Search

Abstract The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission.

The enteric nervous system (ENS) interacts bidirectionally with the local immune system, responding to inflammation within the gastrointestinal (GI) tract. In a previous study using the same samples, several gene targets were identified as being differentially expressed in the inflamed colonic tissue of pigs challenged with dextran sodium sulphate (DSS). Additionally, animals in the basal DSS group, exhibited reduced growth and increased fecal and pathology scores, while the relative abundance of beneficial taxa was reduced and harmful bacteria increased. While changes in the innate immune response and barrier function are widely cited regarding inflammatory bowel disease (IBD), the effects of inflammation on the local structures of the enteric nervous system (ENS) are less well understood. Hence, the objectives of this study were to: (1) evaluate the expression of a range of functionally diverse neuroactive receptors, transporters and neurotrophic factors in RNA derived from the colonic tissue from the same pigs; (2) examine associations with these neuroactive components and inflammatory, barrier function and matrix remodeling targets. Mature pigs were split into two experimental groups: (1) basal diet (n = 10); (2) basal diet + DSS (n = 11). The pigs were orally challenged with DSS once daily for four days and sacrificed humanely. Colonic tissue was collected for gene expression analysis. Most of the targets evaluated in this study were present at low levels or in some cases were undetectable by QPCR, including the dopamine receptor DRD5 and the serotonin receptor HTR3A. The dopamine receptors (DRD1, DRD3, DRD4), serotonin receptor (HTR4), and other selected neuroactive receptors (GRM7, GABRA2) were down-regulated in the DSS-challenged animals relative to the basal group (p < 0.05). Most notably, DRD2, was up-regulated four-fold, suggesting an active process involving this receptor (p < 0.05). Relationships with (previously published) gene expression data from the same samples suggest that DRD1 and DRD2 are influenced by different pathways and may also be interlinked with matrix remodeling and, more specifically, genes relevant to the epithelial to mesenchymal transition (CDH1, CDH2, IL6, IL13, IL10, MMP1, MMP2) an important fibrotic process in the pathogenesis of IBD.

Abstract Severe acute respiratory infections, such as community-acquired pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia, constitute frequent and lethal pulmonary infections in the intensive care unit (ICU). Despite optimal management with early appropriate empiric antimicrobial therapy and adequate supportive care, mortality remains high, in part attributable to the aging, growing number of comorbidities, and rising rates of multidrug resistance pathogens. Biomarkers have the potential to offer additional information that may further improve the management and outcome of pulmonary infections. Available pathogen-specific biomarkers, for example, Streptococcus pneumoniae urinary antigen test and galactomannan, can be helpful in the microbiologic diagnosis of pulmonary infection in ICU patients, improving the timing and appropriateness of empiric antimicrobial therapy since these tests have a short turnaround time in comparison to classic microbiology. On the other hand, host-response biomarkers, for example, C-reactive protein and procalcitonin, used in conjunction with the clinical data, may be useful in the diagnosis and prediction of pulmonary infections, monitoring the response to treatment, and guiding duration of antimicrobial therapy. The assessment of serial measurements overtime, kinetics of biomarkers, is more informative than a single value. The appropriate utilization of accurate pathogen-specific and host-response biomarkers may benefit clinical decision-making at the bedside and optimize antimicrobial stewardship.

Abstract Background Participants in research trials often disclose severe depression symptoms, including thoughts of self-harm and suicidal ideation, in validated self-administered questionnaires such as the Patient Health Questionnaire (PHQ-9). However, there is no standard protocol for responding to such disclosure, and the opportunity to support people at risk is potentially missed. We developed and evaluated a risk assessment protocol for the IBD-BOOST randomised controlled trial (ISRCTN71618461 09/09/2019). Methods Participants completed the PHQ-9 at baseline and 6-month and 12-month follow-ups. The trial database automatically alerted the research team to risk assess participants. Trial researchers, trained in the protocol, contacted participants by telephone, completed the risk assessment, and signposted participants to appropriate professional services. Results Seven hundred eighty participants were randomised in the trial; 41 required risk assessment. One participant declined assessment, so 40 risk assessments were completed. Twenty-four participants were assessed as low-risk and 16 participants as medium-risk, with 12 declaring previous suicide attempts. None were rated as high-risk. Trial participants expressed appreciation for being contacted, and all except two wished to receive information about professional support services. Trial risk assessors reported positive experiences of conducting the risk assessment with suggestions for improvement, which resulted in minor modifications to the protocol. Discussion Our evaluation demonstrated that it was viable for a research trial team to successfully conduct a risk-assessment protocol for trial participants reporting thoughts of self-harm, with training and support from senior colleagues. Resources are required for training and delivery, but it is not unduly onerous. Trial participants appeared to find completing the assessment acceptable.

Abstract Background We report on our methodological experiences during an investigation of how institutional racism functions in healthcare. We found tension between balancing methodological rigor with the unanticipated consequence of interviewer burden. Methods Semi-structured interviews were conducted with patients. Interviews were recorded, transcribed verbatim, and qualitatively analyzed using thematic content analysis. Interviewers also participated in weekly debriefing sessions and reported experiences with patients. Results Interviewers repeatedly experienced negative encounters with white patients during interviews. Themes included privilege to avoid racism, denial of racism, non-verbal discomfort, falsely claiming Native identities, and intimidation. These experiences were most pronounced with Black interviewers. Discussion Interviewer burden may need to be a consideration taken up in a variety of research contexts.

Abstract Hepatitis C virus (HCV) is a plus-stranded RNA virus that often chronically infects liver hepatocytes and causes liver cirrhosis and cancer. These viruses replicate their genomes employing error-prone replicases. Thereby, they routinely generate a large ‘cloud’ of RNA genomes (quasispecies) which—by trial and error—comprehensively explore the sequence space available for functional RNA genomes that maintain the ability for efficient replication and immune escape. In this context, it is important to identify which RNA secondary structures in the sequence space of the HCV genome are conserved, likely due to functional requirements. Here, we provide the first genome-wide multiple sequence alignment (MSA) with the prediction of RNA secondary structures throughout all representative full-length HCV genomes. We selected 57 representative genomes by clustering all complete HCV genomes from the BV-BRC database based on k-mer distributions and dimension reduction and adding RefSeq sequences. We include annotations of previously recognized features for easy comparison to other studies. Our results indicate that mainly the core coding region, the C-terminal NS5A region, and the NS5B region contain secondary structure elements that are conserved beyond coding sequence requirements, indicating functionality on the RNA level. In contrast, the genome regions in between contain less highly conserved structures. The results provide a complete description of all conserved RNA secondary structures and make clear that functionally important RNA secondary structures are present in certain HCV genome regions but are largely absent from other regions. Full-genome alignments of all branches of Hepacivirus C are provided in the supplement.

Abstract Ventrointermediate thalamic stimulation (VIM-DBS) modulates oscillatory activity in a cortical network including primary motor cortex, premotor cortex, and parietal cortex. Here we show that, beyond the beneficial effects of VIM-DBS on motor execution, this form of invasive stimulation facilitates production of sequential finger movements that follow a repeated sequence. These results highlight the role of thalamo–cortical activity in motor learning.

In a recent publication dealing with the sectional-level taxonomy of Garcinia, an illegitimate superfluous sectional name and two illegitimate homonyms were published. Herein we choose a legitimate sectional name, Garcinia section Rheediopsis Pierre, for the superfluous name Garcinia section Rheedia (L.) S.W.Jones ex P.W.Sweeney; and create two new legitimate names in Garcinia for Allanblackia gabonensis (Pellegr.) Bamps and A. parviflora A.Chev.

Abstract Claudin-5 is one of the most essential tight junction proteins at the blood-brain barrier. A single nucleotide polymorphism rs10314 is located in the 3’-untranslated region of claudin-5 and has been shown to be a risk factor for schizophrenia. Here, we show that the pumilio RNA-binding protein, pumilio-1, is responsible for rs10314-mediated claudin-5 regulation. The RNA sequence surrounding rs10314 is highly homologous to the canonical pumilio-binding sequence and claudin-5 mRNA with rs10314 produces 25% less protein due to its inability to bind to pumilio-1. Pumilio-1 formed cytosolic granules under stress conditions and claudin-5 mRNA appeared to preferentially accumulate in these granules. Added to this, we observed granular pumilio-1 in endothelial cells in human brain tissues from patients with psychiatric disorders or epilepsy with increased/accumulated claudin-5 mRNA levels, suggesting translational claudin-5 suppression may occur in a brain-region specific manner. These findings identify a key regulator of claudin-5 translational processing and how its dysregulation may be associated with neurological and neuropsychiatric disorders. Graphical Abstract

Abstract Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Abstract Vestibular schwannomas (VS) are the most common tumor of the skull base with available treatment options that carry a risk of iatrogenic injury to the facial nerve, which can significantly impact patients’ quality of life. As facial nerve outcomes remain challenging to prognosticate, we endeavored to utilize machine learning to decipher predictive factors relevant to facial nerve outcomes following microsurgical resection of VS. A database of patient-, tumor- and surgery-specific features was constructed via retrospective chart review of 242 consecutive patients who underwent microsurgical resection of VS over a 7-year study period. This database was then used to train non-linear supervised machine learning classifiers to predict facial nerve preservation, defined as House-Brackmann (HB) I vs. facial nerve injury, defined as HB II–VI, as determined at 6-month outpatient follow-up. A random forest algorithm demonstrated 90.5% accuracy, 90% sensitivity and 90% specificity in facial nerve injury prognostication. A random variable (rv) was generated by randomly sampling a Gaussian distribution and used as a benchmark to compare the predictiveness of other features. This analysis revealed age, body mass index (BMI), case length and the tumor dimension representing tumor growth towards the brainstem as prognosticators of facial nerve injury. When validated via prospective assessment of facial nerve injury risk, this model demonstrated 84% accuracy. Here, we describe the development of a machine learning algorithm to predict the likelihood of facial nerve injury following microsurgical resection of VS. In addition to serving as a clinically applicable tool, this highlights the potential of machine learning to reveal non-linear relationships between variables which may have clinical value in prognostication of outcomes for high-risk surgical procedures.

Introduction: Surgical decision-making often relies on a surgeon's subjective assessment of a patient's frailty status to undergo surgery. Certain patient demographics can influence subjective judgment when compared to validated objective assessments. In this study, we explore the relationship between subjective and objective frailty assessments according to patient age, sex, and race. Methods: Patients were prospectively enrolled in urology, general surgery, and surgical oncology clinics. Using a visual analog scale (0−100), operating surgeons independently rated the patient's frailty status. Objective frailty was classified using the Fried Frailty Criteria ranging from 0 to 5. Multivariable proportional odds models were conducted to examine the potential association of factors with objective frailty, according to surgeon frailty rating. Subgroup analysis according to patient sex, race, and age was also performed. Results: Seven male surgeons assessed 203 patients preoperatively with a median age of 65. A majority of patients were male (61 %), white (67 %), and 60 % and 40 % underwent urologic and general surgery/surgical oncology procedures respectively. Increased subjective surgeon rating (OR 1.69; p 60, OR 1.75; p = 0.0001) patients, compared to male (OR 1.45; p = 0.0243), non-white (OR 1.48; p = 0.0109) and patients under 60 (OR 1.47; p = 0.0823). Conclusion: The surgeon's subjective assessment of frailty demonstrated tendencies to rate older, female, and non-white patients as frail; however, differences in patient sex, age, and race were not statistically significant.

Homeless service users were screened for autism spectrum disorder through one of Ireland's leading not for profit service providers. Keyworkers acted as proxy informants; their caseloads were screened using the DSM-5--Autistic Traits in the Homeless Interview (DATHI). Client current and historical health and behaviour data was collated. A representative sample of 106 eligible keyworkers caseloads were screened, identifying 3% "present" and 9% "possibly present" for autistic traits with the DATHI. These findings suggest a high estimate of autism prevalence and support emerging evidence that, people with autism are overrepresented in the homeless population, compared to housed populations. Autism may be a risk factor for entry into homelessness and a challenge to exiting homeless and engaging with relevant services.

BACKGROUND. Metastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3[beta]-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes. METHODS. Our prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes. RESULTS. Patients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide. CONCLUSION. These data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible. FUNDING. National Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council., Introduction Prostate cancer has long been recognized to be an androgen-dependent disease, with some cancers being more dependent than others. Androgen deprivation therapy (ADT) with gonadal testosterone suppression has therefore [...]

To explore how an early, RNA-based life form could have functioned, in vitro selection experiments have been used to develop catalytic RNAs (ribozymes) with relevant functions. We previously identified ribozymes that use the prebiotically plausible energy source cyclic trimetaphosphate (cTmp) to convert their 5'-hydroxyl group to a 5'-triphosphate. While these ribozymes were developed in the presence of Mg2+, we tested here whether lanthanides could also serve as catalytic cofactors because lanthanides are ideal catalytic cations for this reaction. After an in vitro selection in the presence of Yb3+, several active sequences were isolated, and the most active RNA was analyzed in more detail. This ribozyme required lanthanides for activity, with highest activity at a 10:1 molar ratio of cTmp : Yb3+. Only the four heaviest lanthanides gave detectable signals, indicating a high sensitivity of ribozyme catalysis to the lanthanide ion radius. Potassium and Magnesium did not facilitate catalysis alone but they increased the lanthanide-mediated kOBS by at least 100-fold, with both K+ and Mg2+ modulating the ribozyme's secondary structure. Together, these findings show that RNA is able to use the unique properties of lanthanides as catalytic cofactor. The results are discussed in the context of early life forms.

BackgroundProstate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression-based subtyping model based on prostate-specific biological processes was sought.MethodsUnsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts.ResultsClustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01-0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09-0.51).ConclusionsWith the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features.Plain language summaryProstate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors-the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.

Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor-naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9 months. The median duration of overall response was 11.7 months, and the median overall survival was 11.6 months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n = 31; 20% each), thrombocytopenia (n = 25; 16%), and neutropenia (n = 20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02719574.

Epigenetic mechanisms are implicated in transcriptional programs driving chronic kidney disease (CKD). Apabetalone is an orally available inhibitor of bromodomain and extraterminal (BET) proteins, which are epigenetic readers that modulate gene expression. In the phase 3 BETonMACE trial, apabetalone reduced risk of major adverse cardiac events (MACE) by 50% in the CKD subpopulation, indicating favorable effects along the kidney-heart axis. Activation of human renal mesangial cells (HRMCs) to a contractile phenotype that overproduces extracellular matrix (ECM) and inflammatory cytokines, and promotes calcification, frequently accompanies CKD to drive pathology. Here, we show apabetalone downregulated HRMC activation with TGF-β1 stimulation by suppressing TGF-β1-induced α-smooth muscle actin (α-SMA) expression, α-SMA assembly into stress fibers, enhanced contraction, collagen overproduction, and expression of key drivers of fibrosis, inflammation, or calcification including thrombospondin, fibronectin, periostin, SPARC, interleukin 6, and alkaline phosphatase. Lipopolysaccharide-stimulated expression of inflammatory genes IL6, IL1B, and PTGS2 was also suppressed. Transcriptomics confirmed apabetalone affected gene sets of ECM remodeling and integrins. Clinical translation of in vitro results was indicated in CKD patients where a single dose of apabetalone reduced plasma levels of key pro-fibrotic and inflammatory markers, and indicated inhibition of TGF-β1 signaling. While plasma proteins cannot be traced to the kidney alone, anti-fibrotic and anti-inflammatory effects of apabetalone identified in this study are consistent with the observed decrease in cardiovascular risk in CKD patients.

BackgroundClinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population, especially when the population affected is undefined.MethodsWe evaluated the utility of the Centers for Disease Control and Prevention's COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), the COVID-19 Case Surveillance System (CCSS), and 2020 United States (US) Census data to determine demographic representation in the 4 stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at US ACTT sites, with respective 95% confidence intervals, to the reference data in forest plots.ResultsUS ACTT sites enrolled 3509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic/Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with US Census and CCSS. The proportion of participants aged ≥65 years was either similar or lower than COVID-NET and higher than CCSS and the US Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets.ConclusionsAlthough surveillance data of hospitalized cases may not be available early in an outbreak, they are a better comparator than US Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.

Algebra is a gatekeeper. For the 6% of students with dyscalculia (i.e., mathematical learning disabilities), an inability to pass algebra may significantly limit academic and career opportunities. Unfortunately, prior research on dyscalculia has focused almost exclusively on elementary-aged students' deficits in speed and accuracy in arithmetic calculation. This case study expands our understanding of dyscalculia by documenting how one college student with dyscalculia understood algebra during a one-on-one design experiment. A detailed case study of 19 video recorded sessions revealed that she relied upon unconventional understandings of algebraic quantities and notation, which led to persistent difficulties. The design experiment involved designing alternative tools to enable the student to reason about algebra, but the unconventional understandings persisted. This exploratory case study provides new insights into the character of difficulties that arose and persisted for one student with dyscalculia in the context of algebra and suggests the utility of documenting the persistent understandings that students with dyscalculia rely upon, particularly in understudied mathematical domains, like algebra.

Background: Expanding primary care multidisciplinary teams (MDTs) was a key component of the 2018 Scottish GP contract, with more than 4700 MDT staff appointed since then. Aim: To explore patients’ views on primary care MDT expansion in Scotland. Design & setting: A mixed-methods evaluation, which included a postal survey and semi-structured telephone interviews with patients in Scotland. Method: A survey was undertaken of patients who had recently consulted a GP in deprived urban, affluent urban, and remote and rural areas, assessing awareness of five MDT roles and attitudes towards receptionist signposting. In addition, 30 individual interviews were conducted, exploring patients' MDT-care experiences. Results: Of 1053 survey responders, most were unaware of the option of MDT rather than GP consultations for three out of five roles (69% unaware of link worker appointments; 69% mental health nurse; and 58% pharmacist). Reception signposting was less popular in deprived urban areas (34% unhappy versus 29% in remote and rural versus 21% affluent urban; P

IntroductionThe aims of this synthesis were to investigate the relationship between IPV severity and mental health outcomes and shed light to gaps and limitations in existing methodologies used to assess IPV severity and its association with mental health outcomes.MethodsWe conducted a two-stage narrative synthesis of 76 studies. First, we identified IPV measures used in at least five studies, focusing on their variations and severity score calculation. Then, we analyzed findings of studies correlating IPV severity with mental health outcomes, identifying features of measures and statistical methods influencing result consistency.ResultsMeasures of intimate partner violence were often modified from their original, potentially impact on the reliability and validity of these measures. The operationalization of violence severity varied across studies, leading to inconsistencies in scoring whereby compromising the consistency of severity levels across studies. We found lack of consistency in applying validated methods for scoring instruments to determine abuse severity. In this review, we consistently found that the severity of IPV and its various subtypes were linked to different mental health outcomes across multiple studies. We discovered evidence suggesting that experiencing more types of IPV was associated with worse mental health outcomes. Generally, higher levels of overall IPV severity and its specific subtypes were correlated with poorer mental health outcomes. However, our analyses did not reveal consistent patterns that would allow for a definitive determination of how individual IPV subtypes differently affect mental health outcomes. Nevertheless, we observed that increasing severity of physical IPV tended to have a notable impact on post-traumatic stress disorder (PTSD). Conversely, increasing severity of psychological IPV was consistently associated with depression. While sexual IPV severity was explored in fewer studies, the evidence regarding its impact on various mental health outcomes was less conclusive.DiscussionTo achieve a comprehensive understanding of the mechanism by which IPV severity is related to mental health it may be time to take an alternative approach to measuring IPV severity. No IPV measures assessed the acceptability of the content to people who have experienced IPV. This is an important omission with significant consequences for the validity of the evidence base.

Abstract For the prosthetic retina, a device replacing dysfunctional cones and rods, with the ability to mimic the spectral response properties of these photoreceptors and provide electrical stimulation signals to activate residual visual pathways, can relay sufficient data to the brain for interpretation as color vision. Organic semiconductors including conjugated polymers with four different bandgaps providing wavelength‐specific electrical responses are ideal candidates for potential full‐color vision restoration. Here, conjugated polymer photocapacitor devices immersed in electrolyte are demonstrated to elicit a photovoltage measured by a Ag/AgCl electrode 100 microns from the device of ≈−40 mV for 15–39 µW mm−2 of incident light power density at three wavelengths: 405 nm for blue photoreceptor candidate material, 534 nm for green, 634 nm for red. Photoresponse is substantially improved by introducing polymer donor/acceptor molecules bulk heterojunctions. Devices with bulk heterojunction configurations achieved at least −70 mV for green candidates with the highest at −200 mV for red cone candidates. These findings highlight the potential for organic materials to bridge the gap toward natural vision restoration for retinal dystrophic conditions such as age‐related macular degeneration, Stargardt disease, or retinitis pigmentosa and contribute to the ongoing advancements in visual prosthetic devices.

Psychedelic therapies are an emerging class of treatments in psychiatry with great potential, however relatively little is known about their interactions with other commonly used psychiatric medications. As psychedelic therapies become more widespread and move closer to the clinic, they likely will need to be integrated into existing treatment models which may include one or more traditional pharmacological therapies, meaning an awareness of potential drug-drug interactions will become vital. This commentary outlines some of the issues surrounding the study of drug-drug interactions of this type, provides a summary of some of the relevant key results to date, and charts a way forward which relies crucially on multimodal neuroimaging investigations. Studies in humans which combine Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI), plus ancillary measures, are likely to provide the most comprehensive assessment of drug-drug interactions involving psychedelics and the relevant effects at multiple levels of the drug response (molecular, functional, and clinical).

Summary: Adiponectin-based therapeutic strategies are promising for managing metabolic diseases and reducing inflammation, prompting the development of adiponectin receptor agonists. However, monitoring their pharmacodynamic actions in clinical applications is challenging. This study aimed to identify peripheral biomarkers to monitor adiponectin actions using ALY688, an adiponectin receptor agonist peptide. RNA sequencing analysis of whole blood identified a cluster of genes that were significantly increased in the ALY688-treated group compared to the control. This gene cluster was validated by qPCR and further confirmed in human peripheral blood mononuclear cells treated with ALY688 ex vivo. We also confirmed a functional outcome of ALY688 action in mice as our study also demonstrated the anti-inflammatory effect of ALY688 in a sublethal LPS mouse model. In summary, a newly identified gene cluster signature is suitable for assessing the pharmacodynamic action of adiponectin or its mimetics in blood samples.

ExaFEL is an HPC-capable X-ray Free Electron Laser (XFEL) data analysis software suite for both Serial Femtosecond Crystallography (SFX) and Single Particle Imaging (SPI) developed in collaboration with the Linac Coherent Lightsource (LCLS), Lawrence Berkeley National Laboratory (LBNL) and Los Alamos National Laboratory. ExaFEL supports real-time data analysis via a cross-facility workflow spanning LCLS and HPC centers such as NERSC and OLCF. Our work therefore constitutes initial path-finding for the US Department of Energy's (DOE) Integrated Research Infrastructure (IRI) program. We present the ExaFEL team's 7 years of experience in developing real-time XFEL data analysis software for the DOE's exascale supercomputers. We present our experiences and lessons learned with the Perlmutter and Frontier supercomputers. Furthermore we outline essential data center services (and the implications for institutional policy) required for real-time data analysis. Finally we summarize our software and performance engineering approaches and our experiences with NERSC's Perlmutter and OLCF's Frontier systems. This work is intended to be a practical blueprint for similar efforts in integrating exascale compute resources into other cross-facility workflows.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Background The metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride‐rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease. Methods and Results We studied 1791 MESA (Multi‐Ethnic Study of Atherosclerosis) participants who took part in an ancillary study on body composition with adipokine levels measured (leptin, adiponectin, and resistin) at either visit 2 or visit 3. RC was calculated as non–high‐density lipoprotein cholesterol minus low‐density lipoprotein cholesterol, measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable‐adjusted linear mixed‐effects models were used to assess the cross‐sectional and longitudinal associations between adipokines and log‐transformed levels of RC. Mean±SD age was 64.5±9.6 years; mean±SD body mass index was 29.9±5.0 kg/m2; and 52.0% were women. In fully adjusted cross‐sectional models that included body mass index, diabetes, low‐density lipoprotein cholesterol, and lipid‐lowering therapy, for each 1‐unit increment in adiponectin, there was 14.6% (95% CI, 12.2–16.9) lower RC. With each 1‐unit increment in leptin and resistin, there was 4.8% (95% CI, 2.7–7.0) and 4.0% (95% CI, 0.2–8.1) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow‐up of 5 (interquartile range, 4–8) years. Conclusions Lower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for body mass index and low‐density lipoprotein cholesterol.

Goose-beaked whales (Ziphius cavirostris) are deep-diving cetaceans known for their elusive nature and specialized foraging behavior. In 2019 and 2020, six telemetry tags were deployed on these whales in Southern California, resulting in 395 h of acoustic and diving data. Foraging dives were manually identified by the presence of echolocation pulses and buzzes, and generalized additive models assessed factors influencing foraging behavior. The median bathymetric depth at foraging sites was 1,419 m (IQR = 359), and the maximum dive depth was highly correlated with bathymetry depth. Individuals started echolocating on descent at a median depth of 410 m (IQR = 74); pulses were not observed shallower than 292 m. Echolocation ceased during the bottom phase for 81.6% of dives, at a median depth of 1,265 m (IQR = 472); pulses were not observed shallower than 587 m on ascent. The median depth of buzzes was 1,215 m (IQR = 479) with 63% occurring during the bottom phase. Deeper dives correlated with longer durations of diving and echolocation, greater echolocation end depths, and wider bottom phase echolocation depth inter-quartile range. The median difference between dive depth and bottom phase median echolocation depth was 98.3 m (IQR = 48.5), suggesting whales in this region forage in a narrow band close to the seafloor. In the San Nicolas Basin, individuals exhibited longer echolocation durations, produced more pulses, and started and ended echolocating at greater depths compared to adjacent regions. These records validate and expand upon previous studies, providing insights into factors influencing foraging behavior in an area with high anthropogenic disturbance.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details assessment and management of the child with overweight or obesity. The term “child” is defined as the child between 2 and 12 years of age. Because children are in a continual state of development during this age range, we will specify when our discussion applies to subsets within this age range. For the purposes of this CPS, we will use the following definitions: overweight in the child is a body mass index (BMI) ≥ 85th and

Summary: Gene promoters filter transcription factor (TF) localization dynamics and changes in the DNA binding affinity of TFs. Here, we present a protocol to probe how promoters decode TF dynamics in Saccharomyces cerevisiae by combining optogenetic control with microscopy. We describe steps for preparing and characterizing a light delivery platform and light-controlled TF mutants. We then detail procedures for subjecting the TFs to light doses that generate defined patterns of localization while measuring fluorescent reporter gene activation via live-cell microscopy.For complete details on the use and execution of this protocol, please refer to Sweeney and McClean.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background: The pharmacy sector is rapidly evolving due to technological advancements, presenting challenges and opportunities for pharmacists. However, limited literature exists on the future of pharmacy work, especially concerning technology adoption. Objective: This exploratory study investigates pharmacists' perspectives on the impact of technologies on the profession - including career security, role evolution, adjustments to changes - and the impact of the COVID-19 pandemic on technology implementation and the broader future of work in pharmacy. Method: A cross-sectional survey design was used, targeting all registered pharmacists in New Zealand. A questionnaire, adapted from Future of Work literature, was piloted and distributed to 3037 pharmacists. Data were analyzed using descriptive statistics, two-step hierarchical analysis, and content and thematic analysis. Ethics approval was obtained. Results: 177 responses met the inclusion criteria, yielding a 5.82% response rate. Respondent demographics included a lower proportion of community pharmacists and individuals of Asian ethnicity, but a higher proportion of males and hospital pharmacists compared to the national workforce. Most respondents were aged between 30 and 59 years, representing all District Health Board locations.Qualitative analysis identified two themes: 1) Factors affecting technology adoption across macro, meso and micro levels, including COVID-19's impact on work efficiency, regulatory gaps, fragmented IT and organizational infrastructures, patient safety, and attitudes at workforce and individual levels; 2) Career impacts, highlighting role expansion, job replacement fears, and the need for adaptation and upskilling. Quantitative findings indicate that early technology adopters are more prepared to learn new skills and plan their careers. Technology impact positively correlates with career planning, while job loss concerns negatively affect skill development readiness. Conclusion: The study underscores the importance of early technological adoption for readiness to acquire new skills and career planning in pharmacy. Embracing technological change, supported by regulatory and policy frameworks, is crucial for advancing the profession.