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Endgame thinking means transitioning from merely trying to ‘control’ the tobacco epidemic to developing plans and measures to bring it to an end within a specific time, by changing the underlying dynamics that have created and perpetuated it for more than a century. Among the innovative policies characterised as ‘endgame’ policies are so-called ‘tobacco-free generation’ or ‘smoke-free generation’ policies, which prohibit sales of some or all tobacco products to individuals born on or after a particular date. Such birthdate-based sales restrictions (BSR) have intuitive appeal, largely because they do not appreciably disrupt the status quo of retail sales, which continue unchanged for all those born before the designated cut-off date. They also hold the potential for further denormalising tobacco use and sales by anticipating the long-term end of tobacco sales. In this Special Communication, we analyse BSR policies through an endgame lens and propose questions that should be discussed in jurisdictions considering them. We suggest that this policy has potential underexamined pitfalls, particularly related to equity, and that if enacted, it should include policy guardrails and be part of a package of endgame measures.

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

Senicapoc, a small molecule inhibitor of the calcium-activated potassium channel KCa3.1, was safe and well-tolerated in clinical trials for sickle cell anemia. We previously reported proof-of-concept data suggesting that both pharmacological inhibition and genetic deletion of KCa3.1 reduces infarction and improves neurologic recovery in rodents by attenuating neuroinflammation. Here we evaluated the potential of repurposing senicapoc for ischemic stroke. In cultured microglia, senicapoc inhibited KCa3.1 currents with an IC50 of 7 nM, reduced Ca2+ signaling induced by the purinergic agonist ATP, suppressed expression of pro-inflammatory cytokines and enzymes (iNOS and COX-2), and prevented induction of the inflammasome component NLRP3. When transient middle cerebral artery occlusion (tMCAO, 60 min) was induced in male C57BL/6 J mice, twice daily administration of senicapoc at 10 and 40 mg/kg starting 12 h after reperfusion dose-dependently reduced infarct area determined by T2-weighted magnetic resonance imaging (MRI) and improved neurological deficit on day 8. Ultra-high-performance liquid chromatography/mass spectrometry analysis of total and free brain concentrations demonstrated sufficient KCa3.1 target engagement. Senicapoc treatment significantly reduced microglia/macrophage and T cell infiltration and activation and attenuated neuronal death. A different treatment paradigm with senicapoc started at 3 h and MRI on day 3 and day 8 revealed that senicapoc reduces secondary infarct growth and suppresses expression of inflammation markers, including T cell cytokines in the brain. Lastly, we demonstrated that senicapoc does not impair the proteolytic activity of tissue plasminogen activator (tPA) in vitro. We suggest that senicapoc could be repurposed as an adjunctive immunocytoprotective agent for combination with reperfusion therapy for ischemic stroke.

Background and aimsThe ubiquity of tobacco retailers helps to sustain the tobacco epidemic. A tobacco retail reduction approach that has not been tried is transitioning tobacco sales to state-controlled alcohol stores (TTS), which are limited in number and operate under some restrictions, e.g. regarding opening hours or marketing materials. This study summarizes policy experts' and advocates' views of TTS, including (1) advantages and disadvantages; (2) feasibility; and (3) potential implementation obstacles.DesignThis study was a qualitative content analysis of semi-structured interviews.SettingTen US states with alcoholic beverage control systems were included.ParticipantsThe participants comprised a total of 103 tobacco control advocates and professionals, public health officials, alcohol policy experts and alcohol control system representatives, including two tribal community representatives.MeasurementsInterviewees' perspectives on their state's alcoholic beverage control agency (ABC, the agency that oversees or operates a state alcohol monopoly) and on TTS were assessed.FindingsInterviewees thought TTS offered potential advantages, including reduced access to tobacco products, less exposure to tobacco advertising and a greater likelihood of successful smoking cessation. Some saw potential long-term health benefits for communities of color, due to the smaller number of state alcohol stores in those communities. Interviewees also raised concerns regarding TTS, including ABCs' limited focus on public health and emphasis on revenue generation, which could conflict with tobacco use reduction efforts. Some interviewees thought TTS could enhance the power of the tobacco and alcohol industries, increase calls for alcohol system privatization or create difficulties for those in recovery.ConclusionsIn the United States, transitioning tobacco sales to state-controlled alcohol stores (TTS) could have a positive public health impact by reducing tobacco availability, marketing exposure and, ultimately, tobacco use. However, tensions exist between alcohol control system goals of providing revenue to the state and protecting public health. Should a state decide to pursue TTS, several guardrails should be established, including building into the legislation an explicit goal of reducing tobacco consumption.

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble models performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.

FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and, unlike other inhibitors, is minimally vulnerable to resistance induced by FLT3 ligand. We conducted a phase 1 dose escalation study of oral FF-10101 in patients with relapsed and/or refractory AML, the majority of whom harbored FLT3-activating mutations and/or had prior exposure to FLT3 inhibitors. Fifty-four participants enrolled in cohorts receiving doses ranging from 10 to 225 mg per day and 50 to 100 mg twice daily (BID). The dose limiting toxicities were diarrhea and QT prolongation. Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. Overall, 56% of participants had prior exposure to FLT3 inhibitors. The recommended phase 2 dose was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03194685.

Microbial biofilms represent an important lifestyle for bacteria and are dynamic three-dimensional structures. Cyclic dimeric guanosine monophosphate (c-di-GMP) is a ubiquitous signaling molecule that is known to be tightly regulated with biofilm processes. While measurements of global levels of c-di-GMP have proven valuable toward understanding the genetic control of c-di-GMP production, there is a need for tools to observe the local changes of c-di-GMP production in biofilm processes. We have developed a label-free method for the direct detection of c-di-GMP in microbial colony biofilms using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). We applied this method to the enteric pathogen Vibrio cholerae, the marine symbiont V. fischeri, and the opportunistic pathogen Pseudomonas aeruginosa PA14 and detected spatial and temporal changes in c-di-GMP signal that accompanied genetic alterations in factors that synthesize and degrade the compound. We further demonstrated how this method can be simultaneously applied to detect additional metabolites of interest from a single sample.

BACKGROUND: Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimers disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. METHODS: Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. RESULTS: Apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. CONCLUSION: Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Since genotype imputation was introduced, researchers have been relying on the estimated imputation quality from imputation software to perform post-imputation quality control (QC). However, this quality estimate (denoted as Rsq) performs less well for lower-frequency variants. We recently published MagicalRsq, a machine-learning-based imputation quality calibration, which leverages additional typed markers from the same cohort and outperforms Rsq as a QC metric. In this work, we extended the original MagicalRsq to allow cross-cohort model training and named the new model MagicalRsq-X. We removed the cohort-specific estimated minor allele frequency and included linkage disequilibrium scores and recombination rates as additional features. Leveraging whole-genome sequencing data from TOPMed, specifically participants in the BioMe, JHS, WHI, and MESA studies, we performed comprehensive cross-cohort evaluations for predominantly European and African ancestral individuals based on their inferred global ancestry with the 1000 Genomes and Human Genome Diversity Project data as reference. Our results suggest MagicalRsq-X outperforms Rsq in almost every setting, with 7.3%-14.4% improvement in squared Pearson correlation with true R2, corresponding to 85-218 K variant gains. We further developed a metric to quantify the genetic distances of a target cohort relative to a reference cohort and showed that such metric largely explained the performance of MagicalRsq-X models. Finally, we found MagicalRsq-X saved up to 53 known genome-wide significant variants in one of the largest blood cell trait GWASs that would be missed using the original Rsq for QC. In conclusion, MagicalRsq-X shows superiority for post-imputation QC and benefits genetic studies by distinguishing well and poorly imputed lower-frequency variants.

We examined whether a community engagement approach and jurisdictional attributes were associated with local action to restrict the sale of flavored tobacco products in Los Angeles County during 2019-2022. We estimated crude and adjusted risk ratios to examine these associations. Jurisdictions that used an active community engagement approach to adopt a flavored tobacco ban ordinance, those with previous experience adopting other tobacco-related ordinances, and those located next to communities that have an existing tobacco retail license ordinance were more likely than jurisdictions without these attributes to adopt a new ordinance to restrict the sale of flavored tobacco products. Efforts to adopt such an ordinance were generally more successful in jurisdictions where community members were engaged and policy makers were familiar with the adoption of public health ordinances.

Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes, ranging from infections to autoimmunity to inflammatory conditions, overlapping with other more common disorders. The prolonged diagnostic odyssey drives excessive system-wide costs before diagnosis. Because there is no single causal mechanism, there are no genetic tests to definitively diagnose CVID. Here, we present PheNet, a machine learning algorithm that identifies patients with CVID from their electronic health records (EHRs). PheNet learns phenotypic patterns from verified CVID cases and uses this knowledge to rank patients by likelihood of having CVID. PheNet could have diagnosed more than half of our patients with CVID 1 or more years earlier than they had been diagnosed. When applied to a large EHR dataset, followed by blinded chart review of the top 100 patients ranked by PheNet, we found that 74% were highly probable to have CVID. We externally validated PheNet using >6 million records from disparate medical systems in California and Tennessee. As artificial intelligence and machine learning make their way into health care, we show that algorithms such as PheNet can offer clinical benefits by expediting the diagnosis of rare diseases.

BackgroundPreterm birth is the leading cause of death in children younger than 5 years worldwide. WHO recommends kangaroo mother care (KMC); however, its effects on mortality in sub-Saharan Africa and its relative costs remain unclear. We aimed to compare the effectiveness, safety, costs, and cost-effectiveness of KMC initiated before clinical stabilisation versus standard care in neonates weighing up to 2000 g.MethodsWe conducted a parallel-group, individually randomised controlled trial in five hospitals across Uganda. Singleton or twin neonates aged younger than 48 h weighing 700-2000 g without life-threatening clinical instability were eligible for inclusion. We randomly assigned (1:1) neonates to either KMC initiated before stabilisation (intervention group) or standard care (control group) via a computer-generated random allocation sequence with permuted blocks of varying sizes, stratified by birthweight and recruitment site. Parents, caregivers, and health-care workers were unmasked to treatment allocation; however, the independent statistician who conducted the analyses was masked. After randomisation, neonates in the intervention group were placed prone and skin-to-skin on the caregiver's chest, secured with a KMC wrap. Neonates in the control group were cared for in an incubator or radiant heater, as per hospital practice; KMC was not initiated until stability criteria were met. The primary outcome was all-cause neonatal mortality at 7 days, analysed by intention to treat. The economic evaluation assessed incremental costs and cost-effectiveness from a disaggregated societal perspective. This trial is registered with ClinicalTrials.gov, NCT02811432.FindingsBetween Oct 9, 2019, and July 31, 2022, 2221 neonates were randomly assigned: 1110 (50·0%) neonates to the intervention group and 1111 (50·0%) neonates to the control group. From randomisation to age 7 days, 81 (7·5%) of 1083 neonates in the intervention group and 83 (7·5%) of 1102 neonates in the control group died (adjusted relative risk [RR] 0·97 [95% CI 0·74-1·28]; p=0·85). From randomisation to 28 days, 119 (11·3%) of 1051 neonates in the intervention group and 134 (12·8%) of 1049 neonates in the control group died (RR 0·88 [0·71-1·09]; p=0·23). Even if policy makers place no value on averting neonatal deaths, the intervention would have 97% probability from the provider perspective and 84% probability from the societal perspective of being more cost-effective than standard care.InterpretationKMC initiated before stabilisation did not reduce early neonatal mortality; however, it was cost-effective from the societal and provider perspectives compared with standard care. Additional investment in neonatal care is needed for increased impact, particularly in sub-Saharan Africa.FundingJoint Global Health Trials scheme of the Department of Health and Social Care, Foreign, Commonwealth and Development Office, UKRI Medical Research Council, and Wellcome Trust; Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P

Photoactivation of the plant photoreceptor and thermosensor phytochrome B (PHYB) triggers its condensation into subnuclear membraneless organelles named photobodies (PBs). However, the function of PBs in PHYB signaling remains frustratingly elusive. Here, we found that PHYB recruits PHYTOCHROME-INTERACTING FACTOR 5 (PIF5) to PBs. Surprisingly, PHYB exerts opposing roles in degrading and stabilizing PIF5. Perturbing PB size by overproducing PHYB provoked a biphasic PIF5 response: while a moderate increase in PHYB enhanced PIF5 degradation, further elevating the PHYB level stabilized PIF5 by retaining more of it in enlarged PBs. Conversely, reducing PB size by dim light, which enhanced PB dynamics and nucleoplasmic PHYB and PIF5, switched the balance towards PIF5 degradation. Together, these results reveal that PB formation spatially segregates two antagonistic PHYB signaling actions - PIF5 stabilization in PBs and PIF5 degradation in the surrounding nucleoplasm - which could enable an environmentally sensitive, counterbalancing mechanism to titrate nucleoplasmic PIF5 and environmental responses.

Health-related social needs are prevalent among cancer patients; associated with substantial negative health consequences; and drive pervasive inequities in cancer incidence, severity, treatment choices and decisions, and outcomes. To address the lack of clinical trial evidence to guide health-related social needs interventions among cancer patients, the National Cancer Institute Cancer Care Delivery Research Steering Committee convened experts to participate in a clinical trials planning meeting with the goal of designing studies to screen for and address health-related social needs among cancer patients. In this commentary, we discuss the rationale for, and challenges of, designing and testing health-related social needs interventions in alignment with the National Academy of Sciences, Engineering, and Medicine 5As framework. Evidence for food, housing, utilities, interpersonal safety, and transportation health-related social needs interventions is analyzed. Evidence regarding health-related social needs and delivery of health-related social needs interventions differs in maturity and applicability to cancer context, with transportation problems having the most maturity and interpersonal safety the least. We offer practical recommendations for health-related social needs interventions among cancer patients and the caregivers, families, and friends who support their health-related social needs. Cross-cutting (ie, health-related social needs agnostic) recommendations include leveraging navigation (eg, people, technology) to identify, refer, and deliver health-related social needs interventions; addressing health-related social needs through multilevel interventions; and recognizing that health-related social needs are states, not traits, that fluctuate over time. Health-related social needs-specific interventions are recommended, and pros and cons of addressing more than one health-related social needs concurrently are characterized. Considerations for collaborating with community partners are highlighted. The need for careful planning, strong partners, and funding is stressed. Finally, we outline a future research agenda to address evidence gaps.

Globe-LFMC 2.0, an updated version of Globe-LFMC, is a comprehensive dataset of over 280,000 Live Fuel Moisture Content (LFMC) measurements. These measurements were gathered through field campaigns conducted in 15 countries spanning 47 years. In contrast to its prior version, Globe-LFMC 2.0 incorporates over 120,000 additional data entries, introduces more than 800 new sampling sites, and comprises LFMC values obtained from samples collected until the calendar year 2023. Each entry within the dataset provides essential information, including date, geographical coordinates, plant species, functional type, and, where available, topographical details. Moreover, the dataset encompasses insights into the sampling and weighing procedures, as well as information about land cover type and meteorological conditions at the time and location of each sampling event. Globe-LFMC 2.0 can facilitate advanced LFMC research, supporting studies on wildfire behaviour, physiological traits, ecological dynamics, and land surface modelling, whether remote sensing-based or otherwise. This dataset represents a valuable resource for researchers exploring the diverse LFMC aspects, contributing to the broader field of environmental and ecological research.

IMPORTANCE: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. OBJECTIVE: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. EVIDENCE REVIEW: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. FINDINGS: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. CONCLUSIONS AND RELEVANCE: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Quantifying the temperature sensitivity of methane (CH4) production is crucial for predicting how wetland ecosystems will respond to climate warming. Typically, the temperature sensitivity (often quantified as a Q10 value) is derived from laboratory incubation studies and then used in biogeochemical models. However, studies report wide variation in incubation-inferred Q10 values, with a large portion of this variation remaining unexplained. Here we applied observations in a thawing permafrost peatland (Stordalen Mire) and a well-tested process-rich model (ecosys) to interpret incubation observations and investigate controls on inferred CH4 production temperature sensitivity. We developed a field-storage-incubation modeling approach to mimic the full incubation sequence, including field sampling at a particular time in the growing season, refrigerated storage, and laboratory incubation, followed by model evaluation. We found that CH4 production rates during incubation are regulated by substrate availability and active microbial biomass of key microbial functional groups, which are affected by soil storage duration and temperature. Seasonal variation in substrate availability and active microbial biomass of key microbial functional groups led to strong time-of-sampling impacts on CH4 production. CH4 production is higher with less perturbation post-sampling, i.e. shorter storage duration and lower storage temperature. We found a wide range of inferred Q10 values (1.2-3.5), which we attribute to incubation temperatures, incubation duration, storage duration, and sampling time. We also show that Q10 values of CH4 production are controlled by interacting biological, biochemical, and physical processes, which cause the inferred Q10 values to differ substantially from those of the component processes. Terrestrial ecosystem models that use a constant Q10 value to represent temperature responses may therefore predict biased soil carbon cycling under future climate scenarios.

Intramedullary nailing is considered the gold-standard treatment for tibial shaft fractures. The goals of treatment for these fractures are correction of axial and rotational alignment and adequate mechanical stability, allowing for optimal healing. The nail is secured in place using screws or other fasteners that are placed through the bone and into the nail itself.2  Another benefit is the ability to preserve the soft tissue around the fracture to safeguard the extraosseous blood supply and minimize soft tissue damage.3 In reference to tibial intramedullary nailing, a start point is the location where a hole is drilled in the tibia to insert the intramedullary nail. The ideal starting point for guide wire placement for the average tibia is described as 2 mm medial to the lateral tibial eminence on AP imaging and just anterior to articular surface and parallel to the anterior tibia cortex on lateral imaging.6,7 It is a critical part of the procedure because it determines the trajectory and positioning of the nail within the medullary canal.7 Having a good, ideal starting point can prevent valgus angulation and translation at the fracture site. If the start point is too far off center or at the wrong angle, the nail may be inserted incorrectly and not provide the necessary support for the bone to heal, leading to malalignment or nonunion.  It is believed that different approaches to tibial intramedullary nailing may have differing abilities to achieve an optimal start point due to associated anatomical visualization and access. These approaches include suprapatellar, parapatellar, and infrapatellar nailing. The suprapatellar approach involves making an incision above the patella and placing instruments across the patellofemoral joint, potentially damaging the joint surface. However, the nail can be inserted at the start point with the knee extended, which leads to better alignment and stability of the fractured bone. Most importantly, the main advantage of the suprapatellar approach is that it reduces anterior angulation by eliminating the extension force of the quadriceps and aids fracture reduction by preventing proximal fragment migration.4,5 The parapatellar approach, proven to be effective and reliable, involves making a smaller incision below the patella with the knee in hyperflexion. This approach is less invasive than the suprapatellar approach regarding the patellofemoral joint, but the patellar tendon needs to be circumnavigated leading to potential for higher incidence of anterior knee pain.6 Also, it can be more difficult to achieve proper alignment and increases the risk of apex anterior deformities.4 The infrapatellar approach is split into transtendinous approach and paratendinous approach where the starting point is established by splitting the patellar tendon or making an incision on either side of the knee, respectively.6 This approach provides good visualization, but it can increase the risk of damage to the patellar tendon and other soft tissue structures around the knee.

Purpose: Flatter organisational structures and nonlinear career trajectories mean intrinsic value and subjective career success are increasingly important for motivating, guiding and rewarding contemporary workers. While objective measures of career success have been well explored, more research is needed to understand the dimensions of subjective career success, their relative importance to graduates and potential variations by personal factors. This is critical for supporting graduates' transition into work and for organisations to attract and retain graduates amid global talent shortages. Design/methodology/approach: Building on assertions of the power to understand how what one seeks in a career affects career achievement, this study investigated the importance and achievement of subjective career success among 324 recent graduates from two Australian universities. Findings: Results include a notable emphasis on financial security and work-life balance, particularly among mature individuals, underscoring the value of adaptable work arrangements. Results suggest shifting priorities, with reduced importance placed on opportunities for innovation and assisting others, potentially indicating a move from collective to more individualised goals. Distinct graduate profiles emerged, showcasing diverse priorities and achievements in subjective career success, spanning from "humanistic" to "self-made" success. Originality/value: Results underscore the significance of higher education embedding program-wide career development plans across the curriculum, including value-based assessments, labour market analyses and career planning and review processes. Comprehensively supporting students in career development will empower them to explore, understand and actively pursue their career goals in alignment with their values and motivations, enhancing their person-organisation fit, career satisfaction and organisational commitment.

Employability development has become a central concern of higher education, with many students attending university to enhance their employability and career development. Universities offer a range of curricular, co-curricular and extracurricular employability-building activities, including work-integrated learning, mentoring and career counselling. However, participation in these activities, barriers to engagement and their impact on employability are unclear. This paper examines student engagement in diverse employability-building activities, barriers impeding participation and their perspectives on how activities develop aspects of employability. The methodological approach encompassed an online survey of recent bachelor graduates (n = 324) from two Australian universities and focus groups to further explore participants' experiences (n = 11). Findings showed relatively low participation rates in most activities, with the greatest engagement in external paid employment and work-related activities (e.g., internship). These activities were also perceived as the most useful for developing a sense of professional self, networks and securing work. Barriers to participation included work/study commitments, financial/health pressures and lack of confidence and awareness, somewhat varying by graduates' background characteristics. Benefits from activities varied by their type, along with students' personal characteristics. Findings highlight the importance of embedding employability-building activities in the curriculum and signal potential ways to increase engagement in diverse cohorts.

This article advances and illustrates the concept of "leaderhood" and argues for its role in the rediscovery and renewal of the inclusive, future-oriented spirit of the enterprise of education. Leaderhood, with its links to such concepts as "citizenhood", "elderhood", and "parenthood", is intended to convey a deep sense both of relatedness and of open-ended, future-focused concern. While leadership concerns an occupation or activity, leaderhood is more a state of being, recognizable not only in formal leadership situations but in every part of life, emerging not from policy and regulation but from a sense of fellowship and an awareness of our responsibilities to others and our community. Highlighting the importance of leaderhood in rediscovering the spirit of the educational enterprise and resisting managerialism and "strongman" leadership, we illustrate four principles governance of leaderhood should embody: clarity of function (particularly where governance ends and leading begins); a commitment to openness, transparency, truth, and accountability in aims and decision-making; democratic dialogue among a wide range of stakeholders based on inclusion and co-production; and an inter-sectoral, whole-system perspective, comprehending the entire meta-system, rather than being tied to one or another part of it. The article contrasts "leadership," which holds on to the past and stifles difference, with "leaderhood," which is attentive to the common good and engages fully with its responsibility to the future. Embedding leaderhood in collective action, we argue, is a key lesson for governance in developing a social contract for education that is open, fair, inclusive, and democratic.

Language planners are increasingly aware of the importance of new speakers (individuals acquiring a language outside the home, typically later-on in life) for the revitalisation of minority languages. Yet, little is known about new speakers' activation (the process by which they become active and habitual minority language users). This article presents a questionnaire-based investigation of new speakers' (n = 264) use of West Frisian in Fryslân, Netherlands--and the role traditional speakers play in new speakers' activation. Qualitative and quantitative data show that participants use West Frisian only rarely; and when they do use it, it is mainly in the classroom. Minority language interactions outside the classroom, with traditional speakers, consist mostly of a few tokenistic words or phrases. The findings show to what extent different behaviours by traditional speakers discourage and/or encourage new speakers' minority language use, highlighting how the complex dynamics between the speaker groups are hindering revitalisation efforts. The article discusses the implications of these findings for language planning to promote the activation of new speakers, and thereby the revitalisation of West Frisian.

Mnemonic devices are memory aids that make it easier to recall information and are widely used by students studying anatomy and physiology. Simple musical instruments and toys can serve as mnemonic devices for students learning the functional anatomy of the larynx: balloons can help learners understand and recall how sound is produced; tuning pegs can help learners understand how tension affects vocal pitch; fingers on a fretboard can help learners understand how pitch is further modulated; and a common coach's whistle can demonstrate how vocal volume is controlled. Using instruments and toys engages adult learners and helps them connect complex laryngeal anatomy with previous experiences.

Autistic individuals with intellectual disability are at greater risk of experiencing anxiety than their non-autistic peers without intellectual disability. Anxiety in this group may present as behaviour that challenges, often leading families to reach out to healthcare or support services. However, many families experience difficulties accessing services and, due to the lack of research into evidence-based anxiety interventions for people with intellectual disability, may not receive individualised support once in a service. This study explored caregivers' experiences of accessing services for autistic individuals with intellectual disability, and their considerations when developing new interventions for this population. Interviews and focus groups were completed with 16 caregivers of autistic people with intellectual disability. Reflexive thematic analysis was used to develop five themes about service access experiences, and three themes about caregiver considerations for anxiety interventions. Caregivers reported that their experiences of accessing services did not meet their expectations, and considerations for future anxiety interventions were often reflective of this. Interventions being flexible to family circumstances to aid accessibility, the embedding of peer support in services, and skills that can be generalised across the lifespan could be applied when aiming to improve outcomes and develop interventions for this under-served population.

This study aims to carry out a global evaluation of 13 Music Education Bachelor Degrees from Colombia, academic programs focused on the higher training of music teachers in this country, and to establish the training guidelines received by the music education professors who study them. The methodology used is empirical-analytical and descriptive-type and makes use of content analysis techniques that NVivo software provide. In addition, mixed and contextual analyses have been combined regarding specific keywords, such as music, pedagogy, and teachers. The instrument applied was a matrix with content validity completed by an international group of nine evaluators. This matrix showed a structure made up of five categories: General description of the program; Curricular characterization; Curriculum structure; Guiding principles of the curriculum; Curriculum management. The results indicate that there are divergences in the approach of the programs at the training of music educators. It is concluded that the differences between these programmes lie mainly in their formative emphasis, music or pedagogy, in a context in which the instructive approaches of higher education in music education have not yet resolved the divergences and the necessary balance between the pedagogy or artistic training.

Background: Little is known about how health issues identified at the annual health check (AHC) are followed up and addressed, how participants self-manage their health in between AHCs, and what support they receive. This research aimed to explore this. Methods: People with intellectual disabilities (n = 12), and/or their supporters residing in Wales, were interviewed following their AHC and again at 6 and 11 months. A recurrent cross-sectional thematic analysis was undertaken. Results: Five main themes emerged from interview one: going for a health check, issues identified, and actions taken, supporting the self-management of health, the personal context, and addressing health inequities. Four main themes emerged from follow-up interviews: follow-up, supporting the self-management of health, the need for reasonably adjusted health services, and going for another health check. Conclusion: A broader system of support around the AHC is required if people are to achieve or maintain the best possible health.

Supporting student interest in science is critical for broadening participation in the field because interest, even more than achievement, is associated with pursuing future science education and careers. In this study, we explore the conjecture that equitable classroom cultures can support interest in science. Specifically, we examine the idea that science classroom cultures that equitably reflect collective enterprise (where students engage collaboratively in scientific sensemaking) and care (where students believe that they are valued and respected members of the classroom community) support students, particularly those from historically marginalized populations, to develop interest in science. The study is part of a field test of a new middle school science curriculum called OpenSciEd. Data consist of survey responses from 847 students across 34 teachers located in nine states. Our analysis employed mixed-effects models to accommodate the nested structure of the data. We found that classrooms vary substantially in the degree to which they reflect collective enterprise and care, indicating that classroom culture is a perceptible and consequential feature of the shared classroom environment. Student background did not predict reports of collective enterprise or care, providing evidence that classrooms in our sample were equitable along these dimensions. Critically, collective enterprise and care are both strongly associated with student-reported interest in science. These findings underscore the importance of attending to classroom culture and the relational aspects of science learning as we seek to expand interest in science, particularly for students from historically marginalized populations.

The growing number of working mothers, dual career couples, and working single parents raises concerns about the impact of work stress on family lifestyles and their ability to balance work and family obligations. The aim of this study is to examine the role of social workers in promoting work-life balance among working mothers at the University of Nigeria, Nsukka. The cross-sectional survey design involving the mixed-methods approach was adopted for the study. A total of 604 questionnaires were distributed to the participants; of those, 99.3% (n = 596) were correctly completed and returned, 0.7% were not, and eight were selected at random for IDI. Data were analyzed using the Statistical Package for Social Sciences (SPSS), while frequency and percentages were used to present the data. According to the study, 83.6% of working mothers experience work-related stress. The results also showed that working mothers' stress levels depend on their level of education, the size of their family, and their income, as well as on their desire to publish in order to advance in their careers. The study concludes that, in order to reduce the stress experiences of working mothers, attention should be paid to their understanding of the stressors confronting them, while also recommending the establishment of an occupational social work office anchored by professional social workers, whose duties will be to offer professional advice on appropriate coping mechanisms to adopt while ensuring the welfare of university students and staff, particularly mothers.

In education, technological advances have boosted digital processes that expand training possibilities, such as xMOOCs (eXtended Massive Open Online Courses). The purpose of this study was to analyze the design of the xMOOC in the light of open and collaborative innovation and the social construction of learning. The quantitative method and descriptive statistical analysis were used to analyze the perceptions of eight expert's MOOC developers based on the results of a Likert scale questionnaire. The results were integrated with a previous study carried out with inferential statistics on 217 xMOOC students. The findings revealed two approaches to innovation to support the social construction of learning and its challenges: (a) design and teaching-learning strategies that integrate social learning activities; (b) learning objectives to strengthen social learning activities through pedagogical and technological innovation. The contribution of this research is to add value to the body of knowledge available to trainers, researchers, and stakeholders in MOOC design, the social construction of learning, and open and collaborative innovation.