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The conversion of white adipose to the highly thermogenic beige adipose tissue has been proposed as a potential strategy to counter the unfavorable consequences of obesity. Three regulators of this conversion have recently emerged but information regarding their control is limited, and contradictory. We present two studies examining the control of these regulators. Study 1: In 10 young men, the plasma concentrations of irisin and fibroblast growth factor 21 (FGF21) were determined prior to and during activation of the sympathetic nervous system via hypoxic gas breathing (FIO2 = 0.11). The measurements were performed twice, once with and once without prior/concurrent sympathetic inhibition via transdermal clonidine administration. FGF21 was unaffected by basal sympathetic inhibition (338±113 vs. 295±80 pg/mL; P = 0.43; mean±SE), but was increased during hypoxia mediated sympathetic activation (368±135); this response was abrogated (P = 0.035) with clonidine (269±93). Irisin was unaffected by sympathetic inhibition and/or hypoxia (P>0.21). Study 2: The plasma concentration of irisin and FGF21, and the skeletal muscle protein content of fibronectin type III domain containing 5 (FNDC5) was determined in 19 young adults prior to and following three weeks of sprint interval training (SIT). SIT decreased FGF21 (338±78 vs. 251±36; P = 0.046) but did not affect FNDC5 (P = 0.79). Irisin was decreased in males (127±18 vs. 90±23 ng/mL; P = 0.045) and increased in females (139±14 vs. 170±18). Collectively, these data suggest a potential regulatory role of acute sympathetic activation pertaining to the browning of white adipose; further, there appears to be a sexual dimorphic response of irisin to SIT.

BACKGROUND: Young adult Mexican Americans (MA) exhibit lower insulin sensitivity (Si) than nonHispanic whites (NHW), even when controlling for fitness and adiposity. It is unclear if MA are as responsive to the same lifestyle intervention as NHW. OBJECTIVE: We developed a model to examine cardiometabolic plasticity (i.e., changes in Si and plasma lipids) in MA compared to NHW adults in response to a diet-exercise intervention. DESIGN: Sedentary subjects (20 NHW: 11F, 9M, 23.0 y, 25.5 kg/m(2); 17 MA: 13F, 4M, 22.7 y, 25.4 kg/m(2)) consumed their habitual diets and remained sedentary for 7 days, after which fasting blood samples were obtained, and a 3-h intravenous glucose tolerance test (IVGTT) was performed with the insulin area under the curve (IAUC) used to estimate Si. Subjects then completed a 7-day diet/exercise intervention (diet: low saturated fat, low added sugar, high fiber; exercise: cycling, six total sessions lasting 40-45 min/session at 65% VO(2) max). Pre-intervention tests were repeated. RESULTS: Pre intervention IAUC was 28% higher (p

Objectives. Many AS patients report periods of perceived higher disease activity (flares). This pilot study aims to document disease activity patterns reported by AS patients and examine associations with disease-specific health status measures. Methods. Consecutive AS patients (n = 114) were asked whether they experience flares, and if they experience symptoms of AS between flares. They were shown the Flare Illustration of disease patterns over time and asked to select the pattern that best described their disease (i) since symptom onset and (ii) in the past year. Associations between reported disease pattern and disease activity (Bath AS Disease Activity Index, BASDAI); functional impairment (Bath AS Functional Index, BASFI); AS Quality of Life (ASQoL); Back Pain (Nocturnal and Overall) and demographic features were assessed in a subsample (n = 83) (statistical significance defined at P ≤ 0.05). Results. Since disease onset 108/113 patients (96%) reported flares, and 82/99 (83%) reported symptoms of AS between flares. Flares typically lasted days or weeks. When patients were asked to characterize their disease pattern using the Flare Illustration, patterns with constant symptoms predominated (>70% of patients) and patterns with constant symptoms since onset (vs intermittent symptoms) were associated with worse health status (ASQoL: P = 0.007; BASDAI: P = 0.029; BASFI: P = 0.013, overall back pain: P = 0.025). Conclusions. Almost all AS patients report flares in disease activity: 70–80% report constant symptoms with single/repeated flares, while 20–30% report flares with no intermittent symptoms. The former is associated with a significantly poorer health status. These findings will be validated in a prospective study. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflicts of interest The full conflicts of interest statement for all authors is provided in Supplementary Appendix S2.

Background: In this work, we compare input level, feature level and decision level data fusion techniques for automatic detection of clinically significant prostate lesions (csPCa)., Methods: Multiple deep learning CNN architectures were developed using the Unet as the baseline. The CNNs use both multiparametric MRI images (T2W, ADC, and High b-value) and quantitative clinical data (prostate specific antigen (PSA), PSA density (PSAD), prostate gland volume & gross tumor volume (GTV)), and only mp-MRI images (n = 118), as input. In addition, co-registered ground truth data from whole mount histopathology images (n = 22) were used as a test set for evaluation., Results: The CNNs achieved for early/intermediate / late level fusion a precision of 0.41/0.51/0.61, recall value of 0.18/0.22/0.25, an average precision of 0.13 / 0.19 / 0.27, and F scores of 0.55/0.67/ 0.76. Dice Sorensen Coefficient (DSC) was used to evaluate the influence of combining mpMRI with parametric clinical data for the detection of csPCa. We compared the DSC between the predictions of CNN's trained with mpMRI and parametric clinical and the CNN's trained with only mpMRI images as input with the ground truth. We obtained a DSC of data 0.30/0.34/0.36 and 0.26/0.33/0.34 respectively. Additionally, we evaluated the influence of each mpMRI input channel for the task of csPCa detection and obtained a DSC of 0.14 / 0.25 / 0.28., Conclusion: The results show that the decision level fusion network performs better for the task of prostate lesion detection. Combining mpMRI data with quantitative clinical data does not show significant differences between these networks (p = 0.26/0.62/0.85). The results show that CNNs trained with all mpMRI data outperform CNNs with less input channels which is consistent with current clinical protocols where the same input is used for PI-RADS lesion scoring., Trial Registration: The trial was registered retrospectively at the German Register for Clinical Studies (DRKS) under proposal number Nr. 476/14 & 476/19., (© 2024. The Author(s).)

Borgs are huge extrachromosomal elements (ECE) of anaerobic methane-consuming "Candidatus Methanoperedens" archaea. Here, we used nanopore sequencing to validate published complete genomes curated from short reads and to reconstruct new genomes. 13 complete and four near-complete linear genomes share 40 genes that define a largely syntenous genome backbone. We use these conserved genes to identify new Borgs from peatland soil and to delineate Borg phylogeny, revealing two major clades. Remarkably, Borg genes encoding nanowire-like electron-transferring cytochromes and cell surface proteins are more highly expressed than those of host Methanoperedens, indicating that Borgs augment the Methanoperedens activity in situ. We reconstructed the first complete 4.00 Mbp genome for a Methanoperedens that is inferred to be a Borg host and predicted its methylation motifs, which differ from pervasive TC and CC methylation motifs of the Borgs. Thus, methylation may enable Methanoperedens to distinguish their genomes from those of Borgs. Very high Borg to Methanoperedens ratios and structural predictions suggest that Borgs may be capable of encapsulation. The findings clearly define Borgs as a distinct class of ECE with shared genomic signatures, establish their diversification from a common ancestor with genetic inheritance, and raise the possibility of periodic existence outside of host cells., (© 2024. The Author(s).)

Studying RNA splicing factor mutations is challenging due to difficulties in distinguishing wild-type and mutant cells within complex human tissues and inaccuracies associated with reconstructing splicing signals from short-read sequencing data. Here, we present Genotyping of Transcriptomes (GoT)-Splice, a protocol that overcomes these limitations by combining GoT with enhanced long-read single-cell transcriptome and cell-surface proteomics profiling. We describe steps for long-read library preparation and analysis, followed by cDNA re-amplification, enrichment of mutation of interest, sample indexing, and GoT library preparation. For complete details on the use and execution of this protocol, please refer to Cortés-López et al. 1 ., Competing Interests: Declaration of interests X.D., S.H., and S.J. are employees of Oxford Nanopore Technologies, Inc. and are shareholders and/or share option holders. D.A.L. has served as a consultant for AbbVie, AstraZeneca, and Illumina and is on the Scientific Advisory Board of Mission Bio, Pangea, Alethiomics, and C2i Genomics; D.A.L. has received prior research funding from BMS, 10× Genomics, Ultima Genomics, and Illumina unrelated to the current manuscript. F.G. serves as a consultant for S2 Genomics, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Telomeres are the protective nucleoprotein structures at the end of linear eukaryotic chromosomes. Telomeres' repetitive nature and length have traditionally challenged the precise assessment of the composition and length of individual human telomeres. Here, we present Telo-seq to resolve bulk, chromosome arm-specific and allele-specific human telomere lengths using Oxford Nanopore Technologies' native long-read sequencing. Telo-seq resolves telomere shortening in five population doubling increments and reveals intrasample, chromosome arm-specific, allele-specific telomere length heterogeneity. Telo-seq can reliably discriminate between telomerase- and ALT-positive cancer cell lines. Thus, Telo-seq is a tool to study telomere biology during development, aging, and cancer at unprecedented resolution., (© 2024. The Author(s).)

This manuscript is designed to complement the previously published primer on salary structures for new pain physicians. The previous manuscript "Employment Contract Financial Models for the Pain Physician: A Primer" had a goal of increasing understanding of financial models by pain fellows when preparing for contract negotiations. This manuscript illustrates the many equally important considerations of "non-monetary" values that are a significant part of contract negotiation outside of salary. It contributes to the overall education for trainees and pain physicians on benefits and job responsibilities., (© 2024 World Institute of Pain.)

Background: Improving shared decision-making (SDM) for patients has become a health policy priority in many countries. Achieving high-quality SDM is particularly important for approximately 313 million surgical treatment decisions patients make globally every year. Large-scale monitoring of surgical patients' experience of SDM in real time is needed to identify the failings of SDM before surgery is performed. We developed a novel approach to automating real-time data collection using an electronic measurement system to address this. Examining usability will facilitate its optimization and wider implementation to inform interventions aimed at improving SDM., Objective: This study examined the usability of an electronic real-time measurement system to monitor surgical patients' experience of SDM. We aimed to evaluate the metrics and indicators relevant to system effectiveness, system efficiency, and user satisfaction., Methods: We performed a mixed methods usability evaluation using multiple participant cohorts. The measurement system was implemented in a large UK hospital to measure patients' experience of SDM electronically before surgery using 2 validated measures (CollaboRATE and SDM-Q-9). Quantitative data (collected between April 1 and December 31, 2021) provided measurement system metrics to assess system effectiveness and efficiency. We included adult patients booked for urgent and elective surgery across 7 specialties and excluded patients without the capacity to consent for medical procedures, those without access to an internet-enabled device, and those undergoing emergency or endoscopic procedures. Additional groups of service users (group 1: public members who had not engaged with the system; group 2: a subset of patients who completed the measurement system) completed user-testing sessions and semistructured interviews to assess system effectiveness and user satisfaction. We conducted quantitative data analysis using descriptive statistics and calculated the task completion rate and survey response rate (system effectiveness) as well as the task completion time, task efficiency, and relative efficiency (system efficiency). Qualitative thematic analysis identified indicators of and barriers to good usability (user satisfaction)., Results: A total of 2254 completed surveys were returned to the measurement system. A total of 25 service users (group 1: n=9; group 2: n=16) participated in user-testing sessions and interviews. The task completion rate was high (169/171, 98.8%) and the survey response rate was good (2254/5794, 38.9%). The median task completion time was 3 (IQR 2-13) minutes, suggesting good system efficiency and effectiveness. The qualitative findings emphasized good user satisfaction. The identified themes suggested that the measurement system is acceptable, easy to use, and easy to access. Service users identified potential barriers and solutions to acceptability and ease of access., Conclusions: A mixed methods evaluation of an electronic measurement system for automated, real-time monitoring of patients' experience of SDM showed that usability among patients was high. Future pilot work will optimize the system for wider implementation to ultimately inform intervention development to improve SDM., International Registered Report Identifier (irrid): RR2-10.1136/bmjopen-2023-079155., (©Christin Hoffmann, Kerry Avery, Rhiannon Macefield, Tadeáš Dvořák, Val Snelgrove, Jane Blazeby, Della Hopkins, Shireen Hickey, Ben Gibbison, Leila Rooshenas, Adam Williams, Jonathan Aning, Hilary L Bekker, Angus GK McNair, The ALPACA Study Team. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 10.04.2024.)

Problem: Establishment of Birthing on Country services owned and governed by Aboriginal and Torres Strait Islander Community Controlled Health Services has been slow., Background: Birthing on Country services have demonstrated health and cost benefits and require redesign of maternity care. During the Building On Our Strengths feasibility study, use of endorsed midwives and licensing of birth centres has proven difficult., Question: What prevents Community Controlled Health Services from implementing Birthing on Country services in Queensland and New South Wales?, Methods: Participatory action research identified implementation barriers. We conducted iterative document analysis of instruments to inform government lobbying through synthesis of policy, economic, social, technological, legal, and environmental factors., Findings: Through cycles of participatory action research, we analysed 17 documents: 1) policy barriers prevent Community Controlled Health Services from employing endorsed midwives to provide intrapartum care in public hospitals; 2) economic barriers include lack of sustainable funding stream and inadequate Medicare-billing for endorsed midwives; and 3) legal barriers require a medical practitioner in a birth centre. While social barriers (e.g., colonisation, medicalisation) underpin regulations, these were beyond the scope; technological and environmental barriers were not identified., Discussion: Findings are consistent with the literature on barriers to midwifery practice. Recommendations include a national audit of barriers to Birthing on Country services including healthcare practice insurance, and development of a funding stream. Additionally, private maternity facility regulation must align with evidence on safe birth centre operation., Conclusion: Government can address barriers to scale-up of Aboriginal and Torres Strait Islander Community Controlled Birthing on Country services., Competing Interests: Conflict of interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Strategies to reduce over-representation of Indigenous children in out-of-home care must start in pregnancy given Indigenous babies are 6 % of infants (<1 year), yet 43 % of infants in out-of-home care., Objective: To determine if an Indigenous-led, multi-agency, partnership redesign of maternity services decreases the likelihood of babies being removed at birth., Participants and Setting: Women carrying an Indigenous baby/babies who gave birth at the Mater Mothers' Public Hospital, Brisbane (2013-2019)., Methods: A prospective, non-randomised, intervention trial evaluated a multi-agency service redesign. Women pregnant with an Indigenous baby birthing at a tertiary hospital were offered standard care or Birthing in Our Community (BiOC) service. We compared likelihood of babies being removed by Child Protection Services (CPS) at birth by model of care. Inverse probability of treatment propensity score weighting controlled baseline confounders and calculated treatment effect. Standardized differences were calculated to assess balance of risk factors for each copy of multiple imputation. Australian New Zealand Clinical Trial Registry, ACTRN12618001365257., Results: In 2013-2019, 1988 women gave birth to 2044 Indigenous babies, with 40 women having babies removed at birth (9 BiOC, 31 standard care). Adjusted odds of baby removal were significantly lower for mothers in BiOC compared to standard care (AOR 0.37, 95 % CI 0.16, 0.84). In total, 2.0 % of Indigenous babies were removed by CPS; eight times higher than non-Indigenous babies at the same hospital (0.25 %)., Conclusions: BiOC reduced removals of newborn Indigenous babies likely disrupting generational cycles of CPS contact, trauma, and maltreatment, and contributing to short and long-term health and wellbeing benefits for mothers and babies., Competing Interests: Declaration of competing interest The research team received an Australian NHMRC partnership grant (GNT1077036), and the partner organisations funded delivery of the new health service, with additional funding from the Queensland Government to the Institute for Urban Indigenous Health (to AC, CN, and KWa) to expand health service delivery. During the study: SKi and YG were employed by Mater Research Institute and University Queensland, then Charles Darwin University; SH was employed by Mater Research Institute then Charles Darwin University; YR was employed by the Institute of Urban Indigenous Health, then Mater Research Institute, then Charles Darwin University. CN, AC, JCu, KWa, and SKr were employed by Institute of Urban Indigenous Health, with JCu then employed by Aboriginal and Torres Strait Islander Community Health Service Brisbane, and SKr then employed by Charles Darwin University. MR, KWi and JCo were employed by Mater Hospital, then JCo employed by the Institute of Urban Indigenous Health. Some of the NHMRC funding that supported the research contributed to salaries of YR, SH and YG. BOD received funding from the Australian Government (Research Training Program Scholarship) and the Alison Mary Jackson and Nancy Rosemary Kingsland Scholarship, through the Molly Wardaguga Research Centre as part of her PhD Candidature at Charles Darwin University. We declare no other competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: TL has received an honorarium for a lecture on this topic from Al Sultan United Medical Co and is head of clinical artificial intelligence at Bradford Teaching Hospitals NHS Foundation Trust, and a potential liability sink All other authors report no conflicts of interest

Introduction: High-quality shared decision-making (SDM) is a priority of health services, but only achieved in a minority of surgical consultations. Improving SDM for surgical patients may lead to more effective care and moderate the impact of treatment consequences. There is a need to establish effective ways to achieve sustained and large-scale improvements in SDM for all patients whatever their background. The ALPACA Study aims to develop, pilot and evaluate a decision support intervention that uses real-time feedback of patients' experience of SDM to change patients' and healthcare professionals' decision-making processes before adult elective surgery and to improve patient and health service outcomes., Methods and Analysis: This protocol outlines a mixed-methods study, involving diverse stakeholders (adult patients, healthcare professionals, members of the community) and three National Health Service (NHS) trusts in England. Detailed methods for the assessment of the feasibility, usability and stakeholder views of implementing a novel system to monitor the SDM process for surgery automatically and in real time are described. The study will measure the SDM process using validated instruments (CollaboRATE, SDM-Q-9, SHARED-Q10) and will conduct semi-structured interviews and focus groups to examine (1) the feasibility of automated data collection, (2) the usability of the novel system and (3) the views of diverse stakeholders to inform the use of the system to improve SDM. Future phases of this work will complete the development and evaluation of the intervention., Ethics and Dissemination: Ethical approval was granted by the NHS Health Research Authority North West-Liverpool Central Research Ethics Committee (reference: 21/PR/0345). Approval was also granted by North Bristol NHS Trust to undertake quality improvement work (reference: Q80008) overseen by the Consent and SDM Programme Board and reporting to an Executive Assurance Committee., Trial Registration Number: ISRCTN17951423; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Documented as one of the oldest living civilizations, there is now evidence that Indigenous communities in Australia followed a sustainable lifestyle with well-designed agricultural practices and adequate physical activity. Commonly known as wattleseeds in Australia, unique cultivars of Acacia have been consumed by Indigenous Australians for over 60,000 years. This research used descriptive sensory profiling to develop a lexicon for the aroma and flavor profiles of four wattleseed species before and after being subjected to different processing techniques. The processing methods selected were pressure cooking, dry roasting, wet roasting, and malting. The species included were Acacia kempeana, Acacia adsurgens, Acacia colei, and Acacia victoriae. Sensory differences were observed between the different cultivars as well as between the different food processing techniques. Results show that wattleseed species diversity is a key driver in determining the aroma profile, while taste profiles are modified by the type of processing method applied. PRACTICAL APPLICATION: This study provides foundational knowledge on these culturally significant seeds, supporting practical opportunities to diversify the uses of wattleseeds in food products., (© 2023 The Authors. Journal of Food Science published by Wiley Periodicals LLC on behalf of Institute of Food Technologists.)

Purpose: MR guidance is used during therapy to detect and compensate for lesion motion. T 2 -weighted MRI often has a superior lesion contrast in comparison to T 1 -weighted real-time imaging. The purpose of this work was to design a fast T 2 -weighted sequence capable of simultaneously acquiring two orthogonal slices, enabling real-time tracking of lesions., Methods: To generate a T 2 contrast in two orthogonal slices simultaneously, a sequence (Ortho-SFFP-Echo) was designed that samples the T 2 -weighted spin echo (S - ) signal in a TR-interleaved acquisition of two slices. Slice selection and phase-encoding directions are swapped between the slices, leading to a unique set of spin-echo signal conditions. To minimize motion-related signal dephasing, additional flow-compensation strategies are implemented. In both the abdominal breathing phantom and in vivo experiments, a time series was acquired using Ortho-SSFP-Echo. The centroid of the target was tracked in postprocessing steps., Results: In the phantom, the lesion could be identified and delineated in the dynamic images. In the volunteer experiments, the kidney was visualized with a T 2 contrast at a temporal resolution of 0.45 s under free-breathing conditions. A respiratory belt demonstrated a strong correlation with the time course of the kidney centroid in the head-foot direction. A hypointense saturation band at the slice overlap did not inhibit lesion tracking in the semi-automatic postprocessing steps., Conclusion: The Ortho-SFFP-Echo sequence delivers real-time images with a T 2 -weighted contrast in two orthogonal slices. The sequence allows for simultaneous acquisition, which could be beneficial for real-time motion tracking in radiotherapy or interventional MRI., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: The Australian Nurse-Family Partnership Program is based on the Nurse-Family Partnership program from the United States, which was designed to support first-time mothers experiencing social and economic disadvantage from early in pregnancy until their child's second birthday. International trials have demonstrated this program measurably improves family environment, maternal competencies, and child development. The Australian program has been tailored for mothers having a First Nations baby., Aim: This study aimed to understand how the program impacts self-efficacy using a qualitative interpretive approach., Methods: The study took place in two sites within one Aboriginal Community Controlled Health Service in Meanjin (Brisbane), Australia. Twenty-nine participants were interviewed: first-time mothers having a First Nations baby who had accessed the program (n = 26), their family members (n = 1), and First Nations Elders (n = 2). Interviews were conducted either face-to-face or by telephone, using a yarning tool and method, to explore women's experiences and perceptions. Yarns were analysed using reflexive thematic analysis., Findings: Three main themes were generated: 1) sustaining connections and relationships; 2) developing self-belief and personal skills; and 3) achieving transformation and growth. We interpret that when the program facilitates the development of culturally safe relationships with staff and peers, it enables behaviour change, skill development, personal goal setting and achievement, leading to self-efficacy., Discussion: Located within a community-controlled health service, the program can foster cultural connection, peer support and access to health and social services; all contributing to self-efficacy., Conclusion: We recommend the program indicators are strengthened to reflect these findings and enable monitoring and reporting of activities that facilitate self-efficacy, growth, and empowerment., (Copyright © 2023 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

Enhanced Maternity Care (EMC) is a new standard of care for women who become unwell during or shortly after pregnancy. Yorkshire and the Humber Maternity Clinical Network established the Maternal Enhanced and Critical Care Group (MEaCC) to create regional guidance with a focus on maternity staff training, development of the MEaCC database and data collection. This article describes the introduction of the MEaCC and regional data collection., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Respiratory syncytial virus (RSV) commonly infects the upper respiratory tract (URT) of humans, manifesting with mild cold or flu-like symptoms. However, in infants and the elderly, severe disease of the lower respiratory tract (LRT) often occurs and can develop into chronic airway disease. A better understanding of how an acute RSV infection transitions to a LRT chronic inflammatory disease is critically important to improve patient care and long-term health outcomes. To model acute and chronic phases of the disease, we infected wild-type C57BL/6 and toll-like receptor 7 knockout (TLR7 KO) mice with RSV and temporally assessed nasal, airway and lung inflammation for up to 42 days post-infection. We show that TLR7 reduced viral titers in the URT during acute infection but promoted pronounced pathogenic and chronic airway inflammation and hyperreactivity in the LRT. This study defines a hitherto unappreciated molecular mechanism of lower respiratory pathogenesis to RSV, highlighting the potential of TLR7 modulation to constrain RSV pathology to the URT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Miles, Liong, Liong, Coward-Smith, Trollope, Oseghale, Erlich, Brooks, Logan, Hickey, Wang, Bozinovski, O’Leary, Brooks and Selemidis.)

RNA splicing factors are recurrently mutated in clonal blood disorders, but the impact of dysregulated splicing in hematopoiesis remains unclear. To overcome technical limitations, we integrated genotyping of transcriptomes (GoT) with long-read single-cell transcriptomics and proteogenomics for single-cell profiling of transcriptomes, surface proteins, somatic mutations, and RNA splicing (GoT-Splice). We applied GoT-Splice to hematopoietic progenitors from myelodysplastic syndrome (MDS) patients with mutations in the core splicing factor SF3B1. SF3B1 mut cells were enriched in the megakaryocytic-erythroid lineage, with expansion of SF3B1 mut erythroid progenitor cells. We uncovered distinct cryptic 3' splice site usage in different progenitor populations and stage-specific aberrant splicing during erythroid differentiation. Profiling SF3B1-mutated clonal hematopoiesis samples revealed that erythroid bias and cell-type-specific cryptic 3' splice site usage in SF3B1 mut cells precede overt MDS. Collectively, GoT-Splice defines the cell-type-specific impact of somatic mutations on RNA splicing, from early clonal outgrowths to overt neoplasia, directly in human samples., Competing Interests: Declaration of interests F.G. serves as a consultant for S2 Genomics Inc. X.D., J.B., A.W.D., S.H., S.J., and E.H. are employees of Oxford Nanopore Technologies Inc. and are shareholders and/or share option holders. I.M.G. serves on the advisory or consulting board of Bristol Myers Squibb, Takeda, Janssen, Sanofi, Novartis, Amgen, Celgene, Cellectar, Pfizer, Menarini Silicon Biosystems, Oncopeptides, The Binding Site, GlazoSmithKlein, AbbVie, Adaptive, and 10x Genomics. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Pfizer, and Janssen, and O.A.-W. is on the Scientific Advisory Board of Envisagenics Inc. and AIChemy. O.A.-W. has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. D.A.L. has served as a consultant for AbbVie, AstraZeneca, and Illumina and is on the Scientific Advisory Board of Mission Bio, Pangea, Alethiomics, and C2i Genomics; D.A.L. has received prior research funding from BMS, 10x Genomics, Ultima Genomics, and Illumina unrelated to the current manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Zinc-bromine flow batteries (ZBFBs) are promising candidates for the large-scale stationary energy storage application due to their inherent scalability and flexibility, low cost, green, and environmentally friendly characteristics. ZBFBs have been commercially available for several years in both grid scale and residential energy storage applications. Nevertheless, their continued development still presents challenges associated with electrodes, separators, electrolyte, as well as their operational chemistry. Therefore, rational design of these components in ZBFBs is of utmost importance to further improve the overall device performance. In this review, the focus is on the scientific understanding of the fundamental electrochemistry and functional components of ZBFBs, with an emphasis on the technical challenges of reaction chemistry, development of functional materials, and their application in ZBFBs. Current limitations of ZBFBs with future research directions in the development of high performance ZBFBs are suggested., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Exploration published by Henan University and John Wiley & Sons Australia, Ltd.)

Staphylococcus aureus causes intramammary infections (IMIs), which are refractory to antibiotic treatment and frequently result in chronic mastitis. IMIs are the leading cause of conventional antibiotic use in dairy farms. Phage therapy represents an alternative to antibiotics to help better manage mastitis in cows, reducing the global spread of resistance. A mouse mastitis model of S. aureus IMI was used to study the efficacy of a new cocktail of five lytic S. aureus -specific phages (StaphLyse™), administered either via the intramammary (IMAM) route or intravenously (IV). The StaphLyse™ phage cocktail was stable in milk for up to one day at 37 °C and up to one week at 4 °C. The phage cocktail was bactericidal in vitro against S. aureus in a dose-dependent manner. A single IMAM injection of this cocktail given 8 h after infection reduced the bacterial load in the mammary glands of lactating mice infected with S. aureus , and as expected, a two-dose regimen was more effective. Prophylactic use (4 h pre-challenge) of the phage cocktail was also effective, reducing S. aureus levels by 4 log10 CFU per gram of mammary gland. These results suggest that phage therapy may be a viable alternative to traditional antibiotics for the control of S. aureus IMIs.

Background: Preterm birth is the leading cause of morbidity and mortality for children under five years with First Nations babies experiencing twice the rate of other Australians. The Birthing in Our Community (BiOC) service was implemented in a metropolitan centre in Australia and showed a significant reduction in preterm birth. We aimed to assess the cost-effectiveness of the BiOC service in reducing preterm births compared to Standard Care, from a health system perspective., Methods: Women who were carrying a First Nations baby and attending the Mater Mothers Public Hospital (Brisbane, QLD, Australia) were allocated to either BiOC or Standard Care service. Birth records were extracted from the hospital's routinely collected and prospectively entered database. The time horizon extended from first presentation in pregnancy up to six weeks after birth for mothers and 28 days for infants, or until discharged from hospital. All direct antenatal, birth, postnatal and neonatal costs were included. The proportion of preterm birth was calculated, and cost was estimated in 2019 Australian dollars. The incremental cost and proportion of preterm birth differences were adjusted using inverse probability of treatment weighting methods., Findings: Between Jan 1 2013, and Jun 30, 2019, 1816 mothers gave births to 1867 First Nations babies at the Mater Mothers Public Hospital. After exclusions, 1636 mother-baby pairs were included in the analyses: 840 in the Standard Care group and 796 in the BiOC service. Relative to Standard Care, the BiOC service was associated with a reduced proportion of preterm birth (-5.34%, [95% CI -8.69%, -1.98%]) and cost savings (-AU$4810, [95% CI -7519, -2101]) per mother-baby pair. The BiOC service was associated with better outcomes and cost less than Standard Care., Interpretation: The BiOC service offers a cost-effective alternative to Standard Care in reducing preterm birth for Australian First Nations families. The cost savings were driven by less interventions and procedures in birth and fewer neonatal admissions. Investing in comprehensive, community-led models of care improves outcomes at reduced cost., Funding: The Australian National Health and Medical Research Council (APP1077036)., Competing Interests: We declare no competing interests., (© 2023 The Author(s).)

Catanionic surfactant vesicles (SVs) composed of sodium dodecylbenzenesulfonate (SDBS) and cetyltrimethylammonium tosylate (CTAT) have potential applications as targeted drug delivery systems, vaccine platforms, and diagnostic tools. To facilitate these applications, we evaluated various methods to attach proteins to the surface of SDBS/CTAT vesicles. Acid phosphatase from wheat germ was used as a model protein. Acid phosphatase was successfully conjugated to vesicles enriched with a Triton-X 100 derivative containing an unsaturated ester. Enzymatic activity of acid phosphatase attached to vesicles was assessed using an acid phosphatase assay. Results from the acid phosphatase assay indicated that 15 ± 3% of the attached protein remained functional but the presence of vesicles interferes with the assay. DLS and zeta potential results correlated with the protein functionalization studies. Acid phosphatase functionalized vesicles had an average diameter of 175 ± 85 nm and an average zeta potential of -61 ± 5 mV in PBS. As a control, vesicles enriched with Triton-X 100 were prepared and analyzed by DLS and zeta potential measurements. Triton X-100 enriched vesicles had an average diameter of 140 ± 67 nm and an average zeta potential of -49 ± 2 mV in PBS. Functionalizing the surface of SVs with proteins may be a key step in developing vesicle-based technologies. For drug delivery, antibodies could be used as targeting molecules; for vaccine formulation, functionalizing the surface with spike proteins may produce novel vaccine platforms.

Background: Real world patterns of cannabis use for health concerns are highly variable and rarely overseen by a physician. Pragmatic effectiveness studies with electronic daily diaries that capture person-specific patterns of cannabis use and health symptoms may help clarify risks and benefits., Methods: As part of a larger, randomized trial (NCT03224468), adults (N = 181) seeking cannabis for insomnia, pain, or anxiety or depressive symptoms were randomized to obtain a medical cannabis card immediately (MCC) or a waitlist control (WLC) and completed 12-weeks of daily web-based surveys on cannabis use and sleep, pain, and depressive symptoms., Results: Completion rates of daily surveys were moderate to high (median completed: 72 out of 90 days). Daily reports of cannabis use were consistent with monthly interview assessments and urinalysis. The MCC group increased cannabis use frequency in the 12 weeks following randomization, while WLC did not. Among the MCC group, self-reported sleep quality was significantly higher on cannabis use days, compared to nonuse days. The MCC group displayed long-term sleep improvements, consistent with increasing cannabis frequency. No improvements were found for pain or depressive symptoms., Conclusion: Cannabis use is associated with same day improvements in self-reported sleep quality, but not pain or depressive symptoms, although sleep improvements occurred in the context of increased frequency of cannabis use, raising the risk for cannabis use disorder. Daily web-based assessments of cannabis appear valid and feasible in adults seeking cannabis for health concerns, providing a flexible, complementary method for future real-world effectiveness studies with expanded and objective measures., Competing Interests: Conflict of Interest No conflict Declared., (Copyright © 2023. Published by Elsevier B.V.)

Background: With the impact of over two centuries of colonisation in Australia, First Nations families experience a disproportionate burden of adverse pregnancy and birthing outcomes. First Nations mothers are 3-5 times more likely than other mothers to experience maternal mortality; babies are 2-3 times more likely to be born preterm, low birth weight or not to survive their first year. 'Birthing on Country' incorporates a multiplicity of interpretations but conveys a resumption of maternity services in First Nations Communities with Community governance for the best start to life. Redesigned services offer women and families integrated, holistic care, including carer continuity from primary through tertiary services; services coordination and quality care including safe and supportive spaces. The overall aim of Building On Our Strengths (BOOSt) is to facilitate and assess Birthing on Country expansion into two settings - urban and rural; with scale-up to include First Nations-operated birth centres. This study will build on our team's earlier work - a Birthing on Country service established and evaluated in an urban setting, that reported significant perinatal (and organisational) benefits, including a 37% reduction in preterm births, among other improvements., Methods: Using community-based, participatory action research, we will collaborate to develop, implement and evaluate new Birthing on Country care models. We will conduct a mixed-methods, prospective birth cohort study in two settings, comparing outcomes for women having First Nations babies with historical controls. Our analysis of feasibility, acceptability, clinical and cultural safety, effectiveness and cost, will use data including (i) women's experiences collected through longitudinal surveys (three timepoints) and yarning interviews; (ii) clinical records; (iii) staff and stakeholder views and experiences; (iv) field notes and meeting minutes; and (v) costs data. The study includes a process, impact and outcome evaluation of this complex health services innovation., Discussion: Birthing on Country applies First Nations governance and cultural safety strategies to support optimum maternal, infant, and family health and wellbeing. Women's experiences, perinatal outcomes, costs and other operational implications will be reported for Communities, service providers, policy advisors, and for future scale-up., Trial Registration: Australia & New Zealand Clinical Trial Registry # ACTRN12620000874910 (2 September 2020)., (© 2023. The Author(s).)

We describe the phenotype of 22 male patients (20 probands) carrying a hemizygous missense variant in MED12. The phenotypic spectrum is very broad ranging from nonspecific intellectual disability (ID) to the three well-known syndromes: Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, or Ohdo syndrome. The identified variants were randomly distributed throughout the gene (p = 0.993, χ 2 test), but mostly outside the functional domains (p = 0.004; χ 2 test). Statistical analyses did not show a correlation between the MED12-related phenotypes and the locations of the variants (p = 0.295; Pearson correlation), nor the protein domain involved (p = 0.422; Pearson correlation). In conclusion, establishing a genotype-phenotype correlation in MED12-related diseases remains challenging. Therefore, we think that patients with a causative MED12 variant are currently underdiagnosed due to the broad patients' clinical presentations., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Given the known downstream implications of choice of respiratory support on patient outcomes, all factors influencing these decisions, even those not limited to the patient, warrant close consideration. We examined the effect of emergency department (ED)-specific system factors, such as work load and census, on the use of noninvasive versus invasive respiratory support., Methods: We conducted a multi-center retrospective cohort study of all adult subjects with severe COVID-19 requiring an ICU admission from 5 EDs within a single urban health care system. Subject demographics, severity of illness, and the type of respiratory support used were obtained. Using continuous measures of ED census, boarding, and active management, we estimated ED work load for each subjects' ED stay. The subjects were categorized by type(s) of respiratory support used: low-flow oxygen, noninvasive respiratory support (eg, noninvasive ventilation [NIV] and/or high-flow nasal cannula [HFNC]), invasive mechanical ventilation, or invasive mechanical ventilation after trial of NIV/HFNC. We used multivariable logistic regression to examine system factors associated with the type of respiratory support used in the ED., Results: A total of 634 subjects were included. Of these, 431 (70.0%) were managed on low-flow oxygen alone, 108 (17.0%) on NIV/HFNC, 54 (8.5%) on invasive mechanical ventilation directly, and 41 (6.5%) on NIV/HFNC prior to invasive mechanical ventilation in the ED. Higher severity of illness and underlying lung disease increased the odds of requiring invasive mechanical ventilation compared to low-flow oxygen (odds ratio 1.05 [95% CI 1.03-1.07] and odds ratio 3.47 [95% CI 1.37-8.78], respectively). Older age decreased odds of being on invasive mechanical ventilation compared to low-flow oxygen (odds ratio 0.96 [95% CI 0.94-0.99]). As ED work load increased, the odds for subjects to be managed initially with NIV/HFNC prior to invasive mechanical ventilation increased 6-8-fold., Conclusions: High ED work load was associated with higher odds on HFNC/NIV prior to invasive mechanical ventilation., Competing Interests: Dr Mathews has received study support from the National Institutes of Health National Heart, Lung, and Blood Institute (Awards: 1K23HL130648-PI: Mathews). The other authors have disclosed no conflicts of interest., (Copyright © 2022 by Daedalus Enterprises.)

There is simultaneous interest in improving the feed efficiency of ruminant livestock and reducing methane (CH 4 ) emissions. The relationship (genetic and phenotypic) between feed efficiency (characterized as residual feed intake: RFI) and greenhouse gases [methane (CH 4 ) and carbon dioxide (CO 2 )] traits in New Zealand (NZ) maternal sheep has not previously been investigated, nor has their relationship with detailed estimates of body composition. To investigate these relationships in NZ maternal sheep, a feed intake facility was established at AgResearch Invermay, Mosgiel, NZ in 2015, comprising automated feeders that record individual feeding events. Individual measures of feed intake, feeding behavior (length and duration of eating events), and gas emissions (estimated using portable accumulation chambers) were generated on 986 growing maternal ewe lambs sourced from three pedigree recorded flocks registered in the Sheep Improvement Limited database (www.sil.co.nz). Additional data were generated from a subset of 591 animals for body composition (estimated using ultrasound and computed tomography scanning). The heritability estimates for RFI, CH 4 , and CH 4 /(CH 4 +CO 2 ) were 0.42 ± 0.09, 0.32 ± 0.08, and 0.29 ± 0.06, respectively. The heritability estimates for the body composition traits were high for carcass lean and fat traits; for example, the heritability for visceral fat (adjusted for body weight) was 0.93 ± 0.19. The relationship between RFI and CH 4 emissions was complex, and although less feed eaten will lead to a lowered absolute amount of CH 4 emitted, there was a negative phenotypic and genetic correlation between RFI and CH 4 /(CH 4 +CO 2 ) of -0.13 ± 0.03 and -0.41 ± 0.15, respectively. There were also genetic correlations, that were different from zero, between both RFI and CH 4 traits with body composition including a negative correlation between the proportion of visceral fat in the body and RFI (-0.52 ± 0.16) and a positive correlation between the proportion of lean in the body and CH 4 (0.54 ± 0.12). Together the results provide the first accurate estimates of the genetic correlations between RFI, CH 4 emissions, and the body composition (lean and fat) in sheep. These correlations will need to be accounted for in genetic improvement programs., Competing Interests: PaJ, SH, KK, JW, BB, MH, AJ, PeJ, KD, JM, and SR were employed by AgResearch Ltd., (Copyright © 2022 Johnson, Hickey, Knowler, Wing, Bryson, Hall, Jonker, Janssen, Dodds, McEwan and Rowe.)

Aim: This study investigated the impact of an interprofessional mock code on students' comfort and competency related to Parkinson's disease (PD) medication administration during care transitions., Backgroud: Patients with PD are at increased risk for medication errors during hospitalization. Individualization of PD medication creates vulnerability during care transitions., Method: Four interprofessional groups took part in this study: baccalaureate degree senior nursing students (n = 113), master's level nurse anesthesia students (n = 35), doctor of osteopathic medicine fourth-year students (n = 32), and doctor of clinical psychology fourth-year students (n = 22). Groups participated in an unfolding case study simulation involving a mock code with a focus on the omission of time-sensitive PD medication. Pre- and postsimulation test results were compared., Results: Findings indicated an increased understanding among three of the four groups relating to medication timing during care transitions., Conclusion: All groups improved with respect to perceived comfort and competency., Competing Interests: The authors have declared no conflict of interest., (Copyright © 2021 National League for Nursing.)

Background: Incorrect, delayed and missed diagnoses can contribute to significant adverse health outcomes. Intervention options have proliferated in recent years necessitating an update to McDonald et al 's 2013 systematic review of interventions to reduce diagnostic error., Objectives: (1) To describe the types of published interventions for reducing diagnostic error that have been evaluated in terms of an objective patient outcome; (2) to assess the risk of bias in the included interventions and perform a sensitivity analysis of the findings; and (3) to determine the effectiveness of included interventions with respect to their intervention type., Methods: MEDLINE, CINAHL and the Cochrane Database of Systematic Reviews were searched from 1 January 2012 to 31 December 2019. Publications were included if they delivered patient-related outcomes relating to diagnostic accuracy, management outcomes and/or morbidity and mortality. The interventions in each included study were categorised and analysed using the six intervention types described by McDonald et al (technique, technology-based system interventions, educational interventions, personnel changes, structured process changes and additional review methods)., Results: Twenty studies met the inclusion criteria. Eighteen of the 20 included studies (including three randomised controlled trials (RCTs)) demonstrated improvements in objective patient outcomes following the intervention. These three RCTs individually evaluated a technique-based intervention, a technology-based system intervention and a structured process change. The inclusion or exclusion of two higher risk of bias studies did not affect the results., Conclusion: Technique-based interventions, technology-based system interventions and structured process changes have been the most studied interventions over the time period of this review and hence are seen to be effective in reducing diagnostic error. However, more high-quality RCTs are required, particularly evaluating educational interventions and personnel changes, to demonstrate the value of these interventions in diverse settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Noncoding and synonymous coding variants that exert their effects via alternative splicing are increasingly recognized as an important category of disease-causing variants. In this report, we describe two siblings who presented with hypotonia, profound developmental delays, and seizures. Brain magnetic resonance imaging (MRI) in the proband at 5 yr showed diffuse cerebral and cerebellar white matter volume loss. Both siblings later developed ventilator-dependent respiratory insufficiency and scoliosis and are currently nonverbal and nonambulatory. Extensive molecular testing including oligo array and clinical exome sequencing was nondiagnostic. Research genome sequencing under an institutional review board (IRB)-approved study protocol revealed that both affected children were compound-heterozygous for variants in the SEPSECS gene. One variant was an initiator codon change (c.1A > T) that disrupted protein translation, consistent with the observation that most disease-causing variants are loss-of-function changes. The other variant was a coding change (c.846G > A) that was predicted to be synonymous but had been demonstrated to disrupt mRNA splicing in a minigene assay. The SEPSECS gene encodes O-phosphoseryl-tRNA(Sec) selenium transferase, an enzyme that participates in the biosynthesis and transport of selenoproteins in the body. Variations in SEPSECS cause autosomal recessive pontocerebellar hypoplasia type 2D (PCHT 2D; OMIM #613811), a neurodegenerative condition characterized by progressive cerebrocerebellar atrophy, microcephaly, and epileptic encephalopathy. The identification of biallelic pathogenic variants in this family-one of which was a synonymous change not identified by prior clinical testing-not only ended the diagnostic odyssey for this family but also highlights the contribution of occult pathogenic variants that may not be recognized by standard genetic testing methodologies., (© 2022 Ramadesikan et al.; Published by Cold Spring Harbor Laboratory Press.)

The primary cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC), causes intoxication and impaired function, with implications for traffic, workplace, and other situational safety risks. There are currently no evidence-based methods to detect cannabis-impaired driving, and current field sobriety tests with gold-standard, drug recognition evaluations are resource-intensive and may be prone to bias. This study evaluated the capability of a simple, portable imaging method to accurately detect individuals with THC impairment. In this double-blind, randomized, cross-over study, 169 cannabis users, aged 18-55 years, underwent functional near-infrared spectroscopy (fNIRS) before and after receiving oral THC and placebo, at study visits one week apart. Impairment was defined by convergent classification by consensus clinical ratings and an algorithm based on post-dose tachycardia and self-rated "high." Our primary outcome, prefrontal cortex (PFC) oxygenated hemoglobin concentration (HbO), was increased after THC only in participants operationalized as impaired, independent of THC dose. ML models using fNIRS time course features and connectivity matrices identified impairment with 76.4% accuracy, 69.8% positive predictive value (PPV), and 10% false-positive rate using convergent classification as ground truth, which exceeded Drug Recognition Evaluator-conducted expanded field sobriety examination (67.8% accuracy, 35.4% PPV, and 35.4% false-positive rate). These findings demonstrate that PFC response activation patterns and connectivity produce a neural signature of impairment, and that PFC signal, measured with fNIRS, can be used as a sole input to ML models to objectively determine impairment from THC intoxication at the individual level. Future work is warranted to determine the specificity of this classifier to acute THC impairment.ClinicalTrials.gov Identifier: NCT03655717., (© 2022. The Author(s).)

Importance: Despite the legalization and widespread use of cannabis products for a variety of medical concerns in the US, there is not yet a strong clinical literature to support such use. The risks and benefits of obtaining a medical marijuana card for common clinical outcomes are largely unknown., Objective: To evaluate the effect of obtaining a medical marijuana card on target clinical and cannabis use disorder (CUD) symptoms in adults with a chief concern of chronic pain, insomnia, or anxiety or depressive symptoms., Design, Setting, and Participants: This pragmatic, single-site, single-blind randomized clinical trial was conducted in the Greater Boston area from July 1, 2017, to July 31, 2020. Participants were adults aged 18 to 65 years with a chief concern of pain, insomnia, or anxiety or depressive symptoms. Participants were randomized 2:1 to either the immediate card acquisition group (n = 105) or the delayed card acquisition group (n = 81). Randomization was stratified by chief concern, age, and sex. The statistical analysis followed an evaluable population approach., Interventions: The immediate card acquisition group was allowed to obtain a medical marijuana card immediately after randomization. The delayed card acquisition group was asked to wait 12 weeks before obtaining a medical marijuana card. All participants could choose cannabis products from a dispensary, the dose, and the frequency of use. Participants could continue their usual medical or psychiatric care., Main Outcomes and Measures: Primary outcomes were changes in CUD symptoms, anxiety and depressive symptoms, pain severity, and insomnia symptoms during the trial. A logistic regression model was used to estimate the odds ratio (OR) for CUD diagnosis, and linear models were used for continuous outcomes to estimate the mean difference (MD) in symptom scores., Results: A total of 186 participants (mean [SD] age 37.2 [14.4] years; 122 women [65.6%]) were randomized and included in the analyses. Compared with the delayed card acquisition group, the immediate card acquisition group had more CUD symptoms (MD, 0.28; 95% CI, 0.15-0.40; P < .001); fewer self-rated insomnia symptoms (MD, -2.90; 95% CI, -4.31 to -1.51; P < .001); and reported no significant changes in pain severity or anxiety or depressive symptoms. Participants in the immediate card acquisition group also had a higher incidence of CUD during the intervention (17.1% [n = 18] in the immediate card acquisition group vs 8.6% [n = 7] in the delayed card acquisition group; adjusted odds ratio, 2.88; 95% CI, 1.17-7.07; P = .02), particularly those with a chief concern of anxiety or depressive symptoms., Conclusions and Relevance: This randomized clinical trial found that immediate acquisition of a medical marijuana card led to a higher incidence and severity of CUD; resulted in no significant improvement in pain, anxiety, or depressive symptoms; and improved self-rating of insomnia symptoms. Further investigation of the benefits of medical marijuana card ownership for insomnia and the risk of CUD are needed, particularly for individuals with anxiety or depressive symptoms., Trial Registration: ClinicalTrials.gov Identifier: NCT03224468.

Background: The Australian Nurse Family Partnership Program (ANFPP) is an evidence-based, home visiting program that offers health education, guidance, social and emotional support to first-time mothers having Aboriginal and/or Torres Strait Islander (First Nations) babies. The community-controlled sector identified the need for specialised support for first time mothers due to the inequalities in birthing and early childhood outcomes between First Nations' and other babies in Australia. The program is based on the United States' Nurse Family Partnership program which has improved long-term health outcomes and life trajectories for mothers and children. International implementation of the Nurse Family Partnership program has identified interagency service integration as key to program recruitment, retention, and efficacy. How the ANFPP integrates with other services in an Australian urban setting and how to improve this is not yet known. Our research explores the barriers and enablers to interagency service integration for the Australian Nurse Family Partnership Program ANFPP in an urban setting., Methods: A qualitative study using individual and group interviews. Purposive and snowball sampling was used to recruit clients, staff (internal and external to the program), Elders and family members. Interviews were conducted using a culturally appropriate 'yarning' method with clients, families and Elders and semi-structured interview guide for staff. Interviews were audio-recorded and transcribed prior to reflexive thematic analysis., Results: Seventy-six participants were interviewed: 26 clients, 47 staff and 3 Elders/family members. Three themes were identified as barriers and three as enablers. Barriers: 1) confusion around program scope, 2) duplication of care, and 3) tensions over 'ownership' of clients. Enablers (existing and potential): 1) knowledge and promotion of the program; 2) cultural safety; and 3) case coordination, co-location and partnership forums., Conclusion: Effective service integration is essential to maximise access and acceptability of the ANFPP; we provide practical recommendations to improve service integration in this context., (© 2021. The Author(s).)

Some of the most spectacular adaptive radiations begin with founder populations on remote islands. How genetically limited founder populations give rise to the striking phenotypic and ecological diversity characteristic of adaptive radiations is a paradox of evolutionary biology. We conducted an evolutionary genomics analysis of genus Metrosideros , a landscape-dominant, incipient adaptive radiation of woody plants that spans a striking range of phenotypes and environments across the Hawaiian Islands. Using nanopore-sequencing, we created a chromosome-level genome assembly for Metrosideros polymorpha var. incana and analyzed whole-genome sequences of 131 individuals from 11 taxa sampled across the islands. Demographic modeling and population genomics analyses suggested that Hawaiian Metrosideros originated from a single colonization event and subsequently spread across the archipelago following the formation of new islands. The evolutionary history of Hawaiian Metrosideros shows evidence of extensive reticulation associated with significant sharing of ancestral variation between taxa and secondarily with admixture. Taking advantage of the highly contiguous genome assembly, we investigated the genomic architecture underlying the adaptive radiation and discovered that divergent selection drove the formation of differentiation outliers in paired taxa representing early stages of speciation/divergence. Analysis of the evolutionary origins of the outlier single nucleotide polymorphisms (SNPs) showed enrichment for ancestral variations under divergent selection. Our findings suggest that Hawaiian Metrosideros possesses an unexpectedly rich pool of ancestral genetic variation, and the reassortment of these variations has fueled the island adaptive radiation., Competing Interests: Competing interest statement: X.D., P.R., S.H., E.H., and S.J. are employees of Oxford Nanopore Technologies and are shareholders and/or share option holders., (Copyright © 2021 the Author(s). Published by PNAS.)

We describe an adaption of Bright et al.'s work modeling peak height variability in CE-DNA profiles to the modeling of allelic aSTR (autosomal short tandem repeats) read counts from NGS-DNA profiles, specifically for profiles generated from the ForenSeq™ DNA Signature Prep Kit, DNA Primer Mix B. Bright et al.'s model consists of three key components within the estimation of total allelic product-template, locus-specific amplification efficiencies, and degradation. In this work, we investigated the two mass parameters-template and locus-specific amplification efficiencies-and used MLE (maximum likelihood estimation) and MCMC (Markov chain Monte Carlo) methods to obtain point estimates to calculate the total allelic product. The expected read counts for alleles were then calculated after proportioning some of the expected stutter product from the total allelic product. Due to preferential amplicon selection introduced by the sample purification beads, degradation is difficult to model from the aSTR outputs alone. Improved modeling of the locus-specific amplification efficiencies may mask the effects of degradation. Whilst this model could be improved by introducing locus specific variances in addition to locus specific priors, our results demonstrate the suitability of adapting Bright et al.'s allele peak height model for NGS-DNA profiles. This model could be incorporated into continuous probabilistic interpretation approaches for mixed DNA profiles., (© 2021 American Academy of Forensic Sciences.)

Context: Little is known about sexual and reproductive health (SRH) access and health promotion for First Nations peoples in Australia. This study aimed to better understand community preferences, knowledge and access to contraception and SRH services, and use this understanding to make recommendations which support approaches led by local Aboriginal community-controlled health organisations (ACCHOs)., Methods: Qualitative First Nations-led yarning circles were conducted with 55 community members and health service providers using and/or working at ACCHOs in urban South East Queensland. Cultural protocols ensured women's and men's interviews were separately collected and analysed. Thematic analysis was conducted by multiple coders, privileging interpretations by First Nations researchers., Results: Family, kin and friends were described as key knowledge holders and ACCHOs as knowledge spaces for sharing information about maintaining positive SRH and wellbeing for First Nations people. Interviewees wanted accurate and timely information in an accessible, culturally appropriate way. Making informed choices about family planning was described as an important process of agency and self-determination for First Nations people, and contextualized within broader aspirations for growing strong families and healthy relationships., Conclusion: Understanding SRH through the concept of "knowledge spaces" and "knowledge holders" highlights the collective importance of community relationality to support individual agency and informed SRH decision-making. ACCHOs appear to be acceptable knowledge spaces for SRH information; and evidence-based recommendations may increase their reach. Health services should consider upskilling community SRH knowledge holders to share consistent, accurate and accessible SRH information., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Hickey et al.)

Background: There is an urgency to redress unacceptable maternal and infant health outcomes for First Nations families in Australia. A multi-agency partnership between two Aboriginal Community-controlled health services and a tertiary hospital in urban Australia designed, implemented, and evaluated the new Birthing in Our Community (BiOC) service. In this study, we aimed to assess and report the clinical effectiveness of the BiOC service on key maternal and infant health outcomes compared with that of standard care., Methods: Pregnant women attending the Mater Mothers Public Hospital (Brisbane, QLD, Australia) who were having a First Nations baby were invited to receive the BiOC service. In this prospective, non-randomised, interventional trial of the service, we specifically enrolled women who intended to birth at the study hospital, and had a referral from a family doctor or Aboriginal Medical Service. Participants were offered either standard care services or the BiOC service. Prespecified primary outcomes to test the effectiveness of the BiOC service versus standard care were the proportion of women attending five or more antenatal visits, smoking after 20 weeks of gestation, who had a preterm birth (<37 weeks), and who were exclusively breastfeeding at discharge from hospital. We used inverse probability of treatment weighting to balance confounders and calculate treatment effect. This trial is registered with the Australian New Zealand Clinical Trial Registry, ACTRN12618001365257., Findings: Between Jan 1, 2013, and June 30, 2019, 1867 First Nations babies were born at the Mater Mothers Public Hospital. After exclusions, 1422 women received either standard care (656 participants) or the BiOC service (766 participants) and were included in the analyses. Women receiving the BiOC service were more likely to attend five or more antenatal visits (adjusted odds ratio 1·54, 95% CI 1·13-2·09; p=0·0064), less likely to have an infant born preterm (0·62, 0·42-0·93; p=0·019), and more likely to exclusively breastfeed on discharge from hospital (1·34, 1·06-1·70; p=0·014). No difference was found between the two groups for smoking after 20 weeks of gestation, with both showing a reduction compared with smoking levels reported at their hospital booking visit., Interpretation: This study has shown the clinical effectiveness of the BiOC service, which was co-designed by stakeholders and underpinned by Birthing on Country principles. The widespread scale-up of this new service should be prioritised. Dedicated funding, knowledge translation, and implementation science are needed to ensure all First Nations families can access Birthing on Country services that are adapted for their specific contexts., Funding: Australian National Health and Medical Research Council., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Importance: Bruising caused by physical abuse is the most common antecedent injury to be overlooked or misdiagnosed as nonabusive before an abuse-related fatality or near-fatality in a young child. Bruising occurs from both nonabuse and abuse, but differences identified by a clinical decision rule may allow improved and earlier recognition of the abused child., Objective: To refine and validate a previously derived bruising clinical decision rule (BCDR), the TEN-4 (bruising to torso, ear, or neck or any bruising on an infant <4.99 months of age), for identifying children at risk of having been physically abused., Design, Setting, and Participants: This prospective cross-sectional study was conducted from December 1, 2011, to March 31, 2016, at emergency departments of 5 urban children's hospitals. Children younger than 4 years with bruising were identified through deliberate examination. Statistical analysis was completed in June 2020., Exposures: Bruising characteristics in 34 discrete body regions, patterned bruising, cumulative bruise counts, and patient's age. The BCDR was refined and validated based on these variables using binary recursive partitioning analysis., Main Outcomes and Measures: Injury from abusive vs nonabusive trauma was determined by the consensus judgment of a multidisciplinary expert panel., Results: A total of 21 123 children were consecutively screened for bruising, and 2161 patients (mean [SD] age, 2.1 [1.1] years; 1296 [60%] male; 1785 [83%] White; 1484 [69%] non-Hispanic/Latino) were enrolled. The expert panel achieved consensus on 2123 patients (98%), classifying 410 (19%) as abuse and 1713 (79%) as nonabuse. A classification tree was fit to refine the rule and validated via bootstrap resampling. The resulting BCDR was 95.6% (95% CI, 93.0%-97.3%) sensitive and 87.1% (95% CI, 85.4%-88.6%) specific for distinguishing abuse from nonabusive trauma based on body region bruised (torso, ear, neck, frenulum, angle of jaw, cheeks [fleshy], eyelids, and subconjunctivae), bruising anywhere on an infant 4.99 months and younger, or patterned bruising (TEN-4-FACESp)., Conclusions and Relevance: In this study, an affirmative finding for any of the 3 BCDR TEN-4-FACESp components in children younger than 4 years indicated a potential risk for abuse; these results warrant further evaluation. Clinical application of this tool has the potential to improve recognition of abuse in young children with bruising.

Background: The use of anticoagulant medications leads to a higher risk of developing traumatic intracranial hemorrhage (tICH) after a mild traumatic brain injury (mTBI). The management of anticoagulated patients can be difficult to determine when the initial head computed tomography is negative for tICH. There has been limited research on the risk of delayed tICH in patients taking direct oral anticoagulant (DOAC) medications., Objective: Our aim was to determine the risk of delayed tICH for patients anticoagulated with DOACs after mTBI., Methods: We conducted a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched several medical databases to examine the risk of delayed tICH in patients on DOACs., Results: There were 1252 nonduplicate studies that were identified through an initial database search, 15 of which met our inclusion and exclusion criteria and were included in our analysis after full-text review. A total of 1375 subjects were combined among the 15 studies, with 20 instances of delayed tICH after mTBI. Nineteen of the 20 patients with a delayed tICH were discharged without any neurosurgical intervention, and 1 patient on apixaban died due to a delayed tICH., Conclusions: This systematic review confirms that delayed tICH after mTBI in patients on DOACs is uncommon. However, large, multicenter, prospective studies are needed to confirm the true incidence of clinically significant delayed tICH after DOAC use. Due to the limited data, we recommend using shared decision-making for patients who are candidates for discharge., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Low-value care, defined as care offering no net benefit in specific clinical scenarios, is associated with harmful outcomes in patients and wasteful spending. Despite a national education campaign and increasing attention on reducing health care waste, recent trends in low-value care delivery remain unknown., Objective: To assess national trends in low-value care use and spending., Design, Setting, and Participants: In this cross-sectional study, analyses of low-value care use and spending from 2014 to 2018 were conducted using 100% Medicare fee-for-service enrollment and claims data. Included individuals were aged 65 years or older and continuously enrolled in Medicare parts A, B, and D during each measurement year and the previous year. Data were analyzed from September 2019 through December 2020., Exposure: Being enrolled in fee-for-service Medicare for a period of time, in years., Main Outcomes and Measures: The Milliman MedInsight Health Waste Calculator was used to assess 32 claims-based measures of low-value care associated with Choosing Wisely recommendations and other professional guidelines. The calculator designates services as wasteful, likely wasteful, or not wasteful based on an absence of indication of appropriate use in the claims history; calculator-designated wasteful services were defined as low-value care. Spending was calculated as claim-line level (ie, spending on the low-value service) and claim level (ie, spending on the low-value service plus associated services), adjusting for inflation., Results: Among 21 045 759 individuals with fee-for-service Medicare (mean [SD] age, 77.4 [7.9] years; 12 515 915 [59.5%] women), the percentage receiving any of 32 low-value services decreased from 36.3% (95% CI, 36.3%-36.4%) to 33.6% (95% CI, 33.6%-33.6%) from 2014 to 2018. Uses of low-value services per 1000 individuals decreased from 677.8 (95% CI, 676.2-679.5) to 632.7 (95% CI, 632.6-632.8) from 2014 to 2018. Three services comprised approximately two-thirds of uses among 32 low-value services per 1000 individuals: preoperative laboratory testing decreased from 213.8 (95% CI, 213.4-214.2) to 166.2 (95% CI, 166.2-166.2), while opioids for back pain increased from 154.4 (95% CI, 153.6-155.2) to 182.1 (95% CI, 182.1-182.1) and antibiotics for upper respiratory infections increased from 75.0 (95% CI, 75.0-75.1) to 82 (95% CI, 82.0-82.0). Spending per 1000 individuals on low-value care also decreased, from $52 765.5 (95% CI, $51 952.3-$53 578.6) to $46 921.7 (95% CI, $46 593.7-$47 249.7) at the claim-line level and from $160 070.4 (95% CI, $158 999.8-$161 141.0) to $144 741.1 (95% CI, $144 287.5-$145 194.7) at the claim level., Conclusions and Relevance: This cross-sectional study found that among individuals with fee-for-service Medicare receiving any of 32 measured services, low-value care use and spending decreased marginally from 2014 to 2018, despite a national education campaign in collaboration with clinician specialty societies and increased attention on low-value care. While most use of low-value care came from 3 services, 1 of these was opioid prescriptions, which increased over time despite the harms associated with their use. These findings may represent several opportunities to prevent patient harm and lower spending.

The coronavirus disease 2019 (COVID-19) pandemic mandated rapid, flexible solutions to meet the anticipated surge in both patient acuity and volume. This paper describes one institution's emergency department (ED) innovation at the center of the COVID-19 crisis, including the creation of a temporary ED-intensive care unit (ICU) and development of interdisciplinary COVID-19-specific care delivery models to care for critically ill patients. Mount Sinai Hospital, an urban quaternary academic medical center, had an existing five-bed resuscitation area insufficiently rescue due to its size and lack of negative pressure rooms. Within 1 week, the ED-based observation unit, which has four negative pressure rooms, was quickly converted into a COVID-19-specific unit, split between a 14-bed stepdown unit and a 13-bed ED-ICU unit. An increase in staffing for physicians, physician assistants, nurses, respiratory therapists, and medical technicians, as well as training in critical care protocols and procedures, was needed to ensure appropriate patient care. The transition of the ED to a COVID-19-specific unit with the inclusion of a temporary expanded ED-ICU at the beginning of the COVID-19 pandemic was a proactive solution to the growing challenges of surging patients, complexity, and extended boarding of critically ill patients in the ED. This pandemic underscores the importance of ED design innovation with flexible spacing, interdisciplinary collaborations on structure and services, and NP ventilation systems which will remain important moving forward.