controlled, two-sided multicentre pilot study conducted in paediatric intensive care units (PICUs) in Australia and New Zealand. Sixty children aged between 28 days and 18 years treated with inotropes for presumed septic shock will be randomized in a 1:1 ratio to either metabolic resuscitation (1 mg/kg hydrocortisone q6h, 30 mg/kg ascorbic acid q6h, 4 mg/kg thiamine q12h) or standard septic shock management. Main outcomes include feasibility of the study protocol and survival free of organ dysfunction censored at 28 days. The study cohort will be followed up at 28-days and 6-months post enrolment to assess neurodevelopment, quality of life and functional status. Biobanking will allow ancillary studies on sepsis biomarkers. Ethics and Dissemination: The study received ethical clearance from Children's Health Queensland Human Research Ethics Committee (HREC/18/QCHQ/49168) and commenced enrolment on June 12th, 2019. The primary study findings will be submitted for publication in a peer-reviewed journal. Trial Regist

INTRODUCTION: Poverty has far-reaching and detrimental effects on children's physical and mental health, across all geographies. Financial advice and income-maximisation services can provide a promising opportunity for shifting the physical and mental health burdens that commonly occur with financial hardship, yet awareness of these services is limited, and referrals are not systematically integrated into existing healthcare service platforms. We aim to map and synthesise evidence on the impact of healthcare-income maximisation models of care for families of children aged 0-5 years in high-income countries on family finances, parent/caregiver(s) or children's health and well-being. METHODS AND ANALYSIS: To be included in the review, studies must be families (expectant mothers or parents/caregivers) of children who are aged between 0 and 5 years, accessing a healthcare service, include a referral from healthcare to an income-maximisation service (ie, financial counselling), and examine impacts on child and family health and well-being. A comprehensive electronic search strategy will be used to identify studies written in English, published from inception to January 2021, and indexed in MEDLINE, EMBase, PsycINFO, CINAHL, Proquest, Family & Society Studies Worldwide, Cochrane Library, and Informit Online. Search strategies will include terms for: families, financial hardship and healthcare, in various combinations. Bibliographies of primary studies and review articles meeting the inclusion criteria will be searched manually to identify further eligible studies, and grey literature will also be searched. Data on objective and self-reported outcomes and study quality will be independently extracted by two review authors; any disagreements will be resolved through a third reviewer. The protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. ETHICS AND DISSEMINATION: Ethical approval is not required. The results will be disseminate

BACKGROUND: Sepsis contributes significantly to morbidity and mortality globally. In Australia, 20,000 develop sepsis every year, resulting in 5,000 deaths, and more than AUD$846 million in expenditure. Prompt, appropriate antibiotic therapy is effective in improving outcomes in sepsis. Conventional culture-based methods to identify appropriate therapy have limited yield and take days to complete. Recently, nanopore technology has enabled rapid sequencing with real-time analysis of pathogen DNA. We set out to demonstrate the feasibility and diagnostic accuracy of pathogen sequencing direct from clinical samples, and estimate the impact of this approach on time to effective therapy when integrated with personalised software-guided antimicrobial dosing in children and adults on ICU with sepsis. METHODS: The DIRECT study is a pilot prospective, non-randomized multicentre trial of an integrated diagnostic and therapeutic algorithm combining rapid direct pathogen sequencing and software-guided, personalised antibiotic dosing in children and adults with sepsis on ICU. PARTICIPANTS AND INTERVENTIONS: DIRECT will collect microbiological and pharmacokinetic samples from approximately 200 children and adults with sepsis admitted to one of four ICUs in Brisbane. In Phase 1, we will evaluate Oxford Nanopore Technologies MinION sequencing direct from blood in 50 blood culture-proven sepsis patients recruited from consecutive patients with suspected sepsis. In Phase 2, a further 50 consecutive patients with suspected sepsis will be recruited in whom MinION sequencing will be combined with Bayesian software-guided (ID-ODS) personalised antimicrobial dosing. OUTCOME MEASURES: The primary outcome is time to effective antimicrobial therapy, defined as trough drug concentrations above the MIC of the pathogen. Secondary outcomes are diagnostic accuracy of MinION sequencing from whole blood, time to pathogen identification and susceptibility testing using sequencing direct from whole bl

© 2020 National Academy of Sciences. All rights reserved. T cells exhibit remarkable sensitivity and selectivity in detecting and responding to agonist peptides (p) bound to MHC molecules in a sea of self pMHC molecules. Despite much work, understanding of the underlying mechanisms of distinguishing such ligands remains incomplete. Here, we quantify T cell discriminatory capacity using channel capacity, a direct measure of the signaling network's ability to discriminate between antigen-presenting cells (APCs) displaying either self ligands or a mixture of self and agonist ligands. This metric shows how differences in information content between these two types of peptidomes are decoded by the topology and rates of kinetic proofreading signaling steps inside T cells. Using channel capacity, we constructed numerically substantiated hypotheses to explain the discriminatory role of a recently identified slow LAT Y132 phosphorylation step. Our results revealed that in addition to the number and kinetics of sequential signaling steps, a key determinant of discriminatory capability is spatial localization of a minimum number of these steps to the engaged TCR. Biochemical and imaging experiments support these findings. Our results also reveal the discriminatory role of early negative feedback and necessary amplification conferred by late positive feedback.

Aim: Refugees are at increased risk of tuberculosis infection due to time spent in crowded camps, decreased nutrition and originating from countries whose own tuberculosis control systems may have been disturbed. In Australia, tuberculosis is screened for in for all refugees aged 11–34 years old and in those aged 2–10 years arriving from high-incidence countries. Our aims were to determine if refugee children aged under 2 years of age should also be screened. Methods: A systematic literature review and meta-regression was carried out on studies in refugee children under 18 years old, involving screening for tuberculosis (active or latent tuberculosis infection (LTBI)). Studies were extracted from the last 10 years from a range of bibliographic databases using the search terms ‘tuberculosis’, ‘children’, ‘screening’ and ‘refugee’, which tested for tuberculosis using the tuberculin skin test (TST) or QuantiFERON-Gold (Interferon Gamma Release Assay (IGRA)). Results: Of the 15 included studies, prevalence of LTBI in < 2-year-olds was 5% using IGRA and 15% using TST (P < 0.05). Prevalence increased with age (odds ratio 1.12; 95% confidence interval: 1.06–1.17) cumulatively and decreased where IGRA was used for screening compared to TST (odds ratio 0.38; 95% confidence interval: 0.25–0.58). Prevalence of LTBI did not differ between general versus clinic refugee cohorts. Conclusions: Refugees are a particularly vulnerable group in their susceptibility to tuberculosis, and LTBI management is a critical part of tuberculosis disease control due to the lifetime risk of developing active tuberculosis. A prevalence of 5–15% for LTBI in the under 2 years age group would support them being included in screening programmes.

Introduction Immigration detention has a profound and negative impact on the physical health, mental health, development and social-emotional well-being of children, adolescents and their families. Australian clinicians will report results from detailed health and well-being assessments of asylum seeking children and adolescents who have experienced prolonged immigration detention. Methods and analysis This is a national, multicentre study with a longitudinal cohort design that will document health and well-being outcomes of the children and adolescents who have been detained in offshore detention on the remote island of Nauru. Outcome measures will be reported from the time arrival in Australia and repeated over a 5-year follow-up period. Measures include demographics, residency history and refugee status, physical health and well-being outcomes (including mental health, development and social-emotional well-being), clinical service utilisation and psychosocial risk and protective factors for health and well-being (eg, adverse childhood experiences). Longitudinal follow-up will capture outcomes over a 5-year period after arrival in Australia. Analysis will be undertaken to explore baseline risk and protective factors, with regression analyses to assess their impact on health and well-being outcomes. To understand how children's outcomes change over time, multilevel regression analysis will be utilised. Structural equation modelling will be conducted to explore the correlation between baseline factors, mediational factors and outcomes to assess trajectories over time. Ethics and dissemination This research project was approved by the Sydney Children's Hospitals Network Human Research Ethics Committee. Subsequent site-specific approvals have been approved in 5 of the 11 governing bodies where the clinical consultations took place. In order to ensure this research is relevant and sensitive to the needs of the cohort, our research team includes an asylum seeker who has

Introduction Immigration detention has a profound and negative impact on the physical health, mental health, development and social-emotional well-being of children, adolescents and their families. Australian clinicians will report results from detailed health and well-being assessments of asylum seeking children and adolescents who have experienced prolonged immigration detention. Methods and analysis This is a national, multicentre study with a longitudinal cohort design that will document health and well-being outcomes of the children and adolescents who have been detained in offshore detention on the remote island of Nauru. Outcome measures will be reported from the time arrival in Australia and repeated over a 5-year follow-up period. Measures include demographics, residency history and refugee status, physical health and well-being outcomes (including mental health, development and social-emotional well-being), clinical service utilisation and psychosocial risk and protective factors for health and well-being (eg, adverse childhood experiences). Longitudinal follow-up will capture outcomes over a 5-year period after arrival in Australia. Analysis will be undertaken to explore baseline risk and protective factors, with regression analyses to assess their impact on health and well-being outcomes. To understand how children's outcomes change over time, multilevel regression analysis will be utilised. Structural equation modelling will be conducted to explore the correlation between baseline factors, mediational factors and outcomes to assess trajectories over time. Ethics and dissemination This research project was approved by the Sydney Children's Hospitals Network Human Research Ethics Committee. Subsequent site-specific approvals have been approved in 5 of the 11 governing bodies where the clinical consultations took place. In order to ensure this research is relevant and sensitive to the needs of the cohort, our research team includes an asylum seeker who has

Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty acid synthesis in CNS leukemia, highlighting stearoyl-CoA desaturase (SCD) as a key player. In vivo SCD overexpression increases CNS disease, whereas genetic or pharmacological inhibition of SCD decreases CNS load. Overall, we demonstrated that leukemic cells dynamically rewire metabolic pathways to suit local conditions and that targeting these adaptations can be exploited therapeutically.

Background: Children from refugee backgrounds are less likely to access appropriate health and social care than non-refugee children. Our aim was to identify refugee children's health/wellbeing strengths and needs, and the barriers and enablers to accessing services while preparing for primary and secondary school, in a low socio-economic multicultural community in Australia. Method: Ten focus groups were facilitated with Arabic-speaking refugee parents of children aged 2-5 years (n = 11) or in first year secondary school (n = 22); refugee adolescents starting high school (n = 16); and key service providers to refugee families (n = 27). Vignettes about a healthy child and a child with difficulties guided the discussions. Data was thematically analysed and feedback sought from the community via the World Café method. Results: Personal resilience and strong family systems were identified as strengths. Mental health was identified as a complex primary need; and whilst refugees were aware of available services, there were issues in knowing how to access them. Opportunities for play/socialisation were recognised as unmet adolescent needs. Adults spoke of a need to support integration of "old" and "new" cultural values. Parents identified community as facilitating health knowledge transfer for new arrivals; whilst stakeholders saw this as a barrier when systems change. Most parents had not heard of early childhood services, and reported difficulty accessing child healthcare. Preschooler parents identified the family "GP" as the main source of health support; whilst parents of adolescents valued their child's school. Health communication in written (not spoken) English was a significant roadblock. Differences in refugee family and service provider perceptions were also evident. Conclusions: Refugee families face challenges to accessing services, but also have strengths that enable them to optimise their children's wellbeing. Culturally-tailored models of care embedded with

BackgroundHepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide.AimTo generate recommendations for the management of Asian Americans infected with HBV.MethodsThese guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women.ResultsAsian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti-viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3 , basal core promoter (BCP) mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life-long anti-viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life-long surveillance for HCC with alpha-fetoprotein (AFP) testing and abdominal ultrasound examination at 6-month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3-month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence.ConclusionsApplication of the re

Item does not contain fulltext, Purpose of review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. Summary: The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.

Image Processing has traditionally been one of the most popular applications of FPGAs. Usually computationally expensive, image processing algorithms are best implemented on customizable hardware platforms like FPGA boards. The process of convolution has been a very powerful tool in identifying the response of a system given an input. The same thing can be extended to image processing in the sense that it is used for the purpose of finding the output image when acted upon by various filters [1]. In this paper, we have restricted ourselves to finding the resultant image when applied upon by sobel mask (to perform edge detection). The sobel mask is used so as to detect edges and identify whether the edges of an image are spurious. The coefficients of the mask are then convolved with the gray scale images so as to produce desired images. This paper presents a novel implementation of Edge detection using a Sobel mask on a Zynq 7000 board

BACKGROUND: Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide. AIM: To generate recommendations for the management of Asian Americans infected with HBV. METHODS: These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women. RESULTS: Asian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>10 CONCLUSIONS: Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.

Congres abstracts: 3rd URSI – RCRS, International Union of Radio Science Regional Conference on Radio Science 2017, Tirupati, India

LiMnBO3 has been identified as a promising cathode material for next-generation lithium-ion batteries. In this study, LiMnBO3 along with glassy lithium borate material (LiMnBO3 (II)) is synthesized by sol-gel method. X-ray diffraction (XRD) analysis depicts the existence of LiBO2 glassy phase along with m-LiMnBO3 phase. Transmission electron microscopy (TEM) analysis confirms the presence of LiBO2 glassy phase. An enhanced electrical conductivity of 3.64 x 10(-7) S/cm is observed for LiMnBO3 (II). The LiBO2 glassy phase is found to promote the Li reaction kinetics in LiMnBO3 (II). The synthesized LiMnBO3 (II) delivers a first discharge capacity of 310 mAh g(-1) within a potential window of 1.5-4.5 V at C/10 rate. Further, a discharge capacity of 186 mAh g(-1) at the 27th cycle shows a better cycle performance. The enhanced capacity is due to the presence of LiBO2 glassy phase and more than one Li-ion transfer in the lithium-rich stoichiometry of LiMnBO3 (II). Density functional theory calculation reveals the exact electronic structure of m-LiMnBO3 with a band gap of 3.05 eV. A charge transfer mechanism is predicted for delithiation process of m-LiMnBO3., QC 20170713

Background: Optimal breastfeeding has benefits for the mother-infant dyads. This study investigated the prevalence and determinants of cessation of exclusive breastfeeding (EBF) in the early postnatal period in a culturally and linguistically diverse population in Sydney, New South Wales, Australia. Methods: The study used routinely collected perinatal data on all live births in 2014 (N = 17,564) in public health facilities in two Local Health Districts in Sydney, Australia. The prevalence of mother's breastfeeding intention, skin-to-skin contact, EBF at birth, discharge and early postnatal period (1-4 weeks postnatal) were estimated. Multivariate logistic regression models that adjusted for confounders were conducted to determine association between cessation of EBF in the early postnatal period and socio-demographic, psychosocial and health service factors. Results: Most mothers intended to breastfeed (92%), practiced skin-to-skin contact (81%), exclusively breastfed at delivery (90%) and discharge (89%). However, the prevalence of EBF declined (by 27%) at the early postnatal period (62%). Younger mothers (<20 years) and mothers who smoked cigarettes in pregnancy were more likely to cease EBF in the early postnatal period compared to older mothers (20-39 years) and those who reported not smoking cigarettes, respectively [Adjusted Odds Ratio (AOR) =2.7, 95%CI 1.9-3.8, P <0.001 and AOR = 2.5, 95%CI 2.1-3.0, P <0.001, respectively]. Intimate partner violence, assisted delivery, low socio-economic status, pre-existing maternal health problems and a lack of partner support were also associated with early cessation of EBF in the postnatal period. Conclusions: Our findings suggest that while most mothers intend to breastfeed, and commence EBF at delivery and at discharge, the maintenance of EBF in the early postnatal period is sub-optimal. This highlights the need for efforts to promote breastfeeding in the wider community along with targeted actions for disadvantaged gr

Neuroimaging increasingly exploits machine learning techniques in an attempt to achieve clinically relevant single-subject predictions. An alternative to machine learning, which tries to establish predictive links between features of the observed data and clinical variables, is the deployment of computational models for inferring on the (patho)physiological and cognitive mechanisms that generate behavioural and neuroimaging responses. This paper discusses the rationale behind a computational approach to neuroimaging-based single-subject inference, focusing on its potential for characterising disease mechanisms in individual subjects and mapping these characterisations to clinical predictions. Following an overview of two main approaches - Bayesian model selection and generative embedding - which can link computational models to individual predictions, we review how these methods accommodate heterogeneity in psychiatric and neurological spectrum disorders, help avoid erroneous interpretations of neuroimaging data, and establish a link between a mechanistic, model-based approach and the statistical perspectives afforded by machine learning.

QC 20170217

Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models and indispensable for development of structural biology processing methods. Here, we established a diffraction data publication and dissemination system, Structural Biology Data Grid (SBDG; data. sbgrid. org), to preserve primary experimental data sets that support scientific publications. Data sets are accessible to researchers through a community driven data grid, which facilitates global data access. Our analysis of a pilot collection of crystallographic data sets demonstrates that the information archived by SBDG is sufficient to reprocess data to statistics that meet or exceed the quality of the original published structures. SBDG has extended its services to the entire community and is used to develop support for other types of biomedical data sets. It is anticipated that access to the experimental data sets will enhance the paradigm shift in the community towards a much more dynamic body of continuously improving data analysis.

Contains fulltext : 157563.pdf (publisher's version ) (Closed access), High-resolution blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at the sub-millimeter scale has become feasible with recent advances in MR technology. In principle, this would enable the study of layered cortical circuits, one of the fundaments of cortical computation. However, the spatial layout of cortical blood supply may become an important confound at such high resolution. In particular, venous blood draining back to the cortical surface perpendicularly to the layered structure is expected to influence the measured responses in different layers. Here, we present an extension of a hemodynamic model commonly used for analyzing fMRI data (in dynamic causal models or biophysical network models) that accounts for such blood draining effects by coupling local hemodynamics across layers. We illustrate the properties of the model and its inversion by a series of simulations and show that it successfully captures layered fMRI data obtained during a simple visual experiment. We conclude that for future studies of the dynamics of layered neuronal circuits with high-resolution fMRI, it will be pivotal to include effects of blood draining, particularly when trying to infer on the layer-specific connections in cortex - a theme of key relevance for brain disorders like schizophrenia and for theories of brain function such as predictive coding.

One of the key challenges in computational biology is prediction of three-dimensional protein structures from amino-acid sequences. For most proteins, the "native state" lies at the bottom of a free-energy landscape. Protein structure prediction involves varying the degrees of freedom of the protein in a constrained manner until it approaches its native state. In the Rosetta protein structure prediction protocols, a large number of independent folding trajectories are simulated, and several lowest-energy results are likely to be close to the native state. The availability of hundred-teraflop, and shortly, petaflop, computing resources is revolutionizing the approaches available for protein structure prediction. Here, we discuss issues involved in utilizing such machines efficiently with the Rosetta code, including an overview of recent results of the Critical Assessment of Techniques for Protein Structure Prediction 7 (CASP7) in which the computationally demanding structure-refinement process was run on 16 racks of the IBM Blue Gene/L (TM) system at the IBM T. J. Watson Research Center. We highlight recent advances in high-performance computing and discuss,future development paths that make use of the next-generation petascale (> 10(12) floating-point operations per second) machines.

With the increasing importance of high dynamic range (HDR) imaging and low availability of HDR displays, the need for efficient tone mapping techniques is very crucial. However the tone mapping operators tend to introduce distortions in the HDR images, thus making it visually unpleasant in normal displays. Subjective evaluation of images is important for rating the tone mapping operators as the users should be able to visualize the complete details present in both the brightly and poorly illuminated regions of the scene. To facilitate a systematic subjective study we have created a database of HDR images tone mapped using popular operators. We conducted a subjective study of the tone mapped images, computed objective scores by using some of the state-of-the-art no-reference low dynamic range image quality assessment algorithms and evaluated their performance. We show that a moderate correlation between objective and subjective scores indicates the need for the consideration of human perception in rating tone mapping operators.

Introduction: Young people are regarded as one of the most vulnerable groups in the Solomon Islands (SI). While improving adolescent sexual and reproductive health (ASRH) and rights is acknowledged as being critical to the wider development agenda of SI, there is little known about ASRH service delivery. Aims: To identify barriers to ASRH service provision in SI, and explore opportunities to effectively address them. Methods: In this mixed methods study, we conducted focus group discussions, semi-structured interviews and a specialised survey, which provided a snapshot of ASRH skills and service provision with 147 teachers, principals, youth and health workers. Stakeholder meetings were held at the beginning and end of data gathering to generate stakeholders’ suggestions on policy recommendations. Results: Survey responses by health and education workers identified ambivalent attitudes toward providing ASRH services, knowledge gaps and inadequate adolescent specific training. The workers identified several barriers to young people accessing ASRH services including cultural issues, poor access to information, resource and infrastructure constraints, uncertainty about professional roles, and a poor understanding of policy related to youth and ASRH. A number of strategies to overcome these barriers were identified: including ASRH in education, welfare and health sector job descriptions; investing in training in ASRH and counselling skills; improving supply of contraceptives; and building sustainable partnerships between sectors. Conclusion: Improving ASRH provision in the SI is possible given the right support from government and global agencies; and a commitment to collaborative inter-sectoral action.

Nephronophthisis (NPHP) is the major cause of pediatric renal failure, yet the disease remains poorly understood, partly due to the lack of appropriate animal models. Joubert syndrome (JBTS) is an inherited ciliopathy giving rise to NPHP with cerebellar vermis aplasia and retinal degeneration. Among patients with JBTS and a cerebello-oculo-renal phenotype, mutations in CEP290 (NPHP6) are the most common genetic lesion. We present a Cep290 gene trap mouse model of JBTS that displays the kidney, eye, and brain abnormalities that define the syndrome. Mutant mice present with cystic kidney disease as neonates. Newborn kidneys contain normal amounts of lymphoid enhancer-binding factor 1 (Lef1) and transcription factor 1 (Tcf1) protein, indicating normal function of the Wnt signaling pathway; however, an increase in the protein Gli3 repressor reveals abnormal Hedgehog (Hh) signaling evident in newborn kidneys. Collecting duct cells from mutant mice have abnormal primary cilia and are unable to form spheroid structures in vitro. Treatment of mutant cells with the Hh agonist purmorphamine restored normal spheroid formation. Renal epithelial cells from a JBTS patient with CEP290 mutations showed similar impairments to spheroid formation that could also be partially rescued by exogenous stimulation of Hh signaling. These data implicate abnormal Hh signaling as the cause of NPHP and suggest that Hh agonists may be exploited therapeutically.

Polymers arewidely utilized as protective coatings to prevent metal surfaces from wear, corrosion, or bio-fouling.Yet, stability and adhesive properties of polymer to metal bondings are not fully understood at themolecular level. Here,wemeasured the interaction forces between a gold electrode surface and amine-functionalized polymers (PEG) using a novel electrochemical surface forces apparatus. We examined the potential dependence of specific amine.gold interactions and measured that the binding strength of amine.gold bonds can range from 0.5 to 40 kBT per binding site, depending on the applied electrochemical potential. Notably, this interaction exhibits a pronounced minimum around the potential of zero charge, where the polymer.gold adhesion is dominated by non-specific interactions between the polymer backbone and electrode surface, consistent with the adhesion of PEG polymers with gold surfaces in the absence of amine functionalization. Further, repulsive hydration interactions were observed to be stronger for amine-terminated PEG compared to non-functionalized PEG, due to increased hydration and presence of counterions in the case of amine-terminated PEG. Our results provide molecular-scale insight into design and optimization of polymer coatings for numerous applications requiring strong, specific binding interactions between polymers and metals (or their native oxides), for example passivating layers in biomedical implants and electronic devices. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.