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While the medical field in the United States is renowned for research and innovation, with large numbers of world-class healthcare facilities and cutting-edge technologies, inequities in overall health outcomes demonstrate pronounced disparities in accessing care. This article addresses increasing provider diversity and cultural humility as critical steps in ensuring advancements are made to equitable care under the current confines of the American healthcare system. Increasing diversity amongst medical providers starts before students begin applying to medical school. Critical strategies are needed at the K-12 level to ensure early exposure to Science, Technology, Engineering, and Mathematics (STEM). Research demonstrates that early exposure to STEM can positively impact children's interest, confidence, and pursuit of STEM careers, including medicine. Early exposure to STEM can increase engagement and motivation in STEM subjects particularly for girls and racially marginalized groups.

The Ebola Data Platform (EDP) was developed to strengthen knowledge and capacity across health, research, and humanitarian communities to reduce the impact of Ebola through responsible data use. This collaborative initiative was established by West African governments, NGOs, academic organisations, and intra-governmental health organisations directly involved in the 2013–2016 West African Ebola outbreak. The platform was established to provide a centralised, standardised dataset of individual patient data collected during the outbreak for the purpose of research to improve Ebola treatment and control, and includes over 13,600 patient records of individuals infected and treated from 22 different Ebola treatment centres across Guinea, Sierra Leone, Liberia, and Nigeria. Patient data are available from treatment centre triage and admission, inpatient clinical observations, and outcomes, with outpatient follow-up available for some datasets. Data include signs and symptoms, pre-existing comorbidities, vital signs, laboratory testing, treatments, complications, dates of admission and discharge, mortality, viral strains, and other data. This publication describes characteristics of the EDP dataset, its architecture, methods for data access and tools for utilising the dataset.

Abstract Postoperative disease recurrence in Crohn’s disease represents a relevant issue despite recent advancements in surgical and medical therapies. Additional criteria are necessary to improve the identification of patients at risk and to enable selective therapeutic approaches. The role of resection margins on disease recurrence remains unclear and general recommendations are lacking. A single-center retrospective analysis was performed including all patients who received ileocecal resection due to Crohn’s disease. Resection margins were analyzed by two independent pathologists and defined by histopathological criteria based on previous consensus reports. 158 patients were included for analysis with a median follow up of 35 months. While postoperative morbidity was not affected, positive resection margins resulted in significantly increased rates of severe endoscopic recurrence at 6 months (2.0% versus 15.6%, p = 0.02) and overall (4.2% versus 19.6%, p = 0.001), which resulted in significantly increased numbers of surgical recurrence (0% versus 4.5%, p = 0.04). Additionally, positive margins were identified as independent risk factor for severe endoscopic disease recurrence in a multivariate analysis. Based on that, positive margins represent an independent risk factor for postoperative endoscopic and surgical disease recurrence. Prospective studies are required to determine whether extended resection or postoperative medical prophylaxis is beneficial for patients with positive resection margins.

Abstract Large population-based cohort studies utilizing device-based measures of physical activity are crucial to close important research gaps regarding the potential protective effects of physical activity on chronic diseases. The present study details the quality control processes and the derivation of physical activity metrics from 100 Hz accelerometer data collected in the German National Cohort (NAKO). During the 2014 to 2019 baseline assessment, a subsample of NAKO participants wore a triaxial ActiGraph accelerometer on their right hip for seven consecutive days. Auto-calibration, signal feature calculations including Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD), identification of non-wear time, and imputation, were conducted using the R package GGIR version 2.10-3. A total of 73,334 participants contributed data for accelerometry analysis, of whom 63,236 provided valid data. The average ENMO was 11.7 ± 3.7 mg (milli gravitational acceleration) and the average MAD was 19.9 ± 6.1 mg. Notably, acceleration summary metrics were higher in men than women and diminished with increasing age. Work generated in the present study will facilitate harmonized analysis, reproducibility, and utilization of NAKO accelerometry data. The NAKO accelerometry dataset represents a valuable asset for physical activity research and will be accessible through a specified application process.

In 2022, concurrent outbreaks of hepatitis A, invasive meningococcal disease (IMD), and mpox were identified in Florida, USA, primarily among men who have sex with men. The hepatitis A outbreak (153 cases) was associated with hepatitis A virus genotype IA. The IMD outbreak (44 cases) was associated with Neisseria meningitidis serogroup C, sequence type 11, clonal complex 11. The mpox outbreak in Florida (2,845 cases) was part of a global epidemic. The hepatitis A and IMD outbreaks were concentrated in Central Florida and peaked during March–­June, whereas mpox cases were more heavily concentrated in South Florida and had peak incidence in August. HIV infection was more common (52%) among mpox cases than among hepatitis A (21%) or IMD (34%) cases. Where feasible, vaccination against hepatitis A, meningococcal disease, and mpox should be encouraged among at-risk groups and offered along with program services that target those groups.

Abstract Porphyromonas gingivalis, a Gram-negative anaerobic bacterium commonly found in human subgingival plaque, is a major etiologic agent for periodontitis and has been associated with multiple systemic pathologies. Many P. gingivalis strains have been identified and different strains possess different virulence factors. Current oral microbiome approaches (16S or shotgun) have been unable to differentiate P. gingivalis strains. This study presents a new approach that aims to improve the accuracy of strain identification, using a detection method based on sequencing of the intergenic spacer region (ISR) which is variable between P. gingivalis strains. Our approach uses two-step PCR to amplify only the P. gingivalis ISR region. Samples are then sequenced with an Illumina sequencer and mapped to specific strains. Our approach was validated by examining subgingival plaque from 153 participants with and without periodontal disease. We identified the avirulent strain ATCC33277/381 as the most abundant strain across all sample types. The W83/W50 strain was significantly enriched in periodontitis, with 13% of participants harboring that strain. Overall, this approach can have significant implications not only for the diagnosis and treatment of periodontal disease but also for other diseases where P. gingivalis or its toxins have been implicated, such as Alzheimer's disease.

Abstract Introduction Healthcare services face significant challenges due to the aging population, increasing complexity of health issues, and a global shortage of health professionals. Health professions education needs to adapt and develop with healthcare services’ needs. Interprofessional education and patient partnership are two trends that are increasingly being reinforced. Health professions students worldwide are expected to acquire competencies in interprofessional collaboration through undergraduate and postgraduate studies. Developing interprofessional collaborative skills in clinical placements is crucial. This study aims to explore two patients’ meetings with an interprofessional student team and better understand how the patient can participate actively in the students´ learning processes. Methods This is a small single-case study. Two patients participated. Data was generated through participant observation and qualitative interviews. A practical iterative framework for qualitative data analysis inspired the analysis. Results The patients observed and reflected on the interprofessional students’ learning process and felt responsible for contributing to their learning. The patients contributed to students’ learning by making themselves available for practicing and sometimes giving feedback. They considered it a win-win situation to be involved in the interprofessional learning activity as they perceived being taken seriously by the students when addressing their problems and experienced positive outcomes for their situation, such as better physical functioning and adjustments to assistive devices. Patients emphasized the importance of learning collaboration between health professionals and how this could contribute to them feeling safer as patients. Discussion This study highlights the importance of including patients in interprofessional students’ learning processes. Patients’ active participation in interprofessional clinical placements can empower them, improve their self-efficacy, and potentially shift the power dynamic between patients and healthcare professionals. The study emphasizes the importance of the patient perspective in future research on interprofessional education in clinical settings. The study also highlights the need for clinical supervisors to facilitate patient involvement in interprofessional clinical placements and reinforce patients’ feedback for the student team. Concluding comments Overall, this study contributes to the growing body of research on interprofessional education and patient partnership and emphasizes the importance of including patients in health professions education.

IntroductionThis study examined the efficacy of a five-module cognitive behavioral therapy for nightmares in children (CBT-NC) and improving sleep.Materials and methodsForty-six youth aged 6–17 years with sleep problems and at least weekly chronic and distressing nightmares were randomized to treatment (n = 23) or waiting list (n = 23) using a block four randomized design. Among participants, 65% (n = 30) were White, 4% (n = 2) were Black/African American, 2% (n = 1) were Asian American, 13% (n = 6) were Native American or Pacific Islander, and 15% (n = 7) were multiracial. Fifty percent of participants (n = 23) were cisgender girls, 35% were cisgender boys (n = 16), 7% were transgender boys (n = 3), and 9% were gender non-binary (n = 4). The baseline nightmare persistence ranged from 6 months to 13.5 years. The treatment adapted exposure, relaxation, and rescription therapy for trauma-related nightmares in adults and added elements of cognitive behavioral therapy for insomnia in children. Psychoeducation included topics of sleep and nightmares, relaxation, anxiety management, and sleep hygiene; the youth were guided through nightmare exposure and rescription.ResultsThere was a statistically significant improvement in the number of nights with awakening (Cohen's d = 1.08), the number of weekly nightmares (Cohen's d = 0.82), and nightmare distress (Cohen's d = 1.05) for the treatment group compared to the wait-list group. Parent-reported youth sleep improved for the entire group from pretreatment to posttreatment (p < 0.001) but did not reach statistical significance for between-subjects analyses of the treatment group compared to the wait-list group (p = 0.05). Between-subjects analyses saw improvement for the treatment group compared to the wait-list group on internalizing and externalizing problems and suicidal thoughts and behaviors.DiscussionThis study supports the efficacy of CBT-NC for improving sleep maintenance, nightmare frequency and distress, and other mental health difficulties in youth. Preliminary evidence of possibly improving suicidal thinking and behavior is also presented.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05588739, identifier: NCT05588739.

Abstract Prevention of intestinal fibrosis remains an unresolved problem in the treatment of Crohn’s disease (CD), as specific antifibrotic therapies are not yet available. Appropriate analysis of fibrosis severity is essential for assessing the therapeutic efficacy of potential antifibrotic drugs. The aim of this study was to develop an observer-independent method to quantify intestinal fibrosis in surgical specimens from patients with CD using structural analysis of the extracellular matrix (ECM). We performed fractal analysis in fibrotic and control histological sections of patients with surgery for CD (n = 28). To specifically assess the structure of the collagen matrix, polarized light microscopy was used. A score to quantify collagen fiber alignment and the color of the polarized light was established. Fractal dimension as a measure for the structural complexity correlated significantly with the histological fibrosis score whereas lacunarity as a measure for the compactness of the ECM showed a negative correlation. Polarized light microscopy to visualize the collagen network underlined the structural changes in the ECM network in advanced fibrosis. In conclusion, observer-independent quantification of the structural complexity of the ECM by fractal analysis is a suitable method to quantify the degree of intestinal fibrosis in histological samples from patients with CD.

Introduction: Older adults often have multiple comorbidities; therefore, they are at high risk for adverse events after discharge. The 4Ms framework—what matters, medications, mentation, mobility—has been used in acute and ambulatory care settings to identify risk factors for adverse events in older adults, although it has not been used in the emergency department (ED). We aimed to determine whether 1) use of the 4Ms worksheet would help emergency clinicians understand older adult patients’ goals of care and 2) use of the worksheet was feasible in the ED. Methods: We conducted a qualitative, descriptive study among patients aged ≥60 years and emergency clinicians from January–June 2022. Patients were asked to fill out a 4Ms worksheet; following this, semi-structured interviews were conducted with patients and clinicians separately. We analysed data to create codes, which were divided into categories and sub-categories. Results: A total of 20 older patients and 19 emergency clinicians were interviewed. We identified two categories based on our aims: understanding patient goals of care (sub-categories: clinician/ patient concordance; understanding underlying goals of care; underlying goals of care discrepancy) and use of 4Ms Worksheet (sub-categories: worksheet to discussion discrepancy; challenges using worksheet; challenge completing worksheet before discharge). Rates of concordance between patient and clinician on main concern/goal of care and underlying goals of care were 82.4% and 15.4%, respectively. Conclusion: We found that most patients and emergency clinicians agreed on the main goal of care, although clinicians often failed to elicit patients’ underlying goal(s) of care. Additionally, many patients preferred to have the interviewer fill out the worksheet for them. There was often discrepancy between what was written and what was discussed with the interviewer. More research is needed to determine the best way to integrate the 4Ms framework within emergency care.

Resumen: Uno de los grandes obstáculos que presenta el trasplante de órganos es el tiempo en que se puede preservar el órgano en isquemia en un estado viable antes de ser implantado. Con la utilización de la técnica estándar de conservación estática en frío (4 °C) los tiempos de conservación se limitan a 6-8 horas, tiempo conocido como tiempo de isquemia fría. Este comienza desde que se realiza el “cross clamp” o cese completo de la circulación en el donante hasta la irrigación del órgano implantado en el receptor.Recientemente se han publicado estudios preclínicos y clínicos que demuestran beneficios de conservación del injerto a 10 °C en comparación con el almacenamiento estándar, además de permitir una prolongación de los tiempos de isquemia con iguales estándares de seguridad para el receptor. Estas nuevas líneas de desarrollo apuntan a facilitar la logística del trasplante pulmonar transformándolo de una cirugía de urgencia a un proceso quirúrgico semi electivo. Dicho cambio ha demostrado beneficios en seguridad quirúrgica y resultados de sobrevida del implante aumentando los tiempos de preservación y abriendo incluso la posibilidad de abrir nuestras fronteras para programas internacionales. Abstract: One of the great obstacles for organ transplantation is the time in which the ischemic organ can be preserved in a viable state before being implanted. With the use of the standard static cold preservation technique (4 °C) preservation times are limited to 6-8 hours, a time known as cold ischemia time. This begins from the moment the “cross-clamp” or complete cessation of circulation in the donor is performed until the organ is irrigated in the recipient.Preclinical and clinical studies have recently been published demonstrating benefits of graft conservation at 10 °C compared to standard storage, in addition to allowing ischemia times to be prolonged with the same safety standards for the recipient. These new lines of development aim to facilitate the logistics of lung transplantation, transforming it from an emergency surgery to a semi-elective surgical procedure, a change that has demonstrated benefits in surgical safety and even in implant survival results.

Cardiomyopathies are major causes of heart failure. Chagas disease (CD) is caused by the parasite Trypanosoma cruzi, and it is endemic in Central and South America. Thirty percent of cases evolve into chronic chagas cardiomyopathy (CCC), which has worse prognosis as compared with other cardiomyopathies. In vivo bioenergetic analysis and ex vivo proteomic analysis of myocardial tissues highlighted worse mitochondrial dysfunction in CCC, and previous studies identified nuclear-encoded mitochondrial gene variants segregating with CCC. Here, we assessed the role of the mitochondrial genome through mtDNA copy number variations and mtDNA haplotyping and sequencing from heart or blood tissues of severe, moderate CCC and asymptomatic/indeterminate Chagas disease as well as healthy controls as an attempt to help decipher mitochondrial-intrinsic genetic involvement in Chagas disease development. We have found that the mtDNA copy number was significantly lower in CCC than in heart tissue from healthy individuals, while blood mtDNA content was similar among asymptomatic Chagas disease, moderate, and severe CCC patients. An MtDNA haplogrouping study has indicated that African haplogroups were over represented in the Chagas subject groups in comparison with healthy Brazilian individuals. The European lineage is associated with protection against cardiomyopathy and the macro haplogroup H is associated with increased risk towards CCC. Using mitochondria DNA sequencing, 84 mtDNA-encoded protein sequence pathogenic variants were associated with CCC. Among them, two variants were associated to left ventricular non-compaction and two to hypertrophic cardiomyopathy. The finding that mitochondrial protein-coding SNPs and mitochondrial haplogroups associate with risk of evolving to CCC is consistent with a key role of mitochondrial DNA in the development of chronic chagas disease cardiomyopathy.

Rhizoctonia large patch (Rhizoctonia solani AG2-2 LP) significantly reduces turfgrass quality, aesthetics, and playability. Synthetic fungicides are commonly used for managing this disease, but they present high costs, potential for fungicide resistance, and environmental concerns. We conducted in vitro assays to test the effectiveness of three biofungicides, seven synthetic fungicides, and ten combinations against R. solani. We then assessed seven spray programs that included Bacillus subtilis QST713 and propiconazole, either alone or tank-mixed, on zoysiagrass ‘El Toro’ in a growth chamber and in field trials. Biofungicide B. subtilis QST713 reduced pathogen growth by up to 100% in vitro. B. subtilis QST713 alone or combined with synthetic fungicides and/or in rotation was as effective as the standalone synthetic fungicide, reducing disease severity and AUDPC by 81 and 77% (growth chamber) and by 71 and 52% (field), respectively, while maintaining acceptable turfgrass quality. Additionally, we screened zoysiagrass genotypes and advanced breeding lines against three R. solani isolates in growth chamber studies. Five genotypes and two breeding lines demonstrated resistance to Rhizoctonia large patch across isolates, highlighting their potential for developing disease-resistant cultivars. Our findings suggest that integrating biofungicides, resistant cultivars with chemical controls offer sustainable and effective strategies for managing Rhizoctonia large patch

Objectives To estimate the shape of the causal relationship between body mass index (BMI) and mortality risk in a Mendelian randomisation framework.Design Mendelian randomisation analyses of two prospective population-based cohorts.Setting Individuals of European ancestries living in Norway or the UK.Participants 56 150 participants from the Trøndelag Health Study (HUNT) in Norway and 366 385 participants from UK Biobank recruited by postal invitation.Outcomes All-cause mortality and cause-specific mortality (cardiovascular, cancer, non-cardiovascular non-cancer).Results A previously published non-linear Mendelian randomisation analysis of these data using the residual stratification method suggested a J-shaped association between genetically predicted BMI and mortality outcomes with the lowest mortality risk at a BMI of around 25 kg/m2. However, the ‘constant genetic effect’ assumption required by this method is violated. The reanalysis of these data using the more reliable doubly-ranked stratification method provided some indication of a J-shaped relationship, but with much less certainty as there was less precision in estimates at the lower end of the BMI distribution. Evidence for a harmful effect of reducing BMI at low BMI levels was only present in some analyses, and where present, only below 20 kg/m2. A harmful effect of increasing BMI for all-cause mortality was evident above 25 kg/m2, for cardiovascular mortality above 24 kg/m2, for cancer mortality above 30 kg/m2 and for non-cardiovascular non-cancer mortality above 26 kg/m2. In UK Biobank, the association between genetically predicted BMI and mortality at high BMI levels was stronger in women than in men.Conclusion This research challenges findings from previous conventional observational epidemiology and Mendelian randomisation investigations that the lowest level of mortality risk is at a BMI level of around 25 kg/m2. Our results provide some evidence that reductions in BMI will increase mortality risk for a small proportion of the population, and clear evidence that increases in BMI will increase mortality risk for those with BMI above 25 kg/m2.

Background Medical educational societies have emphasized the inclusion of marginalized populations, including the lesbian, gay, bisexual, transgender and queer (LGBTQ+) population, in educational curricula. Lack of inclusion can contribute to health inequality and mistreatment due to unconscious bias. Little didactic time is spent on the care of LGBTQ+ individuals in emergency medicine (EM) curricula. Simulation based medical education can be a helpful pedagogy in teaching cross-cultural care and communication skills. In this study, we sought to determine the representation of the LGBTQ+ population in EM simulation curricula. We also sought to determine if representations of the LGBTQ+ population depicted stigmatized behavior. Methods We reviewed 971 scenarios from six simulation case banks for LGBTQ+ representation. Frequency distributions were determined for major demographic variables. Chi-Squared or Fisher’s Exact Test, depending on the cell counts, were used to determine if relationships existed between LGBTQ+ representation and bank type, author type, and stigmatized behavior. Results Of the 971 scenarios reviewed, eight (0.82%) scenarios explicitly represented LGBTQ+ patients, 319 (32.85%) represented heterosexual patients, and the remaining 644 (66.32%) did not specify these patient characteristics. All cases representing LGBTQ+ patients were found in institutional case banks. Three of the eight cases depicted stigmatized behavior. Conclusions LGBTQ+ individuals are not typically explicitly represented in EM simulation curricula. LGBTQ+ individuals should be more explicitly represented to reduce stigma, allow EM trainees to practice using gender affirming language, address health conditions affecting the LGBTQ+ population, and address possible bias when treating LGBTQ+ patients.

Introduction Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer’s disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD).Methods and analysis DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies.Ethics and dissemination Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Abstract The digital environment can pose health risks through exposure to unhealthy content. Yet, little is known about its relation to children’s cognitive functioning. This study investigates the association between digital media (DM) exposure and children’s cognitive functioning. This cross-sectional study is based on examinations of children aged 8–18 years (N = 8673) of the I.Family cohort (2013–2014). Exposure to television, computer, smartphone and internet was self-reported (hours/day). Media multitasking (MMT) was defined as simultaneous use of computers with other digital or non-screen-based activities. Standard instruments were used to assess cognitive inflexibility (score: 0–39), decision-making ability (− 100 to + 100) and impulsivity (12–48). Adjusted regression coefficients and 99.9%CIs were calculated by generalized linear mixed-effects models. In total, 3261 participants provided data for impulsivity, 3441 for cognitive inflexibility and 4046 for decision-making. Exposure to smartphones and media multitasking were positively associated with impulsivity (βsmartphone = 0.74; 99.9%CI = 0.42–1.07; βMMT = 0.73; 99.9%CI = 0.35–1.12) and cognitive inflexibility (βsmartphone = 0.32; 99.9%CI = -0.02–0.66; βMMT = 0.39; 99.9%CI = 0.01–0.77) while being inversely associated with decision-making ability. Extensive smartphone/internet exposure combined with low computer/medium TV exposure was associated with higher impulsivity and cognitive inflexibility scores, especially in girls. DM exposure is adversely associated with cognitive functioning in children and adolescents. Children require protection against the likely adverse impact of digital environment.

Hemoglobin C (HbC) disease is an uncommon disease that is generally considered benign, causing only occasionally painless hematuria, osteomyelitis, and dental abnormalities. Ocular manifestations have rarely been described in these patients. Here we report a novel ophthalmological manifestation of the disease. A 20-year-old woman presented with progressive visual loss in her right eye due to tractional retinal detachment. The left eye was apparently normal, but wide-field fluorescence angiography showed mild peripheral ischemia with multiple vascular abnormalities. Vitrectomy was performed and the systemic workup revealed the presence of hemoglobinopathy C in heterozygous form. HbC disease can be sight-threating due to retinal proliferation, similar to sickle cell retinopathy. Patients affected with this disease should undergo regular surveillance. Ultra-wide angiography is a helpful examination to detect peripheral ischemia in the earlier stages.

Abstract Background MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902). Methods Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy. Results Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings. Conclusions The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients.

Abstract Background Healthcare students must learn to collaborate across professional boundaries so they can make use of each other’s knowledge and competencies in a way that benefits the patient. One aspect of interprofessional collaboration implies negotiating what needs to be done and by whom. Research, focused on the conditions under which students perform this negotiation when they are working together during interprofessional clinical placement, needs to be further developed. The study therefore aimed to explore students’ negotiation of tasks and competencies when students are working together as an interprofessional team during clinical placement. Methods The study was designed as a focused ethnographic observational study. Two Nordic sites where final-year healthcare students perform clinical interprofessional education were included. Data consists of fieldnotes, together with informal conversations, group, and focus group interviews. In total, 160 h of participating observations and 3 h of interviews are included in the study. The analysis was informed by the theory on communities of practice. Results Students relate to intersecting communities of practice when they negotiate what they should do to help a patient and who should do it. When the different communities of practice align, they support students in coming to an agreement. However, these communities of practice sometimes pulled the students in different directions, and negotiations were sometimes interrupted or stranded. On those occasions, observations show how the interprofessional learning practice conflicted with either clinical practice or one of the student’s profession-specific practices. Conditions that had an impact on whether or not communities of practice aligned when students negotiated these situations proved to be ‘having time to negotiate or not’, as well as ‘feeling safe or not’. Conclusions Final-year healthcare students can negotiate who in the team has the competence suited for a specific task. However, they must adapt their negotiations to different communities of practice being enacted at the same time. Educators need to be attentive to this and make an effort to ensure that students benefit from these intersecting communities of practice, both when they align and when they are in conflict.

Abstract Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF.

Abstract Background ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy. Results We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients. Conclusion Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer’s and Parkinson’s diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.

Abstract Exopolysaccharides (EPS) are organic macromolecules naturally secreted by many microorganisms. EPS is increasingly used for agriculture and industrial purposes. This study focuses on isolate Klebsiella pneumonia SSN1, Klebsiella quasipeumonniae SGM81 isolated from rhizosphere to explore its water retention efficiency under drought conditions. Neutron Radiography was used to visualise water distribution in the sand under normal and drought conditions in the presence and absence of EPS producing bacteria. The EPS production was studied by applying Box Behnken design (BBD) under drought stress which was artificially induced by using polyethene glycol 6000 under osmotic stress condition 3.65% w/v of EPS dry weight was obtained. The relative water content (RWC) is used to calculate the amount of water present in the sand and was further studied by Neutron Radiography imaging with appropriate controls. FTIR and HPLC were also carried out for the characterisation of the extracted EPS. The sand experiments revealed that after 24 h of evaporation, the highest RWC was maintained by SSN1 at 29.7% compared to SGM81 (19.06%). SSN1 was found to release L-arabinose as the main sugar of its EPS under drought stress conditions by HPLC method. The FTIR data indicated the presence of β-glucans and polysaccharide α-pyranose between wavenumber 700 cm−1–1500 cm−1 and 1017 cm−1–1200 cm−1 respectively. The HPLC characterization of extracted EPS from osmotic stressed cells (run 3) displayed a peak designated to L-arabinose at 10.3 retention time (RT) for 132.4 mM concentration. While from run 5 with the controlled condition indicated the presence of L-rhamnose at 7.3 RT for 87 mM concentration. Neutron radiography enables the visualisation of water distribution in the sand as well as water transport in root-soil systems in situ. SSN1 has elicited EPS production in drought conditions with a low level of nitrogen and carbon.

Context: Social care need in prisons is increasing in many countries. However, the delivery of social care in prisons has been (at best) inconsistent and there has been no previous review to inform provision for people on release. Objective: To identify and synthesise what is known about the social care needs of people on release from prison and how best to meet these. Method: A scoping review encompassing systematic searches of 26 electronic databases (January 2010–July 2021) included a wide range of literature. No exclusions were made on the basis of study design, method or quality. Findings were organised according to their contribution to the research questions. Findings: Forty-six documents met the review criteria of which 27 were from the UK. Just two focused specifically on the topic of interest and most of the extracted material was descriptive in nature. Almost no information was found on the number of people released from prison in need of social care. However, the challenges of providing care for this group appeared well understood. Although there were many examples of good practice and widespread consensus about its enablers, outcome information was lacking. Limitations: In keeping with the nature of the review, the quality of the literature was not formally assessed. Implications: The review identified several promising initiatives ranging from prison buddy schemes to pre-release training in everyday living skills and personalised pathway documents. Conclusions: Policy makers and researchers must now shift their attention to the effectiveness of particular interventions in improving social care outcomes.

BackgroundPolycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women and is diagnosed using the Rotterdam criteria, including diagnosis of polycystic ovarian morphology (PCOM) by transvaginal ultrasound (TVUS). Due to high cost, availability, and the impact of the operator and ultrasound equipment on the reliability of the antral follicle count (AFC) by TVUS, an unmet need exists for a diagnostic test to determine PCOM without TVUS. A strong positive correlation between elevated anti-Müllerian hormone (AMH) levels and AFCs has been demonstrated in women with PCOS. In addition, recent updates to the international evidence-based PCOS guidelines state that serum AMH can be used as an alternative to TVUS-determined AFC, in the diagnosis of PCOM. The retrospective APHRODITE study derived and validated an AMH cutoff of 3.2 ng/mL for the Elecsys AMH Plus or Elecsys AMH assays (Roche) to diagnose PCOM in patients with PCOS. ObjectiveThis study aims to further validate, in an independent prospective cohort, the AMH cutoff (3.2 ng/mL) for PCOM determination, which was previously derived and validated in the APHRODITE study. MethodsThis large, prospective, multicenter, population-based, noninterventional study will evaluate the previously established AMH cutoff for the determination of PCOM during the diagnosis of PCOS using the Elecsys AMH Plus immunoassay in an independent population. Participants were women born between July 1985 and December 1987 in Northern Finland; the study partially links to the Northern Finland Birth Cohort 1986. We assessed the enrolled women, determined with the 2023 PCOS Guidelines, for current PCOS status and divided them by phenotype if positive. Each participant had 1 study visit to collect serum samples, record clinical data, and undergo a gynecological examination including TVUS. All data were collected by highly trained midwives or trained gynecologists. Sensitivity, specificity, and agreement measures were used to validate the previously determined cutoff in the whole population and in subpopulations based on phenotype and relevant demographic or clinical factors. The minimum target sample size was approximately 1800 women, including approximately 10% with PCOS. ResultsAt the time of manuscript submission, participant recruitment had concluded, and 1803 women were enrolled into the study. Data collection is complete and biostatistical analysis is planned for 2023. ConclusionsTo limit variability, there were few TVUS operators and only 2 TVUS machines of the same type. Additionally, all women who were taking oral contraceptives were excluded from the primary analysis population. Selection bias was limited as this was a population-based study and participants were not seeking treatment for PCOS symptoms. Validating the AMH cutoff in a large, population-based study will provide further evidence on the utility of the Elecsys AMH Plus or Elecsys AMH assays in PCOM diagnosis as an alternative to TVUS. Measuring AMH for PCOM diagnosis could reduce delayed or missed diagnoses due to operator-dependent TVUS examinations. Trial RegistrationClinicalTrials.gov NCT05527353; http://tinyurl.com/2f3ffbdz International Registered Report Identifier (IRRID)DERR1-10.2196/48854

Calcium binding protein, spermatid associated 1 (CABS1) is a protein most widely studied in spermatogenesis. However, mRNA for CABS1 has been found in numerous tissues, albeit with little information about the protein. Previously, we identified CABS1 mRNA and protein in human salivary glands and provided evidence that in humans CABS1 contains a heptapeptide near its carboxyl terminus that has anti-inflammatory activities. Moreover, levels of an immunoreactive form of CABS1 were elevated in psychological stress. To more fully characterize human CABS1 we developed additional polyclonal and monoclonal antibodies to different sections of the protein and used these antibodies to characterize CABS1 in an overexpression cell lysate, human salivary glands, saliva, serum and testes using western blot, immunohistochemistry and bioinformatics approaches exploiting the Gene Expression Omnibus (GEO) database. CABS1 appears to have multiple molecular weight forms, consistent with its recognition as a structurally disordered protein, a protein with structural plasticity. Interestingly, in human testes, its cellular distribution differs from that in rodents and pigs, and includes Leydig cells, primary spermatogonia, Sertoli cells and developing spermatocytes and spermatids, Geodata suggests that CABS1 is much more widely distributed than previously recognized, including in the urogenital, gastrointestinal and respiratory tracts, as well as in the nervous system, immune system and other tissues. Much remains to be learned about this intriguing protein.

BackgroundSocial prescribing interventions connect mental health service users to community resources, to support physical and mental wellbeing and promote recovery. COVID-19 restrictions impacted the delivery of socially prescribed activities, preventing face to face contact for long periods.AimsThe aim of this study was to understand how Voluntary Community and Social Enterprise (VCSE) organisations working with a local NHS mental health Trust responded to the challenges of social distancing during the COVID-19 pandemic. This understanding will be used to make recommendations for future practice, post-lockdown.MethodsUsing a convergent mixed methods design, we surveyed VCSE providers of socially prescribed activities intended to be accessible and appropriate for people with severe mental health needs. Follow-up interviews explored further how they adapted during the first year of the pandemic, the challenges they faced, and how they sought to overcome them. The survey and interview data were analysed separately and then compared to identify convergent and divergent findings.ResultsTwenty VCSE representatives completed the survey which provided a snapshot of changes in levels of connection and numbers reached during lockdown. Of 20 survey respondents, 11 participated in follow-up interviews. Interviews revealed that lockdown necessitated rapid change and responsive adaptation; activities were limited by resource, funding, safeguarding and government restrictions; no single format suited all group members; connection was key; and impact was difficult to gauge.ConclusionsVCSE organisations commissioned to deliver creative socially prescribed activities during the pandemic rapidly adapted their offer to comply with government restrictions. Responsive changes were made, and new knowledge and skills were gained. Drawing on experiences during lockdown, VCSE organisations should develop bespoke knowledge, skills and practices to engage service users in future hybrid delivery of arts, sports, cultural and creative community activities, and to ensure that digital activities offer an equivalent degree of connection to face-to-face ones. Additionally, more effective methods of gaining feedback about patient experience of hybrid delivery is needed.

Anoxia in the mammalian brain leads to hyper-excitability and cell death; however, this cascade of events does not occur in the anoxia-tolerant brain of the western painted turtle, Chrysemys picta belli. The painted turtle has become an important anoxia-tolerant model to study brain, heart, and liver function in the absence of oxygen, but being anoxia-tolerant likely means that decapitation alone is not a suitable method of euthanasia. Many anesthetics have long-term effects on ion channels and are not appropriate for same day experimentation. Using whole-cell electrophysiological techniques, we examine the effects of the anesthetic, Alfaxalone, on pyramidal cell action potential amplitude, threshold, rise and decay time, width, frequency, whole cell conductance, and evoked GABAA receptors currents to determine if any of these characteristics are altered with the use of Alfaxalone for animal sedation. We find that Alfaxalone has no long-term impact on action potential parameters or whole-cell conductance. When acutely applied to naïve tissue, Alfaxalone did lengthen GABAA receptor current decay rates by 1.5-fold. Following whole-animal sedation with Alfaxalone, evoked whole cell GABAA receptor current decay rates displayed an increasing trend with 1 and 2 hours after brain sheet preparation, but showed no significant change after a 3-hour washout period. Therefore, we conclude that Alfaxalone is a suitable anesthetic for same day use in electrophysiological studies in western painted turtle brain tissue.

Alzheimer's disease (AD) is the most common neuronal disorder that leads to the development of dementia. Until nowadays, some therapies may alleviate the symptoms, but there is no pharmacological treatment. Microdosing lithium has been used to modify the pathological characteristics of the disease, with effects in both experimental and clinical conditions. The present work aimed to analyze the effects of this treatment on spatial memory, anxiety, and molecular mechanisms related to long-term memory formation during the aging process of a mouse model of accelerated aging (SAMP-8). Female SAMP-8 showed learning and memory impairments together with disruption of memory mechanisms, neuronal loss, and increased density of senile plaques compared to their natural control strain, the senescence-accelerated mouse resistant (SAMR-1). Chronic treatment with lithium promoted memory maintenance, reduction in anxiety, and maintenance of proteins related to memory formation and neuronal density. The density of senile plaques was also reduced. An increase in the density of gamma-aminobutyric acid A (GABAA) and α7 nicotinic cholinergic receptors was also observed and related to neuroprotection and anxiety reduction. In addition, this microdose of lithium inhibited the activation of glycogen synthase kinase-3beta (GSK-3β), the classical mechanism of lithium cell effects, which could contribute to the preservation of the memory mechanism and reduction in senile plaque formation. This work shows that lithium effects in neuroprotection along the aging process are not related to a unique cellular mechanism but produce multiple effects that slowly protect the brain along the aging process.

Introduction Visceral leishmaniasis (VL) is a parasitic disease with an estimated 30 000 new cases occurring annually. Despite anaemia being a common haematological manifestation of VL, the evolution of different haematological characteristics following treatment remains poorly understood. An individual participant data meta-analysis (IPD-MA) is planned to characterise the haematological dynamics in patients with VL.Methods and analysis The Infectious Diseases Data Observatory (IDDO) VL data platform is a global repository of IPD from therapeutic studies identified through a systematic search of published literature (PROSPERO registration: CRD42021284622). The platform currently holds datasets from clinical trials standardised to a common data format. Corresponding authors and principal investigators of the studies indexed in the IDDO VL data platform meeting the eligibility criteria for inclusion were invited to be part of the collaborative IPD-MA. Mixed-effects multivariable regression models will be constructed to identify determinants of haematological parameters by taking clustering within study sites into account.Ethics and dissemination This IPD-MA meets the criteria for waiver of ethical review as defined by the Oxford Tropical Research Ethics Committee (OxTREC) granted to IDDO, as the research consists of secondary analysis of existing anonymised data (exempt granted on 29 March 2023, OxTREC REF: IDDO). Ethics approval was granted by the ICMR-Rajendra Memorial Research Institute of Medical Sciences ethics committee (letter no.: RMRI/EC/30/2022) on 4 July 2022. The results of this analysis will be disseminated at conferences, the IDDO website and peer-reviewed publications in open-access journals. The findings of this research will be critically important for control programmes at regional and global levels, policymakers and groups developing new VL treatments.PROSPERO registration number CRD42021284622.

Abstract Recent advances in optical underwater imaging technologies enable the acquisition of huge numbers of high-resolution seafloor images during scientific expeditions. While these images contain valuable information for non-invasive monitoring of megabenthic fauna, flora and the marine ecosystem, traditional labor-intensive manual approaches for analyzing them are neither feasible nor scalable. Therefore, machine learning has been proposed as a solution, but training the respective models still requires substantial manual annotation. Here, we present an automated image-based workflow for Megabenthic Fauna Detection with Faster R-CNN (FaunD-Fast). The workflow significantly reduces the required annotation effort by automating the detection of anomalous superpixels, which are regions in underwater images that have unusual properties relative to the background seafloor. The bounding box coordinates of the detected anomalous superpixels are proposed as a set of weak annotations, which are then assigned semantic morphotype labels and used to train a Faster R-CNN object detection model. We applied this workflow to example underwater images recorded during cruise SO268 to the German and Belgian contract areas for Manganese-nodule exploration, within the Clarion–Clipperton Zone (CCZ). A performance assessment of our FaunD-Fast model showed a mean average precision of 78.1% at an intersection-over-union threshold of 0.5, which is on a par with competing models that use costly-to-acquire annotations. In more detail, the analysis of the megafauna detection results revealed that ophiuroids and xenophyophores were among the most abundant morphotypes, accounting for 62% of all the detections within the surveyed area. Investigating the regional differences between the two contract areas further revealed that both megafaunal abundance and diversity was higher in the shallower German area, which might be explainable by the higher food availability in form of sinking organic material that decreases from east-to-west across the CCZ. Since these findings are consistent with studies based on conventional image-based methods, we conclude that our automated workflow significantly reduces the required human effort, while still providing accurate estimates of megafaunal abundance and their spatial distribution. The workflow is thus useful for a quick but objective generation of baseline information to enable monitoring of remote benthic ecosystems.

Abstract Spatial hearing remains one of the major challenges for bilateral cochlear implant (biCI) users, and early deaf patients in particular are often completely insensitive to interaural time differences (ITDs) delivered through biCIs. One popular hypothesis is that this may be due to a lack of early binaural experience. However, we have recently shown that neonatally deafened rats fitted with biCIs in adulthood quickly learn to discriminate ITDs as well as their normal hearing litter mates, and perform an order of magnitude better than human biCI users. Our unique behaving biCI rat model allows us to investigate other possible limiting factors of prosthetic binaural hearing, such as the effect of stimulus pulse rate and envelope shape. Previous work has indicated that ITD sensitivity may decline substantially at the high pulse rates often used in clinical practice. We therefore measured behavioral ITD thresholds in neonatally deafened, adult implanted biCI rats to pulse trains of 50, 300, 900 and 1800 pulses per second (pps), with either rectangular or Hanning window envelopes. Our rats exhibited very high sensitivity to ITDs at pulse rates up to 900 pps for both envelope shapes, similar to those in common clinical use. However, ITD sensitivity declined to near zero at 1800 pps, for both Hanning and rectangular windowed pulse trains. Current clinical cochlear implant (CI) processors are often set to pulse rates ≥ 900 pps, but ITD sensitivity in human CI listeners has been reported to decline sharply above ~ 300 pps. Our results suggest that the relatively poor ITD sensitivity seen at > 300 pps in human CI users may not reflect the hard upper limit of biCI ITD performance in the mammalian auditory pathway. Perhaps with training or better CI strategies good binaural hearing may be achievable at pulse rates high enough to allow good sampling of speech envelopes while delivering usable ITDs.

BACKGROUND Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODS In this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTS Plerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSION Plerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATION Clinicaltrials.gov NCT02231879.FUNDING This study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Introduction Visceral leishmaniasis (VL) is a parasitic disease with an estimated 30 000 new cases occurring annually. There is an observed variation in the efficacy of the current first-line therapies across different regions. Such heterogeneity could be a function of host, parasite and drug factors. An individual participant data meta-analysis (IPD-MA) is planned to explore the determinants of treatment outcomes.Methods and analysis The Infectious Diseases Data Observatory (IDDO) VL living systematic review (IDDO VL LSR) library is an open-access resource of all published therapeutic studies in VL since 1980. For this current review, the search includes all clinical trials published between 1 January 1980 and 2 May 2021. Studies indexed in the IDDO VL LSR library were screened for eligibility for inclusion in this IPD-MA. Corresponding authors and principal investigators of the studies meeting the eligibility criteria for inclusion were invited to be part of the collaborative IPD-MA. Authors agreeing to participate in this collaborative research were requested to share the IPD using the IDDO VL data platform. The IDDO VL data platform currently holds data sets from clinical trials standardised to a common data format and provides a unique opportunity to identify host, parasite and drug determinants of treatment outcomes. Multivariable regression models will be constructed to identify determinants of therapeutic outcomes using generalised linear mixed-effects models accounting for within-study site clustering.Ethics and dissemination This IPD-MA meets the criteria for waiver of ethical review as defined by the Oxford Tropical Research Ethics Committee (OxTREC) granted to IDDO, as the research consists of secondary analysis of existing anonymised data (Exempt granted on 29 March 2023, OxTREC REF: IDDO) Ethics approval was granted by the ICMR-Rajendra Memorial Research Institute of Medical Sciences ethics committee (Letter no: RMRI/EC/30/2022) on 04-07-2022. The results of this IPD-MA will be disseminated at conferences, IDDO website and any peer-reviewed publications. All publications will be open source. Findings of this research will be critically important for the control programmes at regional/global levels, policy makers and groups developing new VL treatments.PROSPERO registration CRD42021284622.

Aging is often accompanied by health events that may disrupt older adults’ desires to age in place. Understanding older adults’ perceptions of planning for their aging process was a priority to identify how planning behaviors occur. Our study explored how people perceive the concept of planning for aging and frailty, and identified the facilitators and barriers involved in the planning process. Using conventional qualitative content analysis, we used the data from semi-structured interviews of twenty community-dwelling older adults aged 50–80 years old. Demographic information was obtained, followed by the participant interviews. Seventeen code categories surfaced including six categories in the perception domain (i.e., internal, external, and future-oriented), seven categories in the facilitators domain (i.e., internal, external, and systems), and four categories in the barriers domain (i.e., internal, and systems). The emergent categories included understanding one’s perception of planning through a holistic lens, the importance of experiences with self/others as facilitators, and the physical/cognitive/emotional factors that serve as barriers within a larger sphere of societal influence. Planning for aging and frailty is an innovative concept that normalizes the aging process and promotes planning through an awareness of aging across the life-course domains. Future research is warranted for intervention development to help older adults recognize and actively plan for aging and to address the barriers involved.

Abstract In cirrhotic patients with hepatocellular carcinoma (HCC), right-sided radioembolization (RE) with Yttrium-90-loaded microspheres is an established palliative therapy and can be considered a “curative intention” treatment when aiming for sequential tumor resection. To become surgical candidate, hypertrophy of the left liver lobe to > 40% (future liver remnant, FLR) is mandatory, which can develop after RE. The amount of radiation-induced shrinkage of the right lobe and compensatory hypertrophy of the left lobe is difficult for clinicians to predict. This study aimed to utilize machine learning to predict left lobe liver hypertrophy in patients with HCC and cirrhosis scheduled for right lobe RE, with external validation. The results revealed that machine learning can accurately predict relative and absolute volume changes of the left liver lobe after right lobe RE. This prediction algorithm could help to estimate the chances of conversion from palliative RE to curative major hepatectomy following significant FLR hypertrophy.

Abstract Background Iron supplementation and erythropoiesis-stimulating agent (ESA) administration represent the hallmark therapies in preoperative anemia treatment, as reflected in a set of evidence-based treatment recommendations made during the 2018 International Consensus Conference on Patient Blood Management. However, little is known about the safety of these therapies. This systematic review investigated the occurrence of adverse events (AEs) during or after treatment with iron and/or ESAs. Methods Five databases (The Cochrane Library, MEDLINE, Embase, Transfusion Evidence Library, Web of Science) and two trial registries (ClinicalTrials.gov, WHO ICTRP) were searched until 23 May 2022. Randomized controlled trials (RCTs), cohort, and case-control studies investigating any AE during or after iron and/or ESA administration in adult elective surgery patients with preoperative anemia were eligible for inclusion and judged using the Cochrane Risk of Bias tools. The GRADE approach was used to assess the overall certainty of evidence. Results Data from 26 RCTs and 16 cohort studies involving a total of 6062 patients were extracted, on 6 treatment comparisons: (1) intravenous (IV) versus oral iron, (2) IV iron versus usual care/no iron, (3) IV ferric carboxymaltose versus IV iron sucrose, (4) ESA+iron versus control (placebo and/or iron, no treatment), (5) ESA+IV iron versus ESA+oral iron, and (6) ESA+IV iron versus ESA+IV iron (different ESA dosing regimens). Most AE data concerned mortality/survival (n=24 studies), thromboembolic (n=22), infectious (n=20), cardiovascular (n=19) and gastrointestinal (n=14) AEs. Very low certainty evidence was assigned to all but one outcome category. This uncertainty results from both the low quantity and quality of AE data due to the high risk of bias caused by limitations in the study design, data collection, and reporting. Conclusions It remains unclear if ESA and/or iron therapy is associated with AEs in preoperatively anemic elective surgery patients. Future trial investigators should pay more attention to the systematic collection, measurement, documentation, and reporting of AE data.

Abstract Alpha-1 antitrypsin deficiency (AATD, OMIM #613490) is a rare metabolic disorder affecting lungs and liver. The purpose of this study is to assess the impact of the US orphan drug act on AATD by providing a quantitative clinical-regulatory insight into the status of FDA orphan drug approvals and designations for compounds intended to treat AATD. This is across-sectional analysis of the FDA database for orphan drug designations. Primary endpoint: orphan drug approvals. Secondary endpoint: orphan drug designations by the FDA. Close of database was 16 July 2021. STROBE criteria were respected. Primary outcome: one compound, alpha-1-proteinase inhibitor (human) was approved as an orphan drug in 1987 with market exclusivity until 1994. Secondary outcome: sixteen compounds received FDA orphan drug designation including protein, anti-inflammatory, mucolytic, gene, or cell therapy. Drug development activities in AATD were comparable to other rare conditions and led to the FDA-approval of one compound, based on a relatively simple technological platform. The current unmet medical need to be addressed are extrapulmonary manifestations, in this case the AATD-associated liver disease. Orphan drug development is actually focusing on (1) diversified recombinant AAT production platforms, and (2) innovative gene therapies, which may encompass a more holistic therapeutic approach.

Abstract The internal mechanisms responsible for modulating physiological condition, particularly those performed by the gut microbiome (GMB), remain under-explored in wildlife. However, as latitudinal and seasonal shifts in resource availability occur, the myriad micro-ecosystem services facilitated by the GMB may be especially important to wildlife health and resilience. Here, we use brown bears (Ursus arctos) as an ecological model to quantify the relationship between wildlife body condition metrics that are commonly used to assess individual and population-level health and GMB community composition and structure. To achieve these aims, we subsampled brown bear fecal samples collected during United States National Park Service research activities at three National Parks and Preserves (Katmai, Lake Clark, and Gates of the Arctic) and extracted microbial DNA for 16S rRNA amplicon sequencing and microbial taxonomic classification. We analyzed GMB communities using alpha diversity indices, subsequently using Spearman’s correlation analysis to examine relationships between alpha diversity and brown bear health metrics. We found no differences in GMB composition among bears with differing body conditions, nor any correlations between alpha diversity and body condition. Our results indicate that GMB composition reflects diverse foraging strategies while allowing brown bears to achieve similar body condition outcomes.

ABSTRACT Objective To reduce surgical center idleness by analyzing the competitive structure of the surgical center in a hospital, and thereby generate value in operations and increase hospital revenue. Methods The study used qualitative and quantitative methods and an action research approach involving the surgical center leadership of a small private specialized hospital in southeastern Brazil. We used the Strengths, Weaknesses, Opportunities, and Threats or SWOT tool to analyze the competitive structure of the surgical center and then implemented interventions as proposed by the science of improvement method proposed by the Institute of Healthcare Improvement. Results By applying the SWOT tool, we identified a concentration of surgeries in the specialty of Otolaryngology and the need to establish a health management system to reduce the idleness of the operating rooms. Based on subsequent intervention, procedures from other specialties were inserted that increased surgical production by 2.62X, reduced idleness by 67.84%, and increased revenue by over US$ 276,609.87 in 2018 compared to the previous year 2017. Conclusion Investing in quality, surgical schedule management, and inducting new surgeons to the clinical staff resulted in decreased surgical idleness, increased production, better uniformity in scheduling, and increased revenue, while costs remained below the linear trend, allowing for increased profits.

The COVID-19 pandemic’s dramatic impact has been a vivid reminder that vaccines—especially in the context of infectious respiratory viruses—provide enormous societal value, well beyond the healthcare system perspective which anchors most Health Technology Assessment (HTA) and National Immunization Technical Advisory Group (NITAG) evaluation frameworks. Furthermore, the development of modified ribonucleic acid-based (mRNA-based) and nanoparticle vaccine technologies has brought into focus several new value drivers previously absent from the discourse on vaccines as public health interventions such as increased vaccine adaptation capabilities, the improved ability to develop combination vaccines, and more efficient vaccine manufacturing and production processes. We review these novel value dimensions and discuss how they might be measured and incorporated within existing value frameworks using existing methods. To realize the full potential of next-generation vaccine platforms and ensure their widespread availability across populations and health systems, it is important that value frameworks utilized by HTAs and NITAGs properly reflect the full range of benefits for population health and well-being and cost efficiencies that these new vaccines platforms provide.

Evaluating the experiences of persons with spinal cord injury (PwSCI) regarding their transitions in care and changes in health, function, and quality of life is complex, fragmented, and involves multiple tools and measures. A staged protocol was implemented with PwSCI and relevant expert stakeholders initially exploring and selecting existing measures or tools through a modified Delphi process, followed by choosing one of two options. The options were to either support the use of the 10 selected tools from the Delphi method or to co-develop one unique condensed tool with relevant measures to evaluate all four domains. The stakeholders chose to co-develop one tool to be used by persons with SCI to monitor their transition experiences across settings and care providers. This includes any issues with care or support they needed to address at the time of discharge from acute care or rehabilitation and in the community at 3, 6, and 12 months or longer post-discharge. Once developed, the tool was made available online for the final stage of the protocol, which proposes that the tool be reliability tested prior to its launch, followed by validation testing by PwSCI.

Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As further treatment options are needed and ACC metastases are sensitive to external beam radiation, novel theranostic approaches could complement established therapeutic concepts. Recent developments focus on targeting adrenal cortex-specific enzymes like the theranostic twin [123/131I]IMAZA that shows a good image quality and a promising therapeutic effect in selected patients. But other established molecular targets in nuclear medicine such as the C-X-C motif chemokine receptor 4 (CXCR4) could possibly enhance the therapeutic regimen as well in a subgroup of patients. The aims of this review are to give an overview of innovative radiopharmaceuticals for the treatment of ACC and to present the different molecular targets, as well as to show future perspectives for further developments since a radiopharmaceutical with a broad application range is still warranted.

Kisspeptins (KPs, KISS1) and their receptor (KISS1R) play a pivotal role as metastasis suppressor for many cancers. Low or lost KP expression is associated with higher tumor grade, increased metastatic potential, and poor prognosis. Therefore, KP expression has prognostic relevance and correlates with invasiveness in cancers. Furthermore, KISS1R represents a very promising target for molecular imaging and therapy for KISS1R-expressing tumors. The goal of this study was to evaluate the developed KISS1-54 derivative, [68Ga]KISS1-54, as a PET-imaging probe for KISS1R-expressing tumors. The NODAGA-KISS1-54 peptide was labeled by Gallium-68, and the stability of the resulting [68Ga]KISS1-54 evaluated in injection solution and human serum, followed by an examination in different KISS1R-expressing tumor cell lines, including HepG2, HeLa, MDA-MB-231, MCF7, LNCap, SK-BR-3, and HCT116. Finally, [68Ga]KISS1-54 was tested in LNCap- and MDA-MB-231-bearing mice, using µ-PET, assessing its potential as an imaging probe for PET. [68Ga]KISS1-54 was obtained in a 77 ± 7% radiochemical yield and at a >99% purity. The [68Ga]KISS1-54 cell uptake amounted to 0.6–4.4% per 100,000 cells. Moreover, the accumulation of [68Ga]KISS1-54 was effectively inhibited by nonradioactive KISS1-54. In [68Ga]KISS1-54-PET, KISS1R-positive LNCap-tumors were clearly visualized as compared to MDA-MB-231-tumor implant with predominantly intracellular KISS1R expression. Our first results suggest that [68Ga]KISS1-54 is a promising candidate for a radiotracer for targeting KISS1R-expressing tumors via PET.

Abstract The growing interest and clinical translation of alpha particle (α) therapies brings with it new challenges to assess target cell engagement and to monitor therapeutic effect. Noninvasive imaging has great potential to guide α-treatment and to harness the potential of these agents in the complex environment of disseminated disease. Poly(ADP) ribose polymerase 1 (PARP-1) is among the most abundantly expressed DNA repair enzymes with key roles in multiple repair pathways—such as those induced by irradiation. Here, we used a third-generation PARP1-specific radiotracer, [18F]-PARPZ, to delineate castrate resistant prostate cancer xenografts. Following treatment with the clinically applied [225Ac]-PSMA-617, positron emission tomography was performed and correlative autoradiography and histology acquired. [18F]-PARPZ was able to distinguish treated from control (saline) xenografts by increased uptake. Kinetic analysis of tracer accumulation also suggests that the localization of the agent to sites of increased PARP-1 expression is a consequence of DNA damage response. Together, these data support expanded investigation of [18F]-PARPZ to facilitate clinical translation in the ⍺-therapy space.

Abstract Materials with insulator-metal transitions promise advanced functionalities for future information technology. Patterning on the microscale is key for miniaturized functional devices, but material properties may vary spatially across microstructures. Characterization of these miniaturized devices requires electronic structure probes with sufficient spatial resolution to understand the influence of structure size and shape on functional properties. The present study demonstrates the use of imaging soft X-ray absorption spectroscopy with a spatial resolution better than 2 $$\upmu$$ μ m to study the insulator-metal transition in vanadium dioxide thin-film microstructures. This novel technique reveals that the transition temperature for the conversion from insulating to metallic vanadium dioxide is lowered by 1.2 K ± 0.4 K close to the structure edges compared to the center. Facilitated strain release during the phase transition is discussed as origin of the observed behavior. The experimental approach enables a detailed understanding of how the electronic properties of quantum materials depend on their patterning at the micrometer scale.

Abstract Background and Aims The population of older adults in rural areas is rising, and they experience higher rates of poverty and chronic illness, have poorer health behaviors, and experience different challenges than those in urban areas. This scoping review seeks to (1) map the state of the science of age‐friendly systems in rural areas regarding structural characteristics, processes for delivering age‐friendly practices, and outcomes of age‐friendly systems, (2) analyze strengths, weakness, opportunities, and threats of age‐friendly system implementation, and (3) make person, practice, and policy‐level recommendations to support active aging and development of age‐friendly communities. Methods An international scoping review was conducted of articles that used age‐friendly framing, had a sample age of 45 years of age or older, self‐identified as rural, and reported empiric data. Searches were conducted in PubMed, CINAHL, AgeLine, PsychINFO, EMBASE, Scopus, and Academic Search Elite on October 26, 2021, and rerun March 10, 2023. Data were charted across three analytic layers: socioecological model, Donabedian's framework, and SWOT analysis. Results Results reveal limited data on outcomes relevant to organizations, such as return on investment or healthcare utilization. While the SWOT analysis revealed many strengths of age‐friendly systems, including their impact on persons' outcomes, it also revealed several weaknesses, threats, and gaps. Namely, age‐friendly systems have weaknesses due to reliance on trained volunteers and staff, communication, and teamwork. System‐level threats include community and health system barriers, and challenges in poor/developing areas. Conclusions While age‐friendly systems in this review were heterogeneous, there is an opportunity to focus on unifying elements including the World Health Organization age‐friendly cities framework or 4Ms framework for age‐friendly care. Despite the many benefits of age‐friendly systems, we must acknowledge limitations of the evidence base, pursue opportunities to examine organizational metrics to support implementation and sustainability of age‐friendly systems, and leverage improvements in age‐friendliness at a community level.

Fenestrated and blood-brain barrier (BBB)-forming endothelial cells constitute major brain capillaries, and this vascular heterogeneity is crucial for region-specific neural function and brain homeostasis. How these capillary types emerge in a brain region-specific manner and subsequently establish intra-brain vascular heterogeneity remains unclear. Here, we performed a comparative analysis of vascularization across the zebrafish choroid plexuses (CPs), circumventricular organs (CVOs), and retinal choroid, and show common angiogenic mechanisms critical for fenestrated brain capillary formation. We found that zebrafish deficient for Gpr124, Reck, or Wnt7aa exhibit severely impaired BBB angiogenesis without any apparent defect in fenestrated capillary formation in the CPs, CVOs, and retinal choroid. Conversely, genetic loss of various Vegf combinations caused significant disruptions in Wnt7/Gpr124/Reck signaling-independent vascularization of these organs. The phenotypic variation and specificity revealed heterogeneous endothelial requirements for Vegfs-dependent angiogenesis during CP and CVO vascularization, identifying unexpected interplay of Vegfc/d and Vegfa in this process. Mechanistically, expression analysis and paracrine activity-deficient vegfc mutant characterization suggest that endothelial cells and non-neuronal specialized cell types present in the CPs and CVOs are major sources of Vegfs responsible for regionally restricted angiogenic interplay. Thus, brain region-specific presentations and interplay of Vegfc/d and Vegfa control emergence of fenestrated capillaries, providing insight into the mechanisms driving intra-brain vascular heterogeneity and fenestrated vessel formation in other organs.

A small percentage of bladder cancers in the general population have been found to harbor DNA viruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer and have an overall poorer outcomes, harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from potential oncoviruses, we performed whole genome and transcriptome sequencing on bladder cancer specimens from 43 transplant patients. Nearly half of the tumors from this patient population contained viral sequences. The most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). Immunohistochemistry revealed variable Large T antigen expression in BKPyV-positive tumors ranging from 100% positive staining of tumor tissue to less than 1%. In most cases of BKPyV-positive tumors, the viral genome appeared to be clonally integrated into the host chromosome consistent with microhomology-mediated end joining and coincided with focal amplifications of the tumor genome similar to other virus-mediated cancers. Significant changes in host gene expression consistent with the functions of BKPyV Large T antigen were also observed in these tumors. Lastly, we identified four mutation signatures in our cases, with those attributable to APOBEC3 and SBS5 being the most abundant. Mutation signatures associated with an antiviral drug, ganciclovir, and aristolochic acid, a nephrotoxic compound found in some herbal medicines, were also observed. The results suggest multiple pathways to carcinogenesis in solid organ transplant recipients with a large fraction being virus-associated.