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Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protects mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and provide potential focus for therapeutic intervention. Preventing axon breakdown is key to treating neurodegeneration. Here, the authors show that after axotomy, DLK kinase drives apoptotic mitochondrial fission in axons. Blocking this reduces axon degeneration and neuron death in both human and mouse models. [ABSTRACT FROM AUTHOR]

Alopecurus aequalis is a winter annual or short-lived perennial bunchgrass which has in recent years emerged as the dominant agricultural weed of barley and wheat in certain regions of China and Japan, causing significant yield losses. Its robust tillering capacity and high fecundity, combined with the development of both target and non-target-site resistance to herbicides means it is a formidable challenge to food security. Here we report on a chromosome-scale assembly of A. aequalis with a genome size of 2.83 Gb. The genome contained 33,758 high-confidence protein-coding genes with functional annotation. Comparative genomics revealed that the genome structure of A. aequalis is more similar to Hordeum vulgare rather than the more closely related Alopecurus myosuroides. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to describe trends in inpatient and outpatient upper extremity fracture surgery between 2008 and 2021, along with identifying patient factors (age, sex, race, socioeconomic status) associated with outpatient surgery. Methods: Retrospectively, 12,593 adult patients who underwent upper extremity fracture repair from 2008 to 2021 at one of five urban hospitals in the Northeastern USA were identified. Using Distressed Communities Index (DCI), patients were divided into five quintiles based on their level of socioeconomic distress. Multivariable logistic regression was performed on patients from 2008 to 2019 to identify independent factors associated with outpatient management. Results: From 2008 to 2019, outpatient procedures saw an average increase of 31%. The largest increases in the outpatient management were seen in humerus (132%) and forearm fractures (127%). Carpal and hand surgeries had the lowest percent increase of 8.1%. Clavicle and wrist fractures were independently associated with outpatient management. Older age, male sex, higher Elixhauser comorbidity index, DCI scores in the 4th or 5th quintile, and fractures of the scapula, humerus, elbow, and forearm were associated with inpatient management. During the onset of the COVID-19 pandemic, there was a decrease in outpatient procedures. Conclusion: There is a shift toward outpatient surgical management of upper extremity fractures from 2008 to 2021. Application of our findings can serve as an institutional guide to allocate patients to appropriate surgical settings. Moreover, physicians and institutions should be aware of the potential socioeconomic disparities and implement plans to allow for equal access to care. [ABSTRACT FROM AUTHOR]

Purpose of Review: We review prevalence, etiology, impact on treatment, and best practices for treatment of posttraumatic stress disorder (PTSD) in a substance use disorder (SUD) treatment setting. Recommendations are given related to screening, assessment, and symptom monitoring. Recent Findings: PTSD and SUDs are highly comorbid. This comorbidity is associated with higher acuity, more difficulty completing treatment, and worse prognosis. Integrated treatment is recommended, and trauma-focused psychotherapies combined with pharmacotherapy show particular promise. Summary: PTSD is highly prevalent in substance using samples, negatively impacting treatment course and worsening prognosis. This comorbidity has been explained by a variety of models, with self-medication having garnered the most support. Trauma-focused psychotherapies combined with pharmacotherapy demonstrate the most efficacy and are recommended when treating co-occurring SUDs and PTSD. Specifically, prolonged exposure (PE), concurrent treatment of PTSD and SUDs using PE (COPE), and cognitive processing therapy (CPT) have been seen as promising trauma-focused treatments. Investigations into ways to best augment therapy are also underway, both through treatment format and neuromodulation. Several recommendations are given. [ABSTRACT FROM AUTHOR]

Purpose: To describe residual arterial supply to the stomach after bariatric surgery via a systematic arterial-phase CT assessment approach that can aid in diagnosis and treatment of postoperative complications and facilitate planning for future procedures. Methods: Arterial-phase CT of 46 patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) at 3 academic institutions were retrospectively reviewed to assess patency of left gastric artery (LGA), right gastric artery (RGA), gastroepiploic artery (GEA), and left inferior phrenic artery (LIPA) and presence of gastric perforators. Results: In 25 RYGB and 21 SG patients, mean diameters were LGA 2.2 ± 0.4 mm, RGA 1.6 ± 0.5 mm, and GEA 1.7 ± 0.4 mm. On RYGB scans, all LGAs, RGAs, and 24/25 (96%) of GEAs were identified. Excellent to good patency was seen in 20/25 (80%) LGAs, 21/25 (84%) RGAs, and 23/24 (96%) GEAs. On SG scans, all LGAs, 18/21 (86%) of RGAs, and 20/21 (95%) GEAs were identified. Excellent to good patency was seen in 17/21 (81%) LGAs, 15/18 (83%) RGAs, and 20/20 (100%) GEAs. In terms of gastric perforators, LGA supply was seen on 23/25 (92%) of RYGB and 17/17 (100%) of SG scans. RGA supply was seen on 13/21 (62%) RYGB and 9/18 (50%) SG scans. GEA supply was seen on 19/23 (83%) RYGB scans. No gastric supply via GEA was seen on SG scans. Conclusion: In this study, arterial supply to the stomach through the LGA was consistently identified in all RYGB and SG cases, indicating an uncomplicated surgical approach with regard to preserving the LGA. Dedicated CT angiography protocol or catheter-directed angiography is recommended for accurate and comprehensive assessment of the gastric blood supply, particularly before surgical re-intervention. [ABSTRACT FROM AUTHOR]

Interlimb differences in reach control could impact the learning of a motor sequence that requires whole-arm movements. The purpose of this study was to investigate the learning of an implicit, 3-dimensional whole-arm sequence task with the non-dominant left arm compared to the dominant right arm. Thirty-one right-hand dominant adults completed two consecutive days of practice of a motor sequence task presented in a virtual environment with either their dominant right or non-dominant left arm. Targets were presented one-at-a-time alternating between Random and Repeated sequences. Task performance was indicated by the time to complete the sequence (response time), and kinematic measures (hand path distance, peak velocity) were used to examine how movements changed over time. While the Left Arm group was slower than the Right Arm group at baseline, both groups significantly improved response time with practice with the Left Arm group demonstrating greater gains. The Left Arm group improved performance by decreasing hand path distance (straighter path to targets) while the Right Arm group improved performance through a smaller decrease in hand path distance combined with increasing peak velocity. Gains made during practice on Day 1 were retained on Day 2 for both groups. Overall, individuals reaching with the non-dominant left arm learned the whole-arm motor sequence task but did so through a different strategy than individuals reaching with the dominant right arm. The strategy adopted for the learning of movement sequences that require whole-arm movements may be impacted by differences in reach control between the nondominant and dominant arms. [ABSTRACT FROM AUTHOR]

People with Intellectual Disability (ID) were more likely to contract COVID-19 infection and more likely to die from the consequences. However, there is no evidence on the long-term impact of COVID-19 infection in people with ID. Post-Covid Syndrome (PCS) is an established diagnosis that requires specialist clinical support. To date there is no data on how common PCS is in people with ID, or how symptoms present. Dysphagia is identified as a clinical marker because of the known association with PCS, and the clear objective diagnostic criteria applicable through specialist assessment. This investigation presents a cohort of people with ID, who developed dysphagia/worsening of dysphagia post diagnosis with COVID-19. Cases were identified through support from the Royal College of Speech and Language Therapists. Data was collected by electronic survey, including application of the COVID-19 Yorkshire Rehabilitation Scale-modified (C19-YRSm). The C19-YRSm is a validated assessment tool for PCS and it's impact upon functional disability. This case series identifies that symptoms consistent with PCS are present in people with ID, post-COVID-19 infection. The risk of diagnostic overshadowing or misdiagnosis is high due to the subjective nature and the quality of PCS symptoms. People with ID who develop PCS may not be readily identified by clinical services and therefore not be accessing the specialist medical support required. Furthermore, changes in behaviour secondary to PCS may lead to unnecessary increased prescribing of psychotropic medication which in itself risks worsening dysphagia. Dysphagia could be an important bellwether to identify PCS in people with ID. [ABSTRACT FROM AUTHOR]

Becoming a psychotherapy supervisor is no easy feat, and conceptual/practical material and empirical data suggest that beginning (compared to more advanced) supervisors are at their most vulnerable and most apt to struggle with issues of identity, confidence, self-efficacy, and competency development. Beginning supervisors can benefit from being helped to navigate through these normative developmental struggles and being transitionally eased into the supervisory role. We consider one way to make that transition and navigation process easier, presenting a supervisor preparation-positivity-purpose action checklist that is organized around three key areas: educating supervisees about the supervision experience; fostering positive supervisee expectations; and collaboratively formulating reasonable supervision goals. Distributed across those three areas, we identify and elaborate upon 20 specific supervisor actions that provide direction about optimizing supervision's start. We view this checklist as a 'handy tool', a useful seminar/workshop reference resource and guidance sheet for those new to the practice of supervision and for those beginning their training as supervisors. [ABSTRACT FROM AUTHOR]

Introduction: Pancreatic cancer is a significant public health concern and a leading cause of cancer-related deaths worldwide. This study aimed to investigate pancreatic cancer mortality trends and disparities in the United States (US) from 1999 to 2020. Methods: Data were obtained from the Centers for Disease Control (CDC) Wide-Ranging Online Data for Epidemiologic Research database. Mortality rates were age-adjusted and standardized to the year 2000 US population. Joinpoint regression was used to analyze temporal trends in age-adjusted mortality rates (AAMRs) by sociodemographic and geographic variables. Results: Between 1999 and 2020, pancreatic cancer led to a total of 810,628 deaths in the US, an average mortality of nearly 39,000 deaths per year. The AAMR slightly increased from 10.6 in 1999 to 11.1 in 2020, with an associated annual percent change (APC) of 0.2. Mortality rates were highest among individuals aged 65 and older. Black individuals experienced the highest overall pancreatic cancer-related AAMR at 13.8. Despite this, Black individuals experienced a decreasing mortality trend over time (APC −0.2) while White individuals experienced an increasing trend in mortality (APC 0.4). Additionally, individuals residing in rural areas experienced steeper rates of mortality increase than those living in urban areas (APC 0.6 for rural vs −0.2 for urban). White individuals in urban and rural populations experienced an increase in mortality, while Black individuals in urban environments experienced a decrease in mortality, and Black individuals in rural environments experienced stable mortality trends. Conclusions: Mortality from pancreatic cancer continues to increase in the US, with racial and regional disparities identified in minorities and rural-dwelling individuals. These disparate findings highlight the importance of ongoing efforts to understand and address pancreatic cancer treatment and outcomes disparities in the US, and future studies should further investigate the underlying etiologies of these disparities and potential for novel therapies to reduce the mortality. [ABSTRACT FROM AUTHOR]

Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer1,2. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans. We also identify intrinsic and environmental mutational processes linked to ecDNA, including those linked to its formation, such as tobacco exposure, and progression, such as homologous recombination repair deficiency. Clinically, ecDNA detection was associated with tumour stage, more prevalent after targeted therapy and cytotoxic treatments, and associated with metastases and shorter overall survival. These results shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumour growth signals, alter transcriptional landscapes and suppress the immune system.A study examines the diversity of extrachromosomal DNA elements in cancer, and provides details on the frequency and origin of extrachromosomal DNA and its role in the development of different types of cancer. [ABSTRACT FROM AUTHOR]

In bioarchaeology, funerary taphonomy and preservation become part of the biocultural narrative of the dead. We evaluate the role of these factors in reconstructing the identities of those buried in an emerging deathway, the ventrally placed legs flexed (VPLF) burial position, during the Terminal Classic (750–900/1000 CE) period at the Maya polity of Lower Dover in western Belize. The term “VPLF” describes a divergent burial practice which may have resulted from intentional binding prior to burial. In our analysis of VPLF burials (n = 12), we use a two-step process to reconstruct the social identities and potential meaning of the burial pattern: (1) interpretation of the archaeological context based on excavation observations and biogeochemistry and (2) osteological analysis of curated individuals to reconstruct their biological profiles and post-mortem/post-excavation histories. Osteological analyses included age and sex estimation, paleopathological assessment of frailty and trauma, and skeletal modifications from cultural and taphonomic forces. Radiocarbon dating and ceramic analyses were used to date the burials. Stable and radiogenic isotopic analyses were applied to reconstruct diet and mobility for a subset of the VPLF burials. Our results show that individuals were buried in the VPLF position irrespective of age, sex, or social status, consistent with patterns at other Terminal Classic and Postclassic Maya sites, although VPLF interment may have been practiced earlier at Lower Dover. We hypothesize that the appearance of VPLF burials in the Terminal Classic period signified an ideological shift in light of emerging social and environmental pressures in the region. [ABSTRACT FROM AUTHOR]

There is a synergistic relationship between epilepsy and intellectual disability (ID), and the approach to managing people with these conditions needs to be holistic. Epilepsy is the main co-morbidity associated with ID, and clinical presentation tends to be complex, associated with higher rates of treatment resistance, multi-morbidity and premature mortality. Despite this relationship, there is limited level 1 evidence to inform treatment choice for this vulnerable population. This review updates the current evidence base for anti-seizure medication (ASM) prescribing for people with ID. Recommendations are made on the basis of evidence and expert clinical opinion and summarised into a Traffic Light System for accessibility. This review builds on work developed through UK's Royal College of Psychiatrists, Faculty of Intellectual Disability Psychiatry and includes newer pragmatic data from the Cornwall UK Ep-ID Research Register, a national research register for England and Wales that has been in existence for the last 10 years. The Register acts as a source for an in-depth exploration of the evidence base for prescribing 'newer' (third generation, specifically post-2004) ASMs. Its findings are discussed and compared. A practical approach to prescribing and choosing ASMs is recommended on the based evidence. This approach considers the drug profile, including adverse effects and clinical characteristics. The review also details newer specialist ASMs restricted to certain epilepsy syndromes, and potential future ASMs that may be available soon. For completeness, we also explore non-pharmacological interventions, including surgeries, to support epilepsy management. [ABSTRACT FROM AUTHOR]

The concept of biological sex guides research, clinical practice, science funding policy, and contemporary political discourse. Despite some substantive differences, all existing candidate philosophical accounts of sex assume its legitimacy as a biological concept. Here, we challenge this view. We argue against realism about biological sex, and that eliminating biological sex from large swaths of biological theory and practice may be preferable compared to conventionalist or fictionalist anti-realisms. There are serious social and epistemic costs to using “biological sex” in place of more specific alternatives. Because of this, biologists and philosophers of science should consider eliminativism about the concept of biological sex. Biological sex eliminativism is worth taking seriously, and it can play important roles in philosophical debate and biological practice, even for those who remain skeptical. The methodological consequences of biological sex eliminativism are compatible with best practices for inquiry in the biological and biomedical sciences, with inclusive approaches to the study of sex and gender, and with feminist philosophical and methodological recommendations. Taking eliminativism seriously reveals important disagreement about the work that a concept of biological sex should do, and imposes a contrastive burden on would-be rivals. [ABSTRACT FROM AUTHOR]

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons. The mechanisms that trigger neurodegeneration in demyelinating disease are unclear. Here, the authors find that impaired remyelination induces a DLK-mediated loss of retinal ganglion cells (RGCs), and that efficient remyelination or DLK inhibition block RGC death. [ABSTRACT FROM AUTHOR]

Marginal zone lymphoma (MZL) can have varied presentations and pathologic features, including high Ki-67 expression (> 20%) as well as increased numbers of large B cells (LC). However, there are limited data available demonstrating the prognostic significance of these variables in patients with MZL. In this multi-institutional retrospective cohort study of patients with MZL treated at 10 centers, we evaluated the association between the presence of Ki-67 expression and increased LCs on survival and risk of histologic transformation (HT). A total of 785 patients were included (60% with extranodal MZL, 20% with nodal MZL, and 20% with splenic MZL). Among the 440 patients with Ki-67 staining, 22% had high Ki-67 (Ki-67 >20%). The median progression-free survival (PFS) for patients with high Ki-67 was 5.4 years compared to 7.0 years for patients with low Ki-67 (HR = 1.45, 95%CI = 1.03–2.05). Ki-67 > 20% strongly correlated with high LDH level. The risk of HT was higher in patients with increased Ki-67 than those without (5-year risk, 9.8% vs 3.87%, p = 0.01). Twelve percent of patients had LC reported on biopsy with 6% having >10% LC. The presence of LC was associated with high Ki-67 (p < 0.001), but not associated with shorter PFS or overall survival (OS). The cumulative risk for HT was higher in patients with LC compared to those without LC (5-year risk, 9.4% vs 2.9%, p = 0.04). Receipt of anthracycline-based therapy did not impact PFS or OS in either group. Ki-67 staining >20% was a prognostic factor for worse survival and strongly correlated with elevated LDH. Novel therapies should be investigated for their potential ability to overcome the high-risk features in MZL. Our data reinforce the importance of obtaining biopsies at relapse or progression, particularly in patients with baseline high Ki-67 and increased LCs, given their increased risk for HT. [ABSTRACT FROM AUTHOR]

Prematurity-associated lung disease (PLD) is a long-term consequence of preterm-birth. Since the underlying mechanisms of PLD remain poorly characterised, we compared the urinary metabolome between recently described spirometry phenotypes of PLD. Preterm- and term-born children aged 7–12 years, from the Respiratory Health Outcomes in Neonates (RHiNO) cohort, underwent spirometry and urine collection. The urinary metabolome was analysed by gas chromatography time-of-flight mass spectrometry. Preterm-born children were classified into phenotypes of prematurity-associated obstructive lung disease (POLD, Forced expiratory volume in 1 s (FEV1) < lower limit of normal (LLN), FEV1/Forced Vital Capacity (FVC) < LLN), prematurity-associated preserved ratio impaired spirometry (pPRISm, FEV1 < LLN, FEV1/FVC ≥ LLN) and Preterm/Term controls (FEV1 ≥ LLN). Metabolite set enrichment analysis was used to link significantly altered metabolites between the groups with metabolic pathways. Univariable and multivariable linear regression models examined associations between early and current life factors and significantly altered metabolites of interest. Urine from 197 preterm- and 94 term-born children was analysed. 23 and 25 were classified into POLD and pPRISm groups respectively. Of 242 identified metabolites, 49 metabolites were significantly altered in the POLD group compared with Preterm controls. Decreased capric acid (log2 fold change − 0.23; p = 0.003), caprylic acid (− 0.18; 0.003) and ceratinic acid (− 0.64; 0.014) in the POLD group, when compared to preterm controls, were linked with reduced β-oxidation of very long chain fatty acids (p = 0.004). Reduced alanine (log2 fold change − 0.21; p = 0.046), glutamic acid (− 0.24; 0.023), and pyroglutamic acid (− 0.17; 0.035) were linked with decreased glutathione metabolism (p = 0.008). These metabolites remained significantly associated with POLD in multivariable models adjusting for early/current life factors. The pPRISm urinary metabolome was minimally changed when compared with preterm-born controls. When compared to term-born subjects, alterations in tryptophan metabolism were implicated (p = 0.01). The urinary metabolome in POLD showed significantly altered β-oxidation of fatty acids and glutathione metabolism, implying alterations in cellular metabolism and oxidative stress. Similar findings have been noted in adults with chronic obstructive pulmonary disease. Given the similarity of findings between the POLD group and those reported for COPD, the POLD group should be considered at future risk of developing COPD. [ABSTRACT FROM AUTHOR]

Intracranial pressure (ICP) is a physiological parameter that conventionally requires invasive monitoring for accurate measurement. Utilising multivariate predictive models, we sought to evaluate the utility of non-invasive, widely accessible MRI biomarkers in predicting ICP and their reversibility following cerebrospinal fluid (CSF) diversion. The retrospective study included 325 adult patients with suspected CSF dynamic disorders who underwent brain MRI scans within three months of elective 24-h ICP monitoring. Five MRI biomarkers were assessed: Yuh sella grade, optic nerve vertical tortuosity (VT), optic nerve sheath distension, posterior globe flattening and optic disc protrusion (ODP). The association between individual biomarkers and 24-h ICP was examined and reversibility of each following CSF diversion was assessed. Multivariate models incorporating these radiological biomarkers were utilised to predict 24-h median intracranial pressure. All five biomarkers were significantly associated with median 24-h ICP (p < 0.0001). Using a pair-wise approach, the presence of each abnormal biomarker was significantly associated with higher median 24-h ICP (p < 0.0001). On multivariate analysis, ICP was significantly and positively associated with Yuh sella grade (p < 0.0001), VT (p < 0.0001) and ODP (p = 0.003), after accounting for age and suspected diagnosis. The Bayesian multiple linear regression model predicted 24-h median ICP with a mean absolute error of 2.71 mmHg. Following CSF diversion, we found pituitary sella grade to show significant pairwise reversibility (p < 0.001). ICP was predicted with clinically useful precision utilising a compact Bayesian model, offering an easily interpretable tool using non-invasive MRI data. Brain MRI biomarkers are anticipated to play a more significant role in the screening, triaging, and referral of patients with suspected CSF dynamic disorders. [ABSTRACT FROM AUTHOR]

Background : Understanding biaxial loading response at the microstructural level is crucial in helping better design sheet manufacturing processes and calibrate/validate material deformation models. Objective : The objective of this work was to develop a low-cost testing apparatus to probe, with sufficient spatial resolution, the micro-mechanical response of a sheet material in-situ under biaxial loading conditions. Methods : The testing apparatus fabricated as a part of this study operates in a similar fashion to a standard bulge test and uses oil pressure to generate biaxial loading conditions. This biaxial testing apparatus was operated within a synchrotron beamline to characterize the mechanical response of a flash-processed steel sheet using in-situ high-energy X-ray diffraction (XRD) measurements. The GSAS-II package was utilized to develop a workflow for the analysis of the large volume of diffraction data acquired. The workflow was then used to extract the peak position, width, and integrated intensity of the XRD peaks corresponding to the major body-centered cubic phase. Results : The equi-biaxial nature of the loading in the measured area was independently corroborated using experimental (XRD) and simulation (finite element analysis) methods. Furthermore, we discuss the evolution of elastic strain in the major body-centered cubic phase as a function of applied oil pressure and location on the steel sheet. Conclusions : A key advantage of the biaxial apparatus fabricated in this synchrotron study is demonstrated using the results obtained for the flash-processed steel sheet – i.e., mapping the lattice plane-dependent response to biaxial loading for a relatively large sample area in a spatially resolved manner. [ABSTRACT FROM AUTHOR]

Rumination is a vulnerability for depression and potentially linked to inhibitory control weaknesses. We aimed to replicate the association observed in adults between inhibitory control and rumination in adolescents, and to examine putative moderating roles of childhood maltreatment and perceived family cohesion in an adolescent sample at risk for depression due to familial/personal history. Ninety adolescents aged 11–17 (M = 14.6, SD = 1.8) completed self-report scales of rumination, maltreatment, and family cohesion, and performed a task assessing inhibitory control. Hierarchical regression models showed no significant relation between inhibitory control and moderator variables on rumination. However, adolescents who reported higher levels of maltreatment and who perceived lower family cohesion tended to indicate higher levels of rumination (BChilhood Maltreatment = 27.52, 95% CIs [5.63, 49.41], BFamily Cohesion = -0.40, 95% CIs [-0.65, -0.15]). These findings demonstrate an alternative understanding of factors that increase depression onset risk and recurrence in adolescents. Summary Statement: This study was funded by the National Institute of Mental Health grants R61MH116080 and F31MH117856. S.A.L. reports financial disclosures from EPI-Q, Otsuka Pharmaceutical, Development and Commercialization, Inc, and Secondary Triad, Inc, all of which are unrelated to the present work. S.A.L. is supported by National Institute of Mental Health grants (Grant Nos. MH116080, MH112705, MH120660, and MH120168). K.L.B. is supported by the National Institutes of Mental Health grant F31MH117856. All other authors have no relevant financial or non-financial interests to disclose. [ABSTRACT FROM AUTHOR]

Background: There has been growing interest in using artificial intelligence/deep learning (DL) to help diagnose prevalent diseases earlier. In this study we sought to survey the landscape of externally validated DL-based computer-aided diagnostic (CADx) models, and assess their diagnostic performance for predicting the risk of malignancy in computed tomography (CT)-detected pulmonary nodules. Methods: An electronic search was performed in four databases (from inception to 10 August 2023). Studies were eligible if they were peer-reviewed experimental or observational articles comparing the diagnostic performance of externally validated DL-based CADx models with models widely used in clinical practice to predict the risk of malignancy. A bivariate random-effect approach for the meta-analysis on the included studies was used. Results: Seventeen studies were included, comprising 8553 participants and 9884 nodules. Pooled analyses showed DL-based CADx models were 11.6% more sensitive than physician judgement alone, and 14.5% more than clinical risk models alone. They had a similar pooled specificity to physician judgement alone [0.77 (95% CI 0.68–0.84) v 0.81 (95% CI 0.71–0.88)], and were 7.4% more specific than clinical risk models alone. They had superior pooled areas under the receiver operating curve (AUC), with relative pooled AUCs of 1.03 (95% CI 1.00–1.07) and 1.10 (95% CI 1.07–1.13) versus physician judgement and clinical risk models alone, respectively. Conclusion: DL-based models are already used in clinical practice in certain settings for nodule management. Our results show their diagnostic performance potentially justifies wider, more routine deployment alongside experienced physician readers to help inform multidisciplinary team decision-making. [ABSTRACT FROM AUTHOR]

Background and Objective: Firsocostat is an oral, liver-targeted inhibitor of acetyl-CoA carboxylase in clinical development for the treatment of metabolic dysfunction-associated steatohepatitis. This work evaluated the potential drug–drug interactions (DDIs) of firsocostat as a victim and as a perpetrator, to inform concomitant medication use. Methods: In this phase I study, healthy participants (n = 13–30 in each of four cohorts) received firsocostat alone or in combination with either victims or perpetrators of cytochrome P450 (CYP) enzymes and drug transporters to evaluate firsocostat as both a victim and perpetrator of DDIs, respectively. Results: Overall, 80 participants completed the study. As a victim of DDI, firsocostat plasma exposure (area under the plasma concentration-time curve [AUC] from 0 to infinity [AUC∝]) was 19-fold, 22-fold, 63%, and 38% higher when administered with single-dose rifampin 600 mg (organic anion transporting polypeptide [OATP] 1B1/B3 inhibitor), single-dose cyclosporine A 600 mg (OATP/P-glycoprotein/CYP3A inhibitor), multiple-dose probenecid 500 mg twice daily (evaluated as a uridine diphosphate glucuronosyltransferase [UGT] inhibitor), and multiple-dose voriconazole 200 mg twice daily (CYP3A inhibitor), respectively, compared with the administration of firsocostat alone. As a perpetrator of DDI, multiple-dose administration of firsocostat did not affect the exposure of midazolam 2 mg (CYP3A substrate) or drospirenone/ethinylestradiol 3 mg/0.02 mg (combined oral contraceptive). Study treatments were well-tolerated and all adverse events were mild. Conclusions: Firsocostat can be administered with CYP3A and UGT inhibitors without dose adjustment. However, firsocostat should not be coadministered with strong OATP1B/3 inhibitors, such as rifampin and cyclosporine A. Firsocostat can be administered with CYP3A substrates or combined oral contraceptives without dose modification. [ABSTRACT FROM AUTHOR]

Objective: Gait disturbance is one of the features of normal pressure hydrocephalus (NPH) and decompensated long-standing overt ventriculomegaly (LOVA). The timed-up-and-go (TUG) test and the timed-10-m-walking test (10MWT) are frequently used assessments tools for gait and balance disturbances in NPH and LOVA, as well as several other disorders. We aimed to make smart-phone apps which perform both the 10MWT and the TUG-test and record the results for individual patients, thus making it possible for patients to have an objective assessment of their progress. Patients with a suitable smart phone can perform repeat assessments in their home environment, providing a measure of progress for them and for their clinical team. Methods: 10MWT and TUG-test were performed by 50 healthy adults, 67 NPH and 10 LOVA patients, as well as 5 elderly patients as part of falls risk assessment using the Watkins2.0 app. The 10MWT was assessed with timed slow-pace and fast-pace. Statistical analysis used SPSS (version 25.0, IBM) by paired t-test, comparing the healthy and the NPH cohorts. Level of precision of the app as compared to a clinical observer using a stopwatch was evaluated using receiver operating characteristics curve. Results: As compared to a clinical observer using a stopwatch, in 10MWT the app showed 100% accuracy in the measure of time taken to cover distance in whole seconds, 95% accuracy in the number of steps taken with an error ± 1–3 steps, and 97% accuracy in the measure of total distance covered with error of ± 0.25–0.50 m. The TUG test has 100% accuracy in time taken to complete the test in whole seconds, 97% accuracy in the number of steps with an error of ± 1–2 steps and 87.5% accuracy in the distance covered with error of ± 0.50 m. In the measure of time, the app was found to have equal sensitivity as an observer. In measure of number of steps and distance, the app demonstrated high sensitivity and precision (AUC > 0.9). The app also showed significant level of discrimination between healthy and gait-impaired individuals. Conclusion: 'Watkins' and 'Watkins2.0' are efficient apps for objective performance of 10MWT and the TUG-test in NPH and LOVA patients and has application in several other pathologies characterised by gait and balance disturbance. [ABSTRACT FROM AUTHOR]

Background: Sarcomas are diverse neoplasms with highly variable histological appearances in which diagnosis is often challenging and management options for metastatic/unresectable disease limited. Many sarcomas have distinctive molecular alterations, but the range of alterations is large, variable in type and rapidly increasing, meaning that testing by limited panels is unable to capture the broad spectrum of clinically pertinent genomic drivers required. Paired whole genome sequencing (WGS) in contrast allows comprehensive assessment of small variants, copy number and structural variants along with mutational signature analysis and germline testing. Methods: Introduction of WGS as a diagnostic standard for all eligible patients with known or suspected soft tissue sarcoma over a 2-year period at a soft tissue sarcoma treatment centre. Results: WGS resulted in a refinement in the diagnosis in 37% of cases, identification of a target for personalised therapy in 33% of cases, and a germline alteration in 4% of cases. Conclusion: Introduction of WGS poses logistical and training challenges, but offers significant benefits to this group of patients. [ABSTRACT FROM AUTHOR]

Simultaneous achievement of lightweight, ultrahigh strength, large fracture strain, and high damping capability is challenging because some of these mechanical properties are mutually exclusive. Here, we utilize self-assembled polymeric carbon precursor materials in combination with scalable nano-imprinting lithography to produce nanoporous carbon nanopillars. Remarkably, nanoporosity induced via sacrificial template significantly reduces the mass density of amorphous carbon to 0.66 ~ 0.82 g cm−3 while the yield and fracture strengths of nanoporous carbon nanopillars are higher than those of most engineering materials with the similar mass density. Moreover, these nanopillars display both elastic and plastic behavior with large fracture strain. A reversible part of the sp2-to-sp3 transition produces large elastic strain and a high loss factor (up to 0.033) comparable to Ni-Ti shape memory alloys. The irreversible part of the sp2-to-sp3 transition enables plastic deformation, leading to a large fracture strain of up to 35%. These findings are substantiated using simulation studies. None of the existing structural materials exhibit a comparable combination of mass density, strength, deformability, and damping capability. Hence, the results of this study illustrate the potential of both dense and nanoporous amorphous carbon materials as superior structural nanomaterials. Simultaneous achievement of lightweight and high strength is challenging. Here, authors combine self-assembly of nanoscale block copolymer and carbonization to create nanoporous amorphous carbon materials, which have the density of elastomers or plastic but the strength of metals or alloys. [ABSTRACT FROM AUTHOR]

Cellular therapy development and manufacturing has focused on providing novel therapeutic cell-based products for various diseases. The International Organization for Standardization (ISO) has provided guidance on critical quality attributes (CQAs) that shall be considered when testing and releasing cellular therapeutic products. Cell count and viability measurements are two of the CQAs that are determined during development, manufacturing, testing, and product release. The ISO Cell Counting Standard Part 1 and 2 addressed the needs for improving the quality of cell counting results. However, there is currently no guidance on the qualification and selection of a fit-for-purpose cell viability detection method. In this work, we present strategies for the characterization and comparison of AO/PI and AO/DAPI staining methods using the heat-killed (HK) and low temperature/nutrient-deprived (LT/ND) cell death models to evaluate the comparability of cell viability measurements and identify potential causes of differences. We compared the AO/PI and AO/DAPI staining methods using HK and LT/ND-generated dead cells, investigated the staining time effects on cell viability measurements, and determined their viability linearity with different mixtures of live and dead cells. Furthermore, we validated AO/PI and AO/DAPI cell viability measurement with a long-term cell proliferation assay. Finally, we demonstrate a practical example of cell viability measurement comparison using AO/PI and AO/DAPI on antibiotic-selected transduced Jurkat and THP-1 cells to select a fit-for-purpose method for functional genomics screening. The proposed strategies may potentially enable scientists to properly characterize, compare, and select cell viability detection methods that are critical for cellular therapeutic product development and manufacturing. [ABSTRACT FROM AUTHOR]

Musculoskeletal (MSK) disorders are associated with large impacts on patient's pain and quality of life. Conventional morphological imaging of tissue structure is limited in its ability to detect pain generators, early MSK disease, and rapidly assess treatment efficacy. Positron emission tomography (PET), which offers unique capabilities to evaluate molecular and metabolic processes, can provide novel information about early pathophysiologic changes that occur before structural or even microstructural changes can be detected. This sensitivity not only makes it a powerful tool for detection and characterization of disease, but also a tool able to rapidly assess the efficacy of therapies. These benefits have garnered more attention to PET imaging of MSK disorders in recent years. In this narrative review, we discuss several applications of multimodal PET imaging in non-oncologic MSK diseases including arthritis, osteoporosis, and sources of pain and inflammation. We also describe technical considerations and recent advancements in technology and radiotracers as well as areas of emerging interest for future applications of multimodal PET imaging of MSK conditions. Overall, we present evidence that the incorporation of PET through multimodal imaging offers an exciting addition to the field of MSK radiology and will likely prove valuable in the transition to an era of precision medicine. [ABSTRACT FROM AUTHOR]

The mpox epidemic in the UK began in May 2022, with rates of new cases unexpectedly and rapidly declining during August 2022. Interpreting trends in infection requires disentangling the underlying growth rate of cases from the delay from symptom onset to presenting to healthcare. We developed a nowcasting Bayesian method which incorporates time-varying delays (EpiLine) to quantify the changes in the delay from symptom onset to healthcare presentation and the underlying mpox growth rate over the period May-August 2022 in the UK. We show that the mean delay between symptom onset and healthcare presentation for mpox in the UK decreased from 22 days in early May 2022 to 10 days by early June and 8 days in August 2022. When we account for these dynamic delays, the time-varying growth rate declined gradually and continuously in the UK during the May-August 2022 period. Not accounting for varying time delays would have incorrectly characterised the growth rate by a sharp increase followed by a rapid decline in mpox cases. Our results highlight the importance of correctly quantifying the delay between symptom onset to healthcare presentation when characterising the epidemic growth of mpox in the UK. The gradual reduction in the rate of epidemic spread, which pre-dated the vaccine roll-out, is consistent with gradual risk reduction or acquired immunity amongst the highest risk individuals. Our study highlights the need for public health agencies to record the delays from symptom onset to healthcare presentation early in an outbreak. [ABSTRACT FROM AUTHOR]

Increased patient access to electronic medical records and resources has resulted in higher volumes of health-related questions posed to clinical staff, while physicians' rising clinical workloads have resulted in less time for comprehensive, thoughtful responses to patient questions. Artificial intelligence chatbots powered by large language models (LLMs) such as ChatGPT could help anesthesiologists efficiently respond to electronic patient inquiries, but their ability to do so is unclear. A cross-sectional exploratory survey-based study comprised of 100 anesthesia-related patient question/response sets based on two fictitious simple clinical scenarios was performed. Each question was answered by an independent board-certified anesthesiologist and ChatGPT (GPT-3.5 model, August 3, 2023 version). The responses were randomized and evaluated via survey by three blinded board-certified anesthesiologists for various quality and empathy measures. On a 5-point Likert scale, ChatGPT received similar overall quality ratings (4.2 vs. 4.1, p =.81) and significantly higher overall empathy ratings (3.7 vs. 3.4, p <.01) compared to the anesthesiologist. ChatGPT underperformed the anesthesiologist regarding rate of responses in agreement with scientific consensus (96.6% vs. 99.3%, p =.02) and possibility of harm (4.7% vs. 1.7%, p =.04), but performed similarly in other measures (percentage of responses with inappropriate/incorrect information (5.7% vs. 2.7%, p =.07) and missing information (10.0% vs. 7.0%, p =.19)). In conclusion, LLMs show great potential in healthcare, but additional improvement is needed to decrease the risk of patient harm and reduce the need for close physician oversight. Further research with more complex clinical scenarios, clinicians, and live patients is necessary to validate their role in healthcare. [ABSTRACT FROM AUTHOR]

In most avian retinas, double cones (consisting of a principal and accessory member) outnumber other photoreceptor types and have been associated with various functions, such as encoding luminance, sensing polarized light, and magnetoreception. However, their down-stream circuitry is poorly understood, particularly across bird species. Analysing species differences is important to understand changes in circuitry driven by ecological adaptations. We compare the ultrastructure of double cones and their postsynaptic bipolar cells between a night-migratory European robin and non-migratory chicken. We discover four previously unidentified bipolar cell types in the European robin retina, including midget-like bipolar cells mainly connected to one principal member. A downstream ganglion cell reveals a complete midget-like circuit similar to a circuit in the peripheral primate retina. Additionally, we identify a selective circuit transmitting information from a specific subset of accessory members. Our data highlight species-specific differences in double cone to bipolar cell connectivity, potentially reflecting ecological adaptations. Volume electron microscopy of retinas from two birds living in different habitats sheds light on species-specific wiring differences of double cone contacting bipolar cells and identifies principal and accessory member specific downstream circuits. [ABSTRACT FROM AUTHOR]

Purpose: Leaks after sleeve gastrectomy remain a deadly complication significantly affecting outcomes and medical costs. The aim of the present review is to provide an updated decalogue on leak prevention. Methods: Risk factors of leakage after LSG were examined based on an extensive review of literature (in period time 2016–2024) and summary of evidence was provided using Oxford levels of evidence scale. Results: Pathogenesis of leakage after LSG still remain related to ischemic and mechanical factors and, therefore, no new evidence has been reported. Conversely, some technical aspect of the procedure has changed: bougie size, antrum resection, staple line reinforcement, and intraoperative leak testing. Conclusions: Bougie size 36 F is effective and safe achieving similar leakage rate compared to larger bougie sizes (EL:2) 2024 UPDATE; There is no significant difference in the leak rate between restrictive (< 6 cm) and conservative (6 cm) antrum resection (EL: 1) 2024 UPDATE; Surgical experience and case volume affect the leak rate more consistently than every kind of SLR (EL: 2) 2024 UPDATE; Intraoperative leak test after LSG represents a decision based on surgeon preference in absence of standardization (endoscopy, bubble test, methylene blue, indocyanine green.) and strong detection/prevention rate (EL: 3) 2024 UPDATE. [ABSTRACT FROM AUTHOR]

Play in early childhood environments is critical to the social development of all children, including those with disabilities. Children with autism often experience delays in the development of play skills and may especially struggle with social play with peers. Thus, strategies to support social play in inclusive preschool settings are needed. The purpose of this article is to provide practitioners with an overview of evidence-based strategies to increase play interactions between children with autism and their peers in inclusive preschool settings. We outline the importance of play in early childhood classrooms, provide an overview of common play and social interaction challenges experienced by young children with autism, and describe and exemplify strategies to promote play between peers. We provide recommendations for collaborations between special educators and speech language pathologists working with children with autism to support children's play in inclusive environments. [ABSTRACT FROM AUTHOR]

The emergence and evolution of engineering biology, and its potential to address multiple global challenges is associated with the rise of biofoundries. These innovation intermediaries are facilities that employ advanced automation and computational analytics to accelerate engineering biology applications. Yet, for biofoundries to fully achieve their promise of generating applications that address grand societal challenges, they need to meet three key challenges: translation of research technology and its commercialization, attention to sustainability, and responsible innovation. Using web content analysis and interviews, this paper explores the functions and capabilities undertaken by existing public biofoundries, the extent to which they address these three challenges, and opportunities and models for enhancement. We also probe the roles undertaken by three other contrasting types of innovation intermediaries to identify practices and opportunities for integration and partnering with public biofoundries. We find that public biofoundries exhibit relatively strong capabilities for research translation, whereas efforts toward sustainability and responsibility are generally less prominent. For biofoundry enhancement, we propose an organisational model based on external partnering where public biofoundries are positioned as intermediaries within regional innovation systems. The framework put forward is reproducible and could be used in other contexts for assessing innovation intermediary organisational functions and capabilities toward meeting societal challenges. [ABSTRACT FROM AUTHOR]

Valproate is the most effective medication for generalised epilepsies, and several specific epilepsy syndromes. For some people, it will be the only medication to establish seizure remission, and withdrawing it carries risks of seizure recurrence and Sudden Unexpected Death in Epilepsy (SUDEP). It is also of proven efficacy for bipolar disorder and migraine prevention. Guidelines based on observational and epidemiological studies stress that maternal valproate related teratogenicity and neurodevelopmental effects are significantly higher than for other antiseizure medications (ASMs). It should, therefore, only be used if other medications are ineffective and after balancing the teratogenicity risk. Regulatory restrictions have changed prescribing practices and reduced valproate use. The number of other medications that must be trialled in the different conditions for which valproate has effectiveness and the consequences of the lack of efficacy of those drugs leading to significant harm including death remains unexplored. Risk minimisation measures (RMMs) for valproate, chiefly Pregnancy Prevention practices (PPP), consider foetal risk and not risk to people living with epilepsy. In the United Kingdom (UK), limitations relating to valproate use in all people < 55 years commenced in January 2024. While the evidence in child-bearing women is not disputed, the data in males are based on animal models, case reports, and one commissioned, unpublished, non-peer reviewed report unavailable to the UK public, stakeholder charities or professionals. Evidence suggests that 30–40% of people switching from valproate have breakthrough seizures. Thus, an estimated 21,000–28000 people in the UK will imminently be exposed to the potential hazards of breakthrough seizures, including death. There is little government investment in monitoring the effects of these changes to valproate prescribing on patient health and quality of life. This review summarises the history of valproate regulation, evidence underpinning it and argues how the latest regulations in the UK do not align with the country's medical regulatory bodies ethical principles nor with the Montgomery principles of informed patient choice and autonomy. It dissects how such regulations infringe Common Law principles, nor give due regard for patient outcomes beyond reproduction. The paper looks to provide recommendations to redress these concerns while appreciating the core need for such governance to emerge in the first place. [ABSTRACT FROM AUTHOR]

Objectives: Maternal mortality and morbidity disproportionately affect birthing people from racialized populations. Unfortunately, researchers can often compound these poor outcomes through a lack of authentic community engagement in research beyond the role of the research subject, leading to ineffective strategies for improving care and increasing equity. This article details the real-life strategies utilized to develop a community-engaged research project of a phased federally funded grant employing community engagement principles of co-leadership and co-creation. It also includes reflections from the researchers and advisory board on promising practices and lessons learned for equitably engaging patients and community partners in research. Methods: This article details the application of principles of community-engaged research in a federally funded phased research project focused on understanding disparities in maternal sepsis to develop better clinical and community interventions. Specifically, it discusses early steps in the research partnership to create a sustainable partnership with a Community Leadership Board guided by the principles of transparency, respect, compensation, and increasing research justice. Results: Based on the authors' experience, recommendations are provided for funders, researchers, and institutions to improve the quality and outcomes of communityengaged research. This work adds to community-based participatory and community-engaged research literature by providing concrete and practical steps for equitably engaging in research partnerships with a variety of collaborators. Conclusions: In conclusion, integrated patient and community co-leadership enhances research by providing insight, access to communities for education and dissemination of information, and identifying critical areas needing change. This report may help others address fundamental principles in this journey. Significance: Community-engaged research can be an equitable approach to research that involves communities most affected by empowering them to guide the research as equal partners. This article serves as a guide for researchers to form these critical partnerships, sustain relationships, and recommend solutions to common challenges based on the reflections of the researchers and advisory board. [ABSTRACT FROM AUTHOR]

Baryon number violation is our most sensitive probe of physics beyond the Standard Model, especially through the study of nucleon decays. Angular momentum conservation requires a lepton in the final state of such decays, kinematically restricted to electrons, muons, or neutrinos. We show that operators involving taus, which are at first sight too heavy to play a role in nucleon decays, still lead to clean nucleon decay channels with tau neutrinos. While many of them are already constrained from existing two-body searches such as p → π+ν, other operators induce many-body decays such as p → ηπ + ν ¯ τ and n → K+π−ντ that have never been searched for. [ABSTRACT FROM AUTHOR]

The rodeo algorithm is an efficient algorithm for eigenstate preparation and eigenvalue estimation for any observable on a quantum computer. This makes it a promising tool for studying the spectrum and structure of atomic nuclei as well as other fields of quantum many-body physics. The only requirement is that the initial state has sufficient overlap probability with the desired eigenstate. While it is exponentially faster than well-known algorithms such as phase estimation and adiabatic evolution for eigenstate preparation, it has yet to be implemented on an actual quantum device. In this work, we apply the rodeo algorithm to determine the energy levels of a random one-qubit Hamiltonian, resulting in a relative error of 0.08 % using mid-circuit measurements on the IBM Q device Casablanca. This surpasses the accuracy of directly-prepared eigenvector expectation values using the same quantum device. We take advantage of the high-accuracy energy determination and use the Hellmann–Feynman theorem to compute eigenvector expectation values for a different random one-qubit observable. For the Hellmann–Feynman calculations, we find a relative error of 0.7 % . We conclude by discussing possible future applications of the rodeo algorithm for multi-qubit Hamiltonians. [ABSTRACT FROM AUTHOR]

Introduction: Travel burden leads to worse cancer outcomes. Understanding travel burden and the level and types of travel support provided at large cancer centers is critical for developing systematic programs to alleviate travel burden. This study analyzed patients who received travel assistance, including their travel burden, types and amount of travel support received, and factors that influenced these outcomes. Methods: We analyzed 1063 patients who received travel support from 1/1/2021 to 5/1/2023 at Winship Cancer Institute, in which ~18,000 patients received cancer care annually. Travel burden was measured using distance and time to Winship sites from patients’ residential address. Travel support was evaluated using the monetary value of total travel support and type of support received. Patients’ sociodemographic and clinical factors were extracted from electronic medical records. Area-level socioeconomic disadvantage was coded by the Area Deprivation Index using patient ZIP codes. Results: On average, patients traveled 57.2 miles and 67.3 min for care and received $74.1 in total for travel support. Most patients (88.3%) received travel-related funds (e.g., gas cards), 5% received direct rides (e.g., Uber), 3.8% received vouchers for taxi or public transportation, and 3% received combined travel support. Male and White had longer travel distance and higher travel time than female and other races, respectively. Patients residing in more disadvantaged neighborhoods had an increased travel distance and travel time. Other races and Hispanics received more travel support ($) than Black and White patients or non-Hispanics. Patients with higher travel distance and travel time were more like to receive travel-related financial support. Conclusion: Among patients who received travel support, those from socioeconomically disadvantaged neighborhoods had greater travel burden. Patients with greater travel burden were more likely to receive travel funds versus other types of support. Further understanding of the impact of travel burden and travel support on cancer outcomes is needed. [ABSTRACT FROM AUTHOR]

Background: People incarcerated in jails are highly impacted by the opioid epidemic, and overdose education and naloxone distribution (OEND) is an effective strategy to reduce opioid overdose deaths. This study examines barriers and facilitators of fast-track OEND implementation within the jails in the Wave 1 Kentucky counties of the HEALing Communities Study during the COVID-19 pandemic. Methods: Meeting minutes with jail stakeholders were qualitatively coded using the Practical, Robust Implementation and Sustainability Model (PRISM) as the coding framework. The analysis highlighted the top barriers and facilitators to fast-track OEND implementation within the PRISM framework. Results: Space and staffing shortages related to the COVID-19 pandemic, disruptions in interorganizational programming from pandemic-related service suspensions, and a lack of technological solutions (e.g., reliable Internet access) for socially distanced delivery were the top barriers to fast-track OEND implementation. In addition, there were limitations on non-jail staff access to jails during COVID-19. Top facilitators included jail leadership support, the option to prioritize high-risk groups, and the incorporation of OEND processes into existing communications and management software. While the COVID-19 pandemic strained jail infrastructure, jail and partner agency collaboration led to creative implementation strategies for the successful integration of OEND into jail operations. Urban jails were more likely than rural jails to be early adopters of OEND during the public health emergency. Conclusions: Understanding the barriers to and facilitators of OEND within jails will improve implementation efforts seeking to curb opioid overdose deaths. Jail leadership support and interorganizational efforts were key facilitators to implementation; therefore, it is recommended to increase buy-in with multiple agencies to promote success. Challenges brought on by COVID-19 have resulted in a need for innovative solutions for implementation. Clinical trial information: ClinicalTrials.gov, NCT04111939, Submitted 30 September 2019, https://clinicaltrials.gov/study/NCT04111939?titles=HEALing%20Communities%20Study&rank=1. [ABSTRACT FROM AUTHOR]

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies. Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment. [ABSTRACT FROM AUTHOR]

According to the “adequacy-for-purpose” view of data evaluation, data should be evaluated as better or worse relative to a given research purpose and corresponding research context. In this paper, I apply the adequacy-for-purpose view to a novel case study—concerning the use of paleoecological data to make predictions about coral reef response to contemporary climate change—and then use the case study to suggest two extensions to the adequacy-for-purpose view. First, I argue that we can evaluate research purposes according to their productivity (how well these research purposes serve other, more ultimate purposes). Second, I argue that we can also evaluate research purposes according to their plausibility (including whether we have access to data that are adequate for these research purposes). The relationship between data evaluation and purpose setting should be seen as an iterative one, in which both data and purposes are refined in concert over time. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) were effective in alleviating wild-type human tau-induced neurodegeneration. In contrast, mutant P301L human tau was less toxic to neurons, despite causing comparable DNA damage. Axonal DLK activation induced by wild-type tau potentiated the impact of DNA damage response, resulting in overt neurotoxicity. In summary, we have established a cellular tauopathy model highly relevant to AD and identified a functional synergy between the DLK-MAPK axis and DNA damage response in the neuronal degenerative process. [ABSTRACT FROM AUTHOR]

Abstract Oncogenic KRAS mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC. In genetically engineered and xenograft (human cell line and patient‐derived) KrasG12D‐driven LAC models, the specific blockade of ADAM17, including with a non‐toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro‐tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL‐6R, to release soluble IL‐6R that drives IL‐6 trans‐signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in KrasG12D‐driven LAC was independent of bone marrow‐derived immune cells. Furthermore, in KRAS mutant human LAC, there was a significant positive correlation between augmented phospho‐ADAM17 levels, observed primarily in epithelial rather than immune cells, and activation of ERK and p38 MAPK pathways. Collectively, these findings identify ADAM17 as a druggable target for oncogenic KRAS‐driven LAC and provide the rationale to employ ADAM17‐based therapeutic strategies for targeting KRAS mutant cancers.

Organisms that settle and grow on other organisms (i.e., epibionts) are often costly to their hosts in terms of locomotion, growth, and/or reproduction. Such costs can potentially result in biotic resistance against invasion when native epibionts colonise non-native hosts, but examples are rare. Here, we examine the extent to which native acorn barnacles Balanus glandula that grow on the non-native Japanese mud snail, Batillaria attramentaria, may offer biotic resistance against this invader. We conducted population surveys, mark-recapture experiments, and behavioural observations in British Columbia, Canada, to measure the effects of barnacles on the movement, growth, and recapture rate, a potential proxy of short-term survival, of mud snails. One-third of mud snails carried barnacles, the weight of which sometimes exceeded the weight of the mud snail carrying them. Barnacle presence, weight, and the ratio of barnacle to snail weight all decreased the probability that mud snails would move, which could have implications for the foraging success of mud snails carrying barnacles. The slopes of the relationship between shell weight and length were similar for mud snails with and without barnacles, suggesting a lack of effect on growth allometry. The probability of recapture was 36% higher for mud snails without barnacles in one of two trials (i.e., 68% probability of recapture for snails without barnacles vs 50% for snails with barnacles), which reflects weak evidence for a small detrimental effect on mud snails carrying barnacles. Overall, native barnacles appear to offer some, though weak, biotic resistance to invasive mud snails, providing new insight into the potential for ecosystems to resist invasions through epibiotic interactions. [ABSTRACT FROM AUTHOR]

Hospital surfaces can harbour bacterial pathogens, which may disseminate and cause nosocomial infections, contributing towards mortality in low- and middle-income countries (LMICs). During the BARNARDS study, hospital surfaces from neonatal wards were sampled to assess the degree of environmental surface and patient care equipment colonisation by Gram-negative bacteria (GNB) carrying antibiotic resistance genes (ARGs). Here, we perform PCR screening for extended-spectrum β-lactamases (blaCTX-M-15) and carbapenemases (blaNDM, blaOXA-48-like and blaKPC), MALDI-TOF MS identification of GNB carrying ARGs, and further analysis by whole genome sequencing of bacterial isolates. We determine presence of consistently dominant clones and their relatedness to strains causing neonatal sepsis. Higher prevalence of carbapenemases is observed in Pakistan, Bangladesh, and Ethiopia, compared to other countries, and are mostly found in surfaces near the sink drain. Klebsiella pneumoniae, Enterobacter hormaechei, Acinetobacter baumannii, Serratia marcescens and Leclercia adecarboxylata are dominant; ST15 K. pneumoniae is identified from the same ward on multiple occasions suggesting clonal persistence within the same environment, and is found to be identical to isolates causing neonatal sepsis in Pakistan over similar time periods. Our data suggests persistence of dominant clones across multiple time points, highlighting the need for assessment of Infection Prevention and Control guidelines. [ABSTRACT FROM AUTHOR]

RNA decay is vital for regulating mRNA abundance and gene expression. Existing technologies lack the spatiotemporal precision or transcript specificity to capture the stochastic and transient decay process. We devise a general strategy to inducibly recruit protein factors to modulate target RNA metabolism. Specifically, we introduce a Rapid Inducible Decay of RNA (RIDR) technology to degrade target mRNAs within minutes. The fast and synchronous induction enables direct visualization of mRNA decay dynamics in cells. Applying RIDR to endogenous ACTB mRNA reveals rapid formation and dissolution of RNA granules in pre-existing P-bodies. Time-resolved RNA distribution measurements demonstrate rapid RNA decay inside P-bodies, which is further supported by knocking down P-body constituent proteins. Light and oxidative stress modulate P-body behavior, potentially reconciling the contradictory literature about P-body function. This study reveals compartmentalized RNA decay kinetics, establishing RIDR as a pivotal tool for exploring the spatiotemporal RNA metabolism in cells. Studying RNA decay remains a challenging task. Here, the authors present a technology that enables inducible rapid degradation of targeted mRNAs. Visualizing mRNA decay dynamics unveils insights into P-body function in RNA metabolism. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced angiosarcoma (RIA) is an uncommon but morbid complication after radiotherapy for breast cancer. Methods: Retrospective analysis of breast RIA patients at Cambridge University Hospital (CUH), a regional treatment centre in the East of England. Results: 22 patients were identified between 2010 and 2022. Median age of diagnosis was 65 years (range 41–78). Median time from breast radiotherapy to RIA diagnosis was 6.5 years (range 2.4–16.0)—this interval has decreased over the last 24 years (r2 = 0.6601). 9% had metastasis at presentation. All patients underwent surgery (55% at CUH, 45% at local hospitals). 27% received peri-operative pegylated liposomal doxorubicin in the first-line setting. 62% relapsed following their primary curative-intent treatments after a median of 28 months. Metastases occurred in 36%, the commonest sites being lung (100%) and lymph node (50%). 2-year and 5-year overall survival (OS) rates for all patients were 73% and 60%, respectively. No correlation between progression-free survival (PFS) and OS was found with tumour size, margin, peri-operative chemotherapy, and whether surgery was performed at CUH. Patients with multifocal disease on their breasts had shorter PFS following surgery compared to single-lesion disease (median 10 vs 65 months; HR = 4.359 [95% CI 1.342–14.16]; P = 0.0143). Patients aged > 72 years had a median OS of 45 months vs 102 months for those ≤ 72 years (HR = 7.129 [95% CI 1.646–30.88]; P = 0.0086). Conclusion: RIA has high rates of recurrence and mortality and appears to be occurring sooner after breast radiotherapy. Further studies on its pathogenesis and effective treatment are warranted. [ABSTRACT FROM AUTHOR]