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Abstract Guideline concordant opioid therapy is a key part of the concerted effort to address the opioid crisis in the United States. The study aimed to compare the rates of guideline concordant care between veterans who solely used VA services (mono users) and veterans who used both VA services and community care (dual-system users). We used electronic health record data from the Washington DC and Baltimore VA Medical Centers from 2015 to 2019. We provided descriptive statistics as well as generalized estimating equations models to find associations between mono vs. dual-system users and each guideline outcome, controlling for demographic factors and comorbid conditions. The study found that overall rates of guideline concordant care were high in both mono and dual-system users with over 90% adherence rates for the majority of recommendations. However, there were variations in adherence to specific guidelines, with urine drug screening at initiation being the least commonly followed recommendation (8.9% of mono-user opioid initiators and 11.2% of dual-user initiators). This study also found that there was no consistent pattern of higher guideline adherence in mono vs. dual-system users but did show that through the course of this study (2015–2019) overall rates of guideline concordance increased. Future research will explore additional guideline recommendations and potential coordination issues among dual-system users.

Abstract After a stroke, the neurogenic response from the subventricular zone (SVZ) to repair the brain is limited. Microglia, as an integral part of the distinctive SVZ microenvironment, control neural stem / precursor cell (NSPC) behavior. Here, we show that discrete stroke-associated SVZ microglial clusters negatively impact the innate neurogenic response, and we propose a repository of relevant microglia–NSPC ligand–receptor pairs. After photothrombosis, a mouse model of ischemic stroke, the altered SVZ niche environment leads to immediate activation of microglia in the niche and an abnormal neurogenic response, with cell-cycle arrest of neural stem cells and neuroblast cell death. Pharmacological restoration of the niche environment increases the SVZ-derived neurogenic repair and microglial depletion increases the formation and survival of newborn neuroblasts in the SVZ. Therefore, we propose that altered cross-communication between microglial subclusters and NSPCs regulates the extent of the innate neurogenic repair response in the SVZ after stroke.

The search for extraterrestrial intelligence is a fascinating and important endeavor, but it raises significant ethical and safety concerns. In the search for extraterrestrial intelligence, scientists use knowledge of physics to identify potential communication methods and signals that may be used by extraterrestrial civilizations. One of the most notable scientists to highlight these concerns was the late physicist Stephen Hawking, who cautioned that actively attempting to communicate with extraterrestrial civilizations could harm humanity. While it is true that we cannot predict the intentions of any potential extraterrestrial civilizations, some scientists argue that the potential advantages of seeking contact outweigh the potential risks. Deciding to initiate contact with extraterrestrial civilizations is a complex issue that requires balancing scientific curiosity with concerns for our own safety. The “Intelligence Trap” is a concept in psychology that suggests that highly intelligent people are more susceptible to cognitive biases and flawed thinking than less intelligent people. It can be argued that Hawking’s warnings may be an example of the so-called intelligence trap, as some evidence from the field of physics suggests. Nonetheless, Hawking emphasized that it is crucial for scientists and policymakers to carefully weigh the potential risks and benefits of such efforts and proceed with caution.

Abstract Hairy cell leukemia is an uncommon B‐cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. However, purine analogs are known to be highly immunosuppressive and the infection burden in this patient population with current therapies is unknown. We therefore conducted a retrospective cohort study following 149 patients. Median follow‐up time was 6.9 years. Thirty‐six percent developed an opportunistic or serious infection requiring hospitalization. Most cases were bacterial and most coincided with neutropenia and/or CD4 T‐lymphopenia. No single treatment agent was significantly associated with increased or decreased incidence of infection. Reassuringly, the cumulative incidence of infections plateaued 2 months after initial treatment suggesting clinically significant immune recovery. Only one patient in our cohort passed away due to infection. Estimated 10‐year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

Abstract Many seafood products marketed as “sustainable” are not. More exacting sustainability standards are needed to respond to a fast-changing world and support United Nations SDGs. Future fisheries must operate on principles that minimise impacts on marine life, adapt to climate change and allow regeneration of depleted biodiversity, while supporting and enhancing the health, wellbeing and resilience of people and communities. We set out 11 actions to achieve these goals.

Abstract SETANTA (Study of HEarT DiseAse and ImmuNiTy After COVID-19 in Ireland) study aimed to investigate symptom burden and incidence of cardiac abnormalities after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 and to correlate these results with biomarkers of immunological response and coagulation. SETANTA was a prospective, single-arm observational cross-sectional study condcuted in a primary practice setting, and prospectively registered with ClinicalTrials.gov (identifier: NCT04823182). Patients with recent COVID-19 infection (≥ 6 weeks and ≤ 12 months) were prospectively enrolled. Primary outcomes of interest were markers of cardiac injury detected by cardiac magnetic resonance imaging (CMR), which included left ventricular ejection fraction, late gadolinium enhancement and pericardial abnormalities, as well as relevant biomarkers testing immunological response and coagulopathy. 100 patients (n = 129 approached) were included, amongst which 64% were female. Mean age of the total cohort was 45.2 years. The median (interquartile range) time interval between COVID-19 infection and enrolment was 189 [125, 246] days. 83% of participants had at least one persistent symptom, while 96% had positive serology for prior SARS-CoV-2 infection. Late gadolinium enhancement, pericardial effusion, was present in 2.2% and 8.3% respectively, while left ventricular ejection fraction was below the normal reference limit in 17.4% of patients. Von Willebrand factor antigen was elevated in 32.7% of patients and Fibrinogen and D-Dimer levels were found to be elevated in 10.2% and 11.1% of patients, respectively. In a cohort of primary practice patients recently recovered from SARS-CoV-2 infection, prevalence of persistent symptoms and markers of abnormal coagulation were high, despite a lower frequency of abnormalities on CMR compared with prior reports of patients assessed in a hospital setting. Trial Registration: Clinicaltrials.gov, NCT04823182 (prospectively registered on 30th March 2021).

Abandoned mine drainage treatment ponds could have contrasting effects on the reproductive success of birds living in the vicinity. The ponds and associated vegetation may, like any other body of freshwater, provide beneficial habitats for the insects that the birds use to feed their young; or instead, the ponds may act as an ecological trap, attracting the birds to a habitat that is poor in quality and negatively impacting their productivity. We monitored nests of an aerial insectivore, the Tree Swallow (Tachycineta bicolor), to determine whether the distance between the ponds and the nests affected various reproductive parameters including clutch size, hatch rate, number of nestlings, nestling size and mass, number of fledglings, fledging rate, and fledge date. Data were collected over two breeding seasons (2022 and 2023) from a swallow population in southwestern Pennsylvania, USA. We found that the nests closest to the treatment ponds had significantly more nestlings and fledglings, earlier fledge dates, and a better fledging rate when compared to nests that were more distant from the ponds. However, all these parameters were well below previously published values, which suggests that the mine drainage ponds provide good nesting habitats relative to what is available in the region but that they do not represent high-quality habitats for this species overall.

Abstract The global population is increasingly reliant on vaccines to maintain population health with billions of doses used annually in immunisation programmes. Substandard and falsified vaccines are becoming more prevalent, caused by both the degradation of authentic vaccines but also deliberately falsified vaccine products. These threaten public health, and the increase in vaccine falsification is now a major concern. There is currently no coordinated global infrastructure or screening methods to monitor vaccine supply chains. In this study, we developed and validated a matrix-assisted laser desorption/ionisation-mass spectrometry (MALDI-MS) workflow that used open-source machine learning and statistical analysis to distinguish authentic and falsified vaccines. We validated the method on two different MALDI-MS instruments used worldwide for clinical applications. Our results show that multivariate data modelling and diagnostic mass spectra can be used to distinguish authentic and falsified vaccines providing proof-of-concept that MALDI-MS can be used as a screening tool to monitor vaccine supply chains.

Abstract During the past two decades evidence has been developed that indicates a handful of viruses with known oncogenic capacity, have potential roles in breast cancer. These viruses are mouse mammary tumour virus (MMTV - the cause of breast cancer in mice), high-risk human papilloma viruses (HPV-the cause of cervical cancer), Epstein Barr virus (EBV-the cause of lymphomas and naso-pharyngeal cancer) and bovine leukemia virus (BLV - the cause of cancers in cattle). These viruses may act alone or in combination. Each of these viruses are significantly more prevalent in breast cancers than in normal and benign breast tissue controls. The odds ratios for the prevalence of these viruses in breast cancer compared to normal and benign breast controls, are based on case control studies - MMTV 13·40, HPV 5.56, EBV 4·43 and BLV 2·57. The odds ratios for MMTV are much greater compared to the other three viruses. The evidence for a causal role for mouse mammary tumour virus and high risk for cancer human papilloma viruses in human breast cancer is increasingly comprehensive. The evidence for Epstein Barr virus and bovine leukemia virus is more limited. Overall the evidence is substantial in support of a viral cause of breast cancer.

The United States Veterans Affairs (VA) Health Care System has a strong history of conducting impactful oncology randomized clinical trials (RCTs). We developed a phase II/III RCT to test the use of metastasis-directed therapy in Veterans with oligometastatic prostate cancer (OMPC)—the first VA RCT in OMPC that leverages novel imaging and advanced radiotherapy techniques. To accomplish this, we developed a clinical trial network to conduct the study. In this manuscript, we describe several challenges we encountered in study development/conduct and our strategies to address them, with the goal of helping investigators establish robust study networks to conduct clinical trials. In the study start-up, we encountered challenges in timely site activation, and leveraged project management to maximize efficiency. Additionally, there were several changes in the clinical paradigms in imaging and treatment that led to protocol amendments to ensure maximum equipoise, recruitment, and impact of the study. Specifically, we amended the trial to add de novo OMPC patients (from initially only recurrent OMPC) and expanded the study to allow up to 10 metastases (from initially five). Finally, in order to maintain local study team engagement, we developed initiatives to maximize collaboration and add value to the overall clinical program through study participation.

Case Presentation: A 22-year-old male with a history of anti-neutrophil cytoplasmic antibody vasculitis, renal transplant, hypertension, and no known family history of sudden cardiac death suffered a witnessed cardiac arrest. An initial rhythm strip recorded by emergency medical services revealed ventricular fibrillation. Return of spontaneous circulation was achieved after three rounds of cardiopulmonary resuscitation, defibrillation, and intravenous epinephrine. The patient was brought to the emergency department and admitted to the intensive care unit. He was diagnosed with Brugada syndrome, and an automatic implantable cardioverter-defibrillator (AICD) was placed after discharge. Discussion: Brugada syndrome is characterized electrocardiographically by ≥2 millimeters (mm) ST-segment elevation in leads V1–V2 with either “coved type” (type 1) or “saddleback” (type 2) ST-segment morphology, or ≤2 mm ST-segment elevation in V1–V2 with either “coved” or “saddleback” morphology (type 3). The absence of these patterns on isolated electrocardiograms (ECG) does not exclude the diagnosis, as dynamic fluctuations in ECG patterns are well-documented and can be induced by various physiologic stressors. This case provides an uncommon, complete electrocardiographic history of Brugada syndrome, from out-of-hospital cardiac arrest to AICD placement and depicts dynamic fluctuations between Brugada patterns and normal ECGs. This highlights the importance of serial ECGs in diagnosis, as sudden cardiac death is often the first or only presentation of Brugada syndrome.

Abstract Calcification has significant influence over cardiovascular diseases and interventions. Detailed characterization of calcification is thus desired for predictive modeling, but calcium deposits on cardiovascular structures are still often manually reconstructed for physics-driven simulations. This poses a major bottleneck for large-scale adoption of computational simulations for research or clinical use. To address this, we propose an end-to-end automated image-to-mesh algorithm that enables robust incorporation of patient-specific calcification onto a given cardiovascular tissue mesh. The algorithm provides a substantial speed-up from several hours of manual meshing to ~1 min of automated computation, and it solves an important problem that cannot be addressed with recent template-based meshing techniques. We validated our final calcified tissue meshes with extensive simulations, demonstrating our ability to accurately model patient-specific aortic stenosis and Transcatheter Aortic Valve Replacement. Our method may serve as an important tool for accelerating the development and usage of personalized cardiovascular biomechanics.

Abstract Mapping neuronal networks is a central focus in neuroscience. While volume electron microscopy (vEM) can reveal the fine structure of neuronal networks (connectomics), it does not provide molecular information to identify cell types or functions. We developed an approach that uses fluorescent single-chain variable fragments (scFvs) to perform multiplexed detergent-free immunolabeling and volumetric-correlated-light-and-electron-microscopy on the same sample. We generated eight fluorescent scFvs targeting brain markers. Six fluorescent probes were imaged in the cerebellum of a female mouse, using confocal microscopy with spectral unmixing, followed by vEM of the same sample. The results provide excellent ultrastructure superimposed with multiple fluorescence channels. Using this approach, we documented a poorly described cell type, two types of mossy fiber terminals, and the subcellular localization of one type of ion channel. Because scFvs can be derived from existing monoclonal antibodies, hundreds of such probes can be generated to enable molecular overlays for connectomic studies.

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a new disease entity occurring in the pediatric population two to six weeks after coronavirus exposure due to a systemic arteritis. We investigated post-hospital-discharge arterial function at short- and mid-term intervals using pulse wave velocity. We assessed associations between arterial function, left ventricular diastolic and systolic function and left ventricular mass. Materials and methods: Retrospective data collection was carried out on 28 patients with MIS-C with at least two outpatient pediatric cardiology clinic visits post hospital admission. The patients underwent assessment of systemic arterial function and cardiac function. Data included pulse wave velocity between carotid and femoral arteries and echocardiographic assessment of left ventricular systolic function (shortening and ejection fraction, longitudinal strain), diastolic function and left ventricular mass. Results: Pulse wave velocity significantly decreased from visit 1 to visit 2 (5.29 ± 1.34 m/s vs. 4.51 ± 0.91 m/s, p = 0.009). Left ventricular mass significantly decreased from visit 1 to visit 2 (42 ± 9 g/m2.7 vs. 38 ± 7 g/m2.7, p = 0.02). There was a significant negative correlation between the pulse wave velocity and E/A mitral inflow (−0.41, p < 0.05). Conclusions: Children have elevated pulse wave velocity and left ventricular mass in the short-term relative to mid-term values after hospital discharge. These results suggest that MIS-C is associated with transient systemic arterial dysfunction, which, in turn, may play a role in cardiac changes.

Abstract The sensitivity and responsiveness of living cells to environmental changes are enabled by dynamic protein structures, inspiring efforts to construct artificial supramolecular protein assemblies. However, despite their sophisticated structures, designed protein assemblies have yet to be incorporated into macroscale devices for real-life applications. We report a 2D crystalline protein assembly of C98/E57/E66L-rhamnulose-1-phosphate aldolase (CEERhuA) that selectively blocks or passes molecular species when exposed to a chemical trigger. CEERhuA crystals are engineered via cobalt(II) coordination bonds to undergo a coherent conformational change from a closed state (pore dimensions

Abstract Background Adverse events (AEs) are commonly reported in clinical studies using the Medical Dictionary for Regulatory Activities (MedDRA), an international standard for drug safety monitoring. However, the technical language of MedDRA makes it challenging for patients and clinicians to share understanding and therefore to make shared decisions about medical interventions. In this project, people with lived experience of depression and antidepressant treatment worked with clinicians and researchers to co-design an online dictionary of AEs associated with antidepressants, taking into account its ease of use and applicability to real-world settings. Methods Through a pre-defined literature search, we identified MedDRA-coded AEs from randomised controlled trials of antidepressants used in the treatment of depression. In collaboration with the McPin Foundation, four co-design workshops with a lived experience advisory panel (LEAP) and one independent focus group (FG) were conducted to produce user-friendly translations of AE terms. Guiding principles for translation were co-designed with McPin/LEAP members and defined before the finalisation of Clinical Codes (CCs, or non-technical terms to represent specific AE concepts). FG results were thematically analysed using the Framework Method. Results Starting from 522 trials identified by the search, 736 MedDRA-coded AE terms were translated into 187 CCs, which balanced key factors identified as important to the LEAP and FG (namely, breadth, specificity, generalisability, patient-understandability and acceptability). Work with the LEAP showed that a user-friendly language of AEs should aim to mitigate stigma, acknowledge the multiple levels of comprehension in ‘lay’ language and balance the need for semantic accuracy with user-friendliness. Guided by these principles, an online dictionary of AEs was co-designed and made freely available ( https://thesymptomglossary.com ). The digital tool was perceived by the LEAP and FG as a resource which could feasibly improve antidepressant treatment by facilitating the accurate, meaningful expression of preferences about potential harms through a shared decision-making process. Conclusions This dictionary was developed in English around AEs from antidepressants in depression but it can be adapted to different languages and cultural contexts, and can also become a model for other interventions and disorders (i.e., antipsychotics in schizophrenia). Co-designed digital resources may improve the patient experience by helping to deliver personalised information on potential benefits and harms in an evidence-based, preference-sensitive way.

Abstract The Ser/Thr protein phosphatase 2 A (PP2A) regulates the dephosphorylation of many phosphoproteins. Substrate recognition are mediated by B regulatory subunits. Here, we report the identification of a substrate conserved motif [RK]-V-x-x-[VI]-R in FAM122A, an inhibitor of B55α/PP2A. This motif is necessary for FAM122A binding to B55α, and computational structure prediction suggests the motif, which is helical, blocks substrate docking to the same site. In this model, FAM122A also spatially constrains substrate access by occluding the catalytic subunit. Consistently, FAM122A functions as a competitive inhibitor as it prevents substrate binding and dephosphorylation of CDK substrates by B55α/PP2A in cell lysates. FAM122A deficiency in human cell lines reduces the proliferation rate, cell cycle progression, and hinders G1/S and intra-S phase cell cycle checkpoints. FAM122A-KO in HEK293 cells attenuates CHK1 and CHK2 activation in response to replication stress. Overall, these data strongly suggest that FAM122A is a short helical motif (SHeM)-dependent, substrate-competitive inhibitor of B55α/PP2A that suppresses multiple functions of B55α in the DNA damage response and in timely progression through the cell cycle interphase.

Abstract Background One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as “genetic constraint”. Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes. Methods We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues. Results We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism. Conclusions Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.

Abstract The global terrestrial water storage (TWS), the most accessible component in the hydrological cycle, is a general indicator of freshwater availability on Earth. The global TWS trend caused by climate change is harder to detect than global mean temperature due to the highly uneven hydrological responses across the globe, the brevity of global freshwater observations, and large noises of internal climate variability. To overcome the climate noise and small sample size of observations, we leverage the vast amount of observed and simulated meteorological fields at daily scales to project global TWS through its fingerprints in weather patterns. The novel method identifies the relationship between annual global mean TWS and daily surface air temperature and humidity fields using multi-model hydrological simulations. We found that globally, approximately 50% of days for most years since 2016 have climate change signals emerged above the noise of internal variability. Climate change signals in global mean TWS have been consistently increasing over the last few decades, and in the future, are expected to emerge from the natural climate variability. Our research indicates the urgency to limit carbon emission to not only avoid risks associated with warming but also sustain water security in the future.

In the folded state, biomolecules exchange between multiple conformational states crucial for their function. However, most structural models derived from experiments and computational predictions only encode a single state. To represent biomolecules accurately, we must move towards modeling and predicting structural ensembles. Information about structural ensembles exists within experimental data from X-ray crystallography and cryo-electron microscopy. Although new tools are available to detect conformational and compositional heterogeneity within these ensembles, the legacy PDB data structure does not robustly encapsulate this complexity. We propose modifications to the macromolecular crystallographic information file (mmCIF) to improve the representation and interrelation of conformational and compositional heterogeneity. These modifications will enable the capture of macromolecular ensembles in a human and machine-interpretable way, potentially catalyzing breakthroughs for ensemble–function predictions, analogous to the achievements of AlphaFold with single-structure prediction.

Abstract Introduction Complexities of robotic distal gastrectomy (RDG) give reason to assess physician's surgical skill. Varying levels in surgical skill affect patient outcomes. We aim to investigate how a novel artificial intelligence (AI) model can be used to evaluate surgical skill in RDG by recognizing surgical instruments. Methods Fifty‐five consecutive robotic surgical videos of RDG for gastric cancer were analyzed. We used Deeplab, a multi‐stage temporal convolutional network, and it trained on 1234 manually annotated images. The model was then tested on 149 annotated images for accuracy. Deep learning metrics such as Intersection over Union (IoU) and accuracy were assessed, and the comparison between experienced and non‐experienced surgeons based on usage of instruments during infrapyloric lymph node dissection was performed. Results We annotated 540 Cadiere forceps, 898 Fenestrated bipolars, 359 Suction tubes, 307 Maryland bipolars, 688 Harmonic scalpels, 400 Staplers, and 59 Large clips. The average IoU and accuracy were 0.82 ± 0.12 and 87.2 ± 11.9% respectively. Moreover, the percentage of each instrument's usage to overall infrapyloric lymphadenectomy duration predicted by AI were compared. The use of Stapler and Large clip were significantly shorter in the experienced group compared to the non‐experienced group. Conclusions This study is the first to report that surgical skill can be successfully and accurately determined by an AI model for RDG. Our AI gives us a way to recognize and automatically generate instance segmentation of the surgical instruments present in this procedure. Use of this technology allows unbiased, more accessible RDG surgical skill.

Vaporization enthalpies and vapor pressures of 5α-androstane and 5α-cholestane are reported using correlation gas chromatography (CGC). The results for 5α-cholestane are compared to both estimated and experimental values reported previously for 5α-cholestane. The results are generally in agreement with the literature within the reported uncertainties. A simple method for reducing the amount of curvature in logarithm plots of vapor pressures as a function of K/T when using n-alkanes as standards in CGC experiments is also reported. This may prove useful in evaluating vapor pressures of rigid hydrocarbons at high temperatures.

Abstract The electrocardiogram (ECG) can capture obesity-related cardiac changes. Artificial intelligence-enhanced ECG (AI-ECG) can identify subclinical disease. We trained an AI-ECG model to predict body mass index (BMI) from the ECG alone. Developed from 512,950 12-lead ECGs from the Beth Israel Deaconess Medical Center (BIDMC), a secondary care cohort, and validated on UK Biobank (UKB) (n = 42,386), the model achieved a Pearson correlation coefficient (r) of 0.65 and 0.62, and an R2 of 0.43 and 0.39 in the BIDMC cohort and UK Biobank, respectively for AI-ECG BMI vs. measured BMI. We found delta-BMI, the difference between measured BMI and AI-ECG-predicted BMI (AI-ECG-BMI), to be a biomarker of cardiometabolic health. The top tertile of delta-BMI showed increased risk of future cardiometabolic disease (BIDMC: HR 1.15, p

Abstract Background Buprenorphine is an effective and safe treatment for opioid use disorder, but the requirement for moderate opioid withdrawal symptoms to emerge prior to initiation is a significant treatment barrier. Case Presentation We report on two cases of hospitalized patients with severe, active opioid use disorder, in which we initiated treatment with transdermal buprenorphine over 48 h, followed by the administration of a single dose of sublingual buprenorphine/naloxone and then extended-release subcutaneous buprenorphine. The patients did not experience precipitated withdrawal and only had mild withdrawal symptoms. Conclusions This provides preliminary evidence for a rapid induction strategy that may improve tolerability, caregiver burden, and treatment retention as compared to previous induction strategies.

Abstract Quantum chemical calculations of the ground-state properties of positron-molecule complexes are challenging. The main difficulty lies in employing an appropriate basis set for representing the coalescence between electrons and a positron. Here, we tackle this problem with the recently developed Fermionic neural network (FermiNet) wavefunction, which does not depend on a basis set. We find that FermiNet produces highly accurate, in some cases state-of-the-art, ground-state energies across a range of atoms and small molecules with a wide variety of qualitatively distinct positron binding characteristics. We calculate the binding energy of the challenging non-polar benzene molecule, finding good agreement with the experimental value, and obtain annihilation rates which compare favourably with those obtained with explicitly correlated Gaussian wavefunctions. Our results demonstrate a generic advantage of neural network wavefunction-based methods and broaden their applicability to systems beyond the standard molecular Hamiltonian.

Abstract Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. However, the site-specific delivery of common gene vectors such as adeno-associated viruses (AAVs) is typically performed via invasive injections, which limit its applicable scope of research and clinical applications. Alternatively, focused ultrasound blood-brain-barrier opening (FUS-BBBO), performed noninvasively, enables the site-specific entry of AAVs into the brain from systemic circulation. However, when used in conjunction with natural AAV serotypes, this approach has limited transduction efficiency and results in substantial undesirable transduction of peripheral organs. Here, we use high throughput in vivo selection to engineer new AAV vectors specifically designed for local neuronal transduction at the site of FUS-BBBO. The resulting vectors substantially enhance ultrasound-targeted gene delivery and neuronal tropism while reducing peripheral transduction, providing a more than ten-fold improvement in targeting specificity in two tested mouse strains. In addition to enhancing the only known approach to noninvasively target gene delivery to specific brain regions, these results establish the ability of AAV vectors to be evolved for specific physical delivery mechanisms.

Abstract Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, filtering water, controlling primary producers, and providing food for predators. Their differences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, efforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specific taxa to assessing the success of legislative and management restoration efforts.

Geomorphic change detection (GCD) using high resolution topographic data can provide important insights into geomorphological systems. However, considerations must first be given to the mechanisms and dynamics producing landscape change when considering an appropriate experimental design. Khan et al. (2023) investigate gully erosion rates and processes in different untreated and rehabilitated gullies using multi-temporal aerial lidar survey (ALS) data. However, an inappropriate time interval between sampling, a lack of uncertainty measures and lack of baseline monitoring survey data lead them to arrive at incorrect conclusions. Additional data is presented from the same field sites, which demonstrate gully sediment losses have been underestimated by at least 330% and potentially over an order of magnitude. A number of critical shortcomiongs of the paper are outlined. Insufficient time intervals between data collection have led to a lack of detection of some sediment transport processes. Earthworks associated with gully rehabilitation have been conflated with geomorphic change, as no post-construction baseline data was collected. A lack of post-construction baseline data for this analysis means ongoing erosion and deposition cannot be resolved in the rehabilitated gully landscape. Given these errors in approach, discussions of gully geomorphic processes, erosion mechanisms and evaluations of rehabilitation efforts are unsupported, overstated and inaccurate. This has important implications for land management efforts and planning as well ongoing research on alluvial gully erosion, which is largely overlooked by Khan et al. (2023).

Summary: Background: Human immune responses to infection and vaccination are heterogenous, driven by multiple factors including genetics, environmental exposures and personal infection histories. For malaria caused by Plasmodium falciparum parasites, host factors that impact on humoral immunity are poorly understood. Methods: We investigated the role of latent cytomegalovirus (CMV) on the host immune response to malaria using samples obtained from individuals in previously conducted Phase 1 trials of blood stage P. falciparum Controlled Human Malaria Infection (CHMI) and in a MSP1 vaccine clinical trial. Induced antibody and functions of antibodies, as well as CD4 T cell responses were quantified. Findings: CMV seropositivity was associated with reduced induction of parasite specific antibodies following malaria infection and vaccination. During infection, reduced antibody induction was associated with modifications to the T -follicular helper (Tfh) cell compartment. CMV seropositivity was associated with a skew towards Tfh1 cell subsets before and after malaria infection, and reduced activation of Tfh2 cells. Protective Tfh2 cell activation was only associated with antibody development in individuals who were CMV seronegative, and a higher proportion of Tfh1 cells was associated with lower antibody development in individuals who were CMV seropositive. During MSP1 vaccination, reduced antibody induction in individuals who were CMV seropositive was associated with CD4 T cell expression of terminal differentiation marker CD57. Interpretation: These findings suggest that CMV seropositivity may be negatively associated with malaria antibody development. Further studies in larger cohorts, particularly in malaria endemic regions are required to investigate whether CMV infection may modify immunity to malaria gained during infection or vaccination in children. Funding: Work was funded by National Health and Medical Research Council of Australia, CSL Australia and Snow Medical Foundation. Funders had no role in data generation, writing of manuscript of decision to submit for publication.

Objective: Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass. Methods: We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation. Results: Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved. Conclusion: Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.

Listeria monocytogenes is a pathogen frequently associated with ready-to-eat (RTE) meat and poultry products. Nitrite is a key antimicrobial additive that can offer some degree of protection against L. monocytogenes when included in meat product formulations. The objectives of this study were to determine the potential of nitrite-embedded film to affect the growth of L. monocytogenes following postthermal processing of conventionally-cured and nitrite-free bologna. Two bologna treatment formulations, a conventionally-cured control formulation (CON) and a nitrite-free formulation (UCC), were manufactured, packaged in conventional (CF) or nitrite-embedded (NEF) film, inoculated with 3.5 log CFU/cm2 of a cocktail of L. monocytogenes strains, and stored at 10 ± 1 °C. CON-NEF and UCC-NEF treatments had significantly slower (P

Regenerative and resource conserving agriculture has gained recognition as a sustainable substitute to intensive agricultural models to reduce soil degradation and loss of ecosystem services. However, the major stumbling block to the successful implementation of these practices by farmers is the difficulty in measuring their sustainability and effectiveness. Understanding the status of soil quality in agroecosystems has been proposed as a fundamental step towards agricultural productivity and sustainability. In this research, different indicators were used to evaluate soil quality and function within differently managed land uses with special emphasis on soil macrofauna as biological indicators. Soil physical, chemical and biological samples were collected using soil monoliths within four land uses located in the Thabo Mofutsanyane district, Free State province, South Africa (Bethlehem and Reitz areas): (1) conservation management, (2) livestock integration within the cropping systems, (3) conventional management, and (4) natural grasslands used as reference sites. These data allowed for the identification of soil macrofauna bioindicator species which represented important features of soil quality (biodiversity, chemical fertility, and physical quality). The integrated land use demonstrated the uppermost values of soil quality according to the biological, chemical, and physical indicators. Most of the indicator variables which indicated poor soil quality were greatly associated with the conventional land use. The biodiversity indicator was found to be closely linked with the overall indicator, suggesting that soil macrofauna might be the major drivers of soil quality but importantly can be used to assess overall soil quality. Twenty-five species were identified as bioindicators of soil quality. The soil macrofauna bioindicators could greatly simplify the assessments of land use management effects by farmers within the study area, thereby encouraging them to actively participate in decision-making concerning land use management. The overall results demonstrated that regenerative practices could restore degraded soils and ecosystem services.

Critical knowledge gaps have impeded progress towards reducing the global burden of disease due to Mycobacterium ulcerans, the cause of the neglected tropical disease Buruli ulcer (BU). Development of a controlled human infection model of BU has been proposed as an experimental platform to explore host-pathogen interactions and evaluate tools for prevention, diagnosis, and treatment. We have previously introduced the use case for a new human model and identified M. ulcerans JKD8049 as a suitable challenge strain. Here, we present a provisional protocol for an initial study, for transparent peer review during the earliest stages of protocol development. Following simultaneous scientific peer review and community/stakeholder consultation of this provisional protocol, we aim to present a refined protocol for institutional review board (IRB) evaluation.

Objectives Ultrasound-guided regional anesthesia (UGRA) relies on acquiring and interpreting an appropriate view of sonoanatomy. Artificial intelligence (AI) has the potential to aid this by applying a color overlay to key sonoanatomical structures.The primary aim was to determine whether an AI-generated color overlay was associated with a difference in participants’ ability to identify an appropriate block view over a 2-month period after a standardized teaching session (as judged by a blinded assessor). Secondary outcomes included the ability to identify an appropriate block view (unblinded assessor), global rating score and participant confidence scores.Design Randomized, partially blinded, prospective cross-over study.Setting Simulation scans on healthy volunteers. Initial assessments on 29 November 2022 and 30 November 2022, with follow-up on 25 January 2023 – 27 January 2023.Participants 57 junior anesthetists undertook initial assessments and 51 (89.47%) returned at 2 months.Intervention Participants performed ultrasound scans for six peripheral nerve blocks, with AI assistance randomized to half of the blocks. Cross-over assignment was employed for 2 months.Main outcome measures Blinded experts assessed whether the block view acquired was acceptable (yes/no). Unblinded experts also assessed this parameter and provided a global performance rating (0–100). Participants reported scan confidence (0–100).Results AI assistance was associated with a higher rate of appropriate block view acquisition in both blinded and unblinded assessments (p=0.02 and

Aims To evaluate the myopia control efficacy of Diffusion Optics Technology (DOT) spectacle lenses in children over a 4-year treatment period.Methods CYPRESS Part 1 (NCT03623074) was a 3-year multicentre, randomised, controlled, double-masked trial comparing two investigational spectacle lens DOT designs (Test 1, Test 2) and standard single vision Control lenses in 256 North American children aged 6–10 years. Children completing Part 1 (n=200) were invited to enrol in CYPRESS Part 2 (NCT04947735) for an additional 1-year period. In Part 2, Test 1 (n=35) and Control groups (n=42) continued with their original lens assignment and the Test 2 group (n=21) were crossed over to Test 1 (DOT 0.2) lenses. The co-primary endpoints were change from baseline in axial length (AL) and cycloplegic spherical equivalent refraction (cSER).Results Test 1 spectacle lenses demonstrated superiority to the Control in both co-primary endpoints: with a difference between means (Test 1−Control) of −0.13 mm for AL (p=0.018) and 0.33 D for cSER (p=0.008) in Part 1 and −0.05 mm for AL (p=0.038) and 0.13 D for cSER (p=0.043) in Part 2. Comparing treatment effects in Part 1 and 2 suggests that COVID-19 public health restrictions negatively impacted treatment efficacy in study years 2 and 3.Conclusion DOT 0.2 spectacle lenses are safe and effective at reducing myopia progression, with additional benefit evident in year 4 of wear. These results support the hypothesis that a mild reduction in retinal contrast can slow myopia progression in young children. The unprecedented disruption in participant schooling and lifestyle during the COVID-19 pandemic may have depressed treatment efficacy in Part 1.

Communication about health often involves descriptions of risk: the probability or likelihood of an unfavorable outcome. Communicating risk helps individuals make choices about their own health by building understanding of potential outcomes and providing context for the importance of procedures, health interventions, and lifestyle choices. However, medical education in the United States does not provide future physicians with adequate statistical literacy to communicate risk effectively and rarely encourages them to practice communicating risk in pre-clinical years. Risk communication in military intelligence, a field with formalized risk language and training, offers a unique perspective into potential improvements for medical risk communication. With backgrounds in the military, public health, communication, surgery, and medical education, the authors offer the following recommendations to improve risk communication for medical students. (1) Encourage the use of numerical absolute risk when communicating among health practitioners to avoid varied interpretations of what different risk descriptors (“uncommon,” “likely,” or “low”) might mean; (2) build efficient, teachable skills in use of patient-facing risk communication tools like comparative probabilities and visual aids; and (3) practice estimating risk through role-play of risk communication between medical students and standardized patients. By improving risk communication in medical education, future doctors will be better equipped to build trust through open communication and improve the health of the patients and the communities for whom they care.

Over recent decades, management of people with hemophilia (PwH) has been greatly improved by scientific advances that have resulted in a rich and varied therapeutic landscape. Nevertheless, treatment limitations continue to drive innovation, and emerging options have the potential to realize further improvement. We advocate four general principles to optimize benefits from innovation: individualizing the treatment approach, targeting ‘normal,’ making the most of available resources, and considering treatment affordability. Ultimately, all PwH—men and women, of all ages and severities, and worldwide—should have access to treatment that fully prevents bleeding, while allowing personal, social, family, and professional lives of choice. Clearly, we are not there yet, but developing goals/milestones based on the principles we describe may help to achieve this.

The COVID-19 pandemic has caused the death of 7.1 million people worldwide as of 7 July 2024. In Nigeria, the first confirmed case was reported on 27 February 2020, subsequently followed by a nationwide spread of SARS-CoV-2 with morbidity and mortality reaching 267 173 and 3155, respectively, as of 7 July 2024. At the beginning of the pandemic, only a few public health laboratories in Nigeria had the capacity for SARS-CoV-2 molecular diagnosis. The National Veterinary Research Institute (NVRI), already experienced in influenza diagnosis, responded to the public health challenge for the diagnosis of COVID-19 samples from humans. The feat was possible through the collective utilisation of NVRI human and material resources, including biosafety facilities, equipment, reagents and consumables donated by international partners and collaborators. Within 6 months of the reported COVID-19 outbreak in Nigeria, over 33 000 samples were processed in NVRI facilities covering five states. Thereafter, many field and laboratory projects were jointly implemented between NVRI and collaborating sectors including the Nigerian Centre for Disease Control (NCDC) and the National Institute for Medical Research (NIMR), which brought together professionals in the health, veterinary, education and socio-sciences. In addition, One Health grants were secured to enhance surveillance for coronavirus and other zoonoses and build capacity in genomics. Bio-surveillance for coronaviruses and other emerging zoonotic pathogens at the human–animal interface was activated and continued with sample collection and analysis in the laboratory for coronaviruses, Lassa fever virus and Mpox. One Health approach has shown that inter-sectoral and multinational collaboration for diagnosis, research and development in animals, and the environment to better understand pathogen spillover events at the human–animal interface is an important global health priority and pandemic preparedness.

Abstract Estimating correlations among demographic parameters is an important method in population ecology. A recent paper by Deane et al. (Ecology and Evolution 13:e9847, 2023) attempted to explore the effects of different priors for covariance matrices on inference when using mark‐recovery data. Unfortunately, Deane et al. (2023) made a mistake when parameterizing some of their models. Rather than exploring the effects of different priors, they examined the effects of the use of incorrect equations on inference. In this manuscript, we clearly describe the mistake in Deane et al. (2023). We then demonstrate the use of an alternative and appropriate method and reach different conclusions regarding the effects of priors on inference. Consistent with other recent literature, informative inverse Wishart priors can lead to flawed inference, while vague priors on covariance matrix components have little impact when sample sizes are adequate.

MET is a receptor tyrosine kinase (RTK) responsible for initiating signaling pathways involved in development and wound repair. MET activation relies on ligand binding to the extracellular receptor, which prompts dimerization, intracellular phosphorylation, and recruitment of associated signaling proteins. Mutations, which are predominantly observed clinically in the intracellular juxtamembrane and kinase domains, can disrupt typical MET regulatory mechanisms. Understanding how juxtamembrane variants, such as exon 14 skipping (METΔEx14), and rare kinase domain mutations can increase signaling, often leading to cancer, remains a challenge. Here, we perform a parallel deep mutational scan (DMS) of the MET intracellular kinase domain in two fusion protein backgrounds: wild-type and METΔEx14. Our comparative approach has revealed a critical hydrophobic interaction between a juxtamembrane segment and the kinase ⍺C-helix, pointing to potential differences in regulatory mechanisms between MET and other RTKs. Additionally, we have uncovered a β5 motif that acts as a structural pivot for the kinase domain in MET and other TAM family of kinases. We also describe a number of previously unknown activating mutations, aiding the effort to annotate driver, passenger, and drug resistance mutations in the MET kinase domain.

Bulk density (Db) and subsequent physical properties are determined by the substrate and packing method. Packing method is the way one fills and compresses a substrate within a given volume. Bulk density produced in the laboratory may not align with “expected” published ranges due to variations in packing. Additionally, it is unknown if ranges identified as “typical” using a small volume sample ring reflect Db occurring in larger production size containers packed using commercial potting practices. Therefore, our objectives were to 1) emulate nursery practices and document the Db associated with a potted 2.8-L (#1) container, 2) develop and test the new “shim and compression” method to determine if it consistently packs sample rings to a Db commensurate with that of a 2.8-L nursery container, and 3) demonstrate how static physical properties are affected by the new “shim and compression” sample ring packing method compared with the traditional bench top tap method. When emulating nursery potting practices with 100% pine bark, coir, and peat, and blends of each, Db ranged from 0.08 g⋅cm−3 (coconut coir) to 0.17 g⋅cm−3 (pine bark). We used an espresso tamp and shims to pack the aforementioned substrates in sample rings. The Db achieved using a range in number of presses and discs was largely dependent on the substrate, but the desired Db was consistently achieved for each substrate. There was no effect of disc number on Db (P = 1.000) for any substrate. There was no effect of tamp number (P ≥ 0.0602) for all substrates except peat-amended, for which five tamps yielded a greater Db than one tamp (P = 0.0324). In an experiment in which a different technician who was accustomed to the conventional benchtop tap packing method performed both methods, method influenced Db (P < 0.0001), and the conventional method more closely attained the target Db. To our knowledge, this is the only report of Db observed in commercial container production facilities (i.e., “native”).

In numerous animals, dramatic coloration (e.g. bright red or yellow) often indicates potential fitness, but it is less clear whether subtle coloration in the same individuals (e.g. grey or brown) could also encode such signals. To determine if subtle coloration could indicate health in a bird species with colorful feathers, house finches (Haemorhous mexicanus), we used spectrometry to objectively quantify leg brightness and saturation before, six days after, and 13 days after captive individuals were inoculated with a naturally‐occurring bacterial pathogen, Mycoplasma gallisepticum. We found that legs became less bright six days after infection (near the typical peak of infection), then more bright and less saturated at 13 days (entering the typical recovery period). These results suggest that subtle colors could reliably indicate current infection status, and therefore survival potential.

Background: An increase in opioid-related overdoses, notably from potent synthetic opioids like fentanyl, prompted this consideration of characteristics of emergency department (ED) patients with evidence for illicit fentanyl use or exposure, the correlation with intentional opioid misuse, and subsequent ED management. Methods: A retrospective review was performed of patients presenting to an urban academic medical center ED with evidence for illicit fentanyl use, determined by positive urine drug screens (UDS), from 6/2021 through 11/2021. Participant demographics, comorbidities, ED chief complaint and disposition, and evidence of intentional opioid misuse were considered. Secondary outcomes included provision of buprenorphine/naloxone and/or naloxone kits at discharge, ED recidivism, and six-month mortality. Bivariate comparisons and logistic regression models were performed. Results: Among 409 unique patients, most were white and male with a mean age of 39.4. Approximately half presented with opioid-related complaints. Evidence of intentional opioid misuse was identified in 72.6 % of patients. Black patients had 79 % lower odds of intentional opioid misuse compared to white patients. Regarding ED management, 28.8 % were discharged with buprenorphine/naloxone and 14.0 % with a naloxone kit. Black patients had 63 % lower odds of receiving buprenorphine/naloxone compared to white patients after controlling for covariates. Nearly 6 % of the study population died within six months of the initial ED visit. Conclusion: This fentanyl-focused review describes patient characteristics which largely mirror the epidemiology of the current opioid epidemic; however, despite evidence of objective exposure, it also suggests that Black patients may be less likely to use fentanyl intentionally. It also highlights potential disparities related to ED-based opioid misuse patient management.

Biocrusts dominate the soil surface in deserts and are composed of diverse microbial communities that provide important ecosystem services. Cyanobacteria in biocrusts produce many secondary metabolites, including the neurotoxins BMAA, AEG, DAB, anatoxin-a(S) (guanitoxin), and the microcystin hepatotoxins, all known or suspected to cause disease or illness in humans and other animals. We examined cyanobacterial growth and prevalence of these toxins in biocrusts at millimeter-scales, under a desert-relevant illumination gradient. In contrast to previous work, we showed that hydration had an overall positive effect on growth and toxin accumulation, that nitrogen was not correlated with growth or toxin production, and that phosphorus enrichment negatively affected AEG and BMAA concentrations. Excess illumination positively correlated with AEG, and negatively correlated with all other toxins and growth. Basic pH negatively affected only the accumulation of BMAA. Anatoxin-a(S) (guanitoxin) was not correlated with any tested variables, while microcystins were not detected in any of the samples. Concerning toxin pools, AEG and BMAA were good predictors of the presence of one another. In a newly conceptualized scheme, we integrate aspects of biocrust growth and toxin pool accumulations with arid-relevant desertification drivers.

Abstract Background Randomized clinical trials (RCTs) are the gold standard for assessing treatment effectiveness; however, they have been criticized for generalizability issues such as how well trial participants represent those who receive the treatments in clinical practice. We assessed the representativeness of participants from eight RCTs for chronic spine pain in the U.S., which were used for an individual participant data meta-analysis on the cost-effectiveness of spinal manipulation for spine pain. In these clinical trials, spinal manipulation was performed by chiropractors. Methods We conducted a retrospective secondary analysis of RCT data to compare trial participants’ socio-demographic characteristics, clinical features, and health outcomes to a representative sample of (a) U.S. adults with chronic spine pain and (b) U.S. adults with chronic spine pain receiving chiropractic care, using secondary data from the National Health Interview Survey (NHIS) and Medical Expenditure Panel Survey (MEPS). We assessed differences between trial and U.S. spine populations using independent t-tests for means and z-tests for proportions, accounting for the complex multi-stage survey design of the NHIS and MEPS. Results We found the clinical trials had an under-representation of individuals from health disparity populations with lower percentages of racial and ethnic minority groups (Black/African American 7% lower, Hispanic 8% lower), less educated (No high school degree 19% lower, high school degree 11% lower), and unemployed adults (25% lower) with worse health outcomes (physical health scores 2.5 lower and mental health scores 5.3 lower using the SF-12/36) relative to the U.S. population with spine pain. While the odds of chiropractic use in the U.S. are lower for individuals from health disparity populations, the trials also under-represented these populations relative to U.S. adults with chronic spine pain who visit a chiropractor. Conclusions Health disparity populations are not well represented in spine pain clinical trials. Embracing key community-based approaches, which have shown promise for increasing participation of underserved communities, is needed.

Abstract Deep mutational scanning (DMS) measures the effects of thousands of genetic variants in a protein simultaneously. The small sample size renders classical statistical methods ineffective. For example, p-values cannot be correctly calibrated when treating variants independently. We propose Rosace, a Bayesian framework for analyzing growth-based DMS data. Rosace leverages amino acid position information to increase power and control the false discovery rate by sharing information across parameters via shrinkage. We also developed Rosette for simulating the distributional properties of DMS. We show that Rosace is robust to the violation of model assumptions and is more powerful than existing tools.

Abstract Background Persistent pain is a common yet debilitating complication after breast cancer surgery. Given the pervasive effects of this pain disorder on the patient and healthcare system, post-mastectomy pain syndrome (PMPS) is becoming a larger population health problem, especially as the prognosis and survivorship of breast cancer increases. Interventions that prevent persistent pain after breast surgery are needed to improve the quality of life of breast cancer survivors. An intraoperative intravenous lidocaine infusion has emerged as a potential intervention to decrease the incidence of PMPS. We aim to determine the definitive effects of this intervention in patients undergoing breast cancer surgery. Methods PLAN will be a multicenter, parallel-group, blinded, 1:1 randomized, placebo-controlled trial of 1,602 patients undergoing breast cancer surgery. Adult patients scheduled for a lumpectomy or mastectomy will be randomized to receive an intravenous 2% lidocaine bolus of 1.5 mg/kg with induction of anesthesia, followed by a 2.0 mg/kg/h infusion until the end of surgery, or placebo solution (normal saline) at the same volume. The primary outcome will be the incidence of persistent pain at 3 months. Secondary outcomes include the incidence of pain and opioid consumption at 1 h, 1–3 days, and 12 months after surgery, as well as emotional, physical, and functional parameters, and cost-effectiveness. Discussion This trial aims to provide definitive evidence on an intervention that could potentially prevent persistent pain after breast cancer surgery. If this trial is successful, lidocaine infusion would be integrated as standard of care in breast cancer management. This inexpensive, widely available, and easily administered intervention has the potential to reduce pain and suffering in an already afflicted patient population, decrease the substantial costs of chronic pain management, potentially decrease opioid use, and improve the quality of life in patients. Trial registration This trial has been registered on clinicaltrials.gov (NCT04874038, Dr. James Khan. Date of registration: May 5, 2021).

Abstract Cutaneous squamous cell carcinoma (SCC) is an increasingly prevalent global health concern. Current diagnostic and surgical methods are reliable, but they require considerable resources and do not provide metabolomic insight. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) enables detailed, spatially resolved metabolomic analysis of tissue samples. Integrated with machine learning, MALDI-MSI could yield detailed information pertaining to the metabolic alterations characteristic for SCC. These insights have the potential to enhance SCC diagnosis and therapy, improving patient outcomes while tackling the growing disease burden. This study employs MALDI-MSI data, labelled according to histology, to train a supervised machine learning model (logistic regression) for the recognition and delineation of SCC. The model, based on data acquired from discrete tumor sections (n = 25) from a mouse model of SCC, achieved a predictive accuracy of 92.3% during cross-validation on the labelled data. A pathologist unacquainted with the dataset and tasked with evaluating the predictive power of the model in the unlabelled regions, agreed with the model prediction for over 99% of the tissue areas. These findings highlight the potential value of integrating MALDI-MSI with machine learning to characterize and delineate SCC, suggesting a promising direction for the advancement of mass spectrometry techniques in the clinical diagnosis of SCC and related keratinocyte carcinomas.