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Abstract Background The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better understand patterns and potential causes of genomic instability. Patients and methods Homologous recombination deficiency (HRD) was assessed in 2147 tumor samples from SOLO1, PAOLA-1, Study 19, SOLO2, OPINION, and LIGHT using next-generation sequencing technology. Genomic instability scores (GIS) were assessed in BRCA1 and/or BRCA2 (BRCA)-mutated (BRCAm), non-BRCA homologous recombination repair-mutated (non-BRCA HRRm), and non-HRRm tumors. Results BRCAm was identified in 1021/2147 (47.6%) tumors. BRCAm tumors had significantly higher GIS than non-BRCAm tumors (P

Abstract The Tri-Service Microbiome Consortium (TSMC) was founded to enhance collaboration, coordination, and communication of microbiome research among DoD organizations and to facilitate resource, material and information sharing among consortium members, which includes collaborators in academia and industry. The 2023 annual symposium was a hybrid meeting held in Washington DC on 26–27 September 2023 concurrent with the virtual attendance, with oral and poster presentations and discussions centered on microbiome-related topics within five broad thematic areas: 1) Environmental Microbiome Characterization; 2) Microbiome Analysis; 3) Human Microbiome Characterization; 4) Microbiome Engineering; and 5) In Vitro and In Vivo Microbiome Models. Collectively, the symposium provided an update on the scope of current DoD and DoD-affiliated microbiome research efforts and fostered collaborative opportunities. This report summarizes the presentations and outcomes of the 7th annual TSMC symposium.

Sensorimotor reflex circuits engage distinct neuronal subtypes, defined by precise connectivity, to transform sensation into compensatory behavior. Whether and how motor neuron populations specify the subtype fate and/or sensory connectivity of their pre-motor partners remains controversial. Here, we discovered that motor neurons are dispensable for proper connectivity in the vestibular reflex circuit that stabilizes gaze. We first measured activity following vestibular sensation in pre-motor projection neurons after constitutive loss of their extraocular motor neuron partners. We observed normal responses and topography indicative of unchanged functional connectivity between sensory neurons and projection neurons. Next, we show that projection neurons remain anatomically and molecularly poised to connect appropriately with their downstream partners. Lastly, we show that the transcriptional signatures that typify projection neurons develop independently of motor partners. Our findings comprehensively overturn a long-standing model: that connectivity in the circuit for gaze stabilization is retrogradely determined by motor partner-derived signals. By defining the contribution of motor neurons to specification of an archetypal sensorimotor circuit, our work speaks to comparable processes in the spinal cord and advances our understanding of principles of neural development.

Numerous aspects of cellular signaling are regulated by the kinome—the network of over 500 protein kinases that guides and modulates information transfer throughout the cell. The key role played by both individual kinases and assemblies of kinases organized into functional subnetworks leads to kinome dysregulation driving many diseases, particularly cancer. In the case of pancreatic ductal adenocarcinoma (PDAC), a variety of kinases and associated signaling pathways have been identified for their key role in the establishment of disease as well as its progression. However, the identification of additional relevant therapeutic targets has been slow and is further confounded by interactions between the tumor and the surrounding tumor microenvironment. In this work, we attempt to link the state of the human kinome, or kinotype, with cell viability in treated, patient-derived PDAC tumor and cancer-associated fibroblast cell lines. We applied classification models to independent kinome perturbation and kinase inhibitor cell screen data, and found that the inferred kinotype of a cell has a significant and predictive relationship with cell viability. We further find that models are able to identify a set of kinases whose behavior in response to perturbation drive the majority of viability responses in these cell lines, including the understudied kinases CSNK2A1/3, CAMKK2, and PIP4K2C. We next utilized these models to predict the response of new, clinical kinase inhibitors that were not present in the initial dataset for model devlopment and conducted a validation screen that confirmed the accuracy of the models. These results suggest that characterizing the perturbed state of the human protein kinome provides significant opportunity for better understanding of signaling behavior and downstream cell phenotypes, as well as providing insight into the broader design of potential therapeutic strategies for PDAC.

Later eating rhythm (LER) refers to later timing, greater energy intake (EI), and higher frequency of eating occasions (meal/snack) in the evening. The significance of LER in child health is becoming increasingly recognised. However, the lack of consensus regarding definitions of LER make it challenging to fully comprehend its role. This data note describes LER variables derived in the Avon Longitudinal Study of Parents and Children (ALSPAC), an ongoing birth cohort which enrolled 14,541 pregnant women living in Avon, UK, with an expected date of delivery between April 1991 - December 1992. When children were 7 years, parents completed a structured 3-day food diary, recording all foods/drinks consumed over 3 days (preferably 1 weekend day and 2 weekdays). Data was available for 7,285 children (50.1% response rate). A subsample of 4,869 children had exact time of eating occasions added to the existing database, which only included broad indications of eating timing based on 2-7 hour long meal slots. 13 LER variables were derived for the entire week and weekdays/weekend days separately. These comprise: 1) eating around individual bedtime (number days); 2) eating around average bedtime (number days); 3) time of evening main meal (hrs:mins); 4) time of last eating occasion (hrs:mins); 5) EI in the evening (percentage of total daily energy intake, %TDEI); 6) EI within 2hrs before bedtime (%TDEI); 7) EI for evening main meal (%TDEI); 8) EI for evening snacks (%TDEI); 9) Night eating1 (NE1): eating over 30% of total daily energy intake after 18:00 (number days); 10) NE2: eating over 25% of total daily energy intake within 2hrs before bedtime (number days); 11) eating frequency after 17:00 (number of eating occasions); 12) regularity of dinner (number of days); 13) frequency of evening snacks (number days). We describe the derivation, prevalence and inter-corelations between LER variables.

Maternal choline supplementation (MCS) improves cognition in Alzheimer’s disease (AD) models. However, the effects of MCS on neuronal hyperexcitability in AD are unknown. We investigated the effects of MCS in a well-established mouse model of AD with hyperexcitability, the Tg2576 mouse. The most common type of hyperexcitability in Tg2576 mice are generalized EEG spikes (interictal spikes [IIS]). IIS also are common in other mouse models and occur in AD patients. In mouse models, hyperexcitability is also reflected by elevated expression of the transcription factor ∆FosB in the granule cells (GCs) of the dentate gyrus (DG), which are the principal cell type. Therefore, we studied ΔFosB expression in GCs. We also studied the neuronal marker NeuN within hilar neurons of the DG because reduced NeuN protein expression is a sign of oxidative stress or other pathology. This is potentially important because hilar neurons regulate GC excitability. Tg2576 breeding pairs received a diet with a relatively low, intermediate, or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC ∆FosB expression was reduced, and hilar NeuN expression was restored. Using the novel object location task, spatial memory improved. In contrast, offspring exposed to the relatively low choline diet had several adverse effects, such as increased mortality. They had the weakest hilar NeuN immunoreactivity and greatest GC ΔFosB protein expression. However, their IIS frequency was low, which was surprising. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have mixed effects. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, ΔFosB, and spatial memory in an animal model of AD.

Abstract Dysfunctional fear responses in post-traumatic stress disorder (PTSD) may be partly explained by an inability to effectively extinguish fear responses elicited by trauma-related cues. However, only a subset of individuals exposed to traumatic stress develop PTSD. Therefore, studying fear extinction deficits in animal models of individual differences could help identify neural substrates underlying vulnerability or resilience to the effects of stress. We used a rat model of social defeat in which rats segregate into passively and actively coping rats. In previous work, we showed that passively coping rats exhibit disruptions in social interaction whereas actively coping rats do not display behaviors differently from controls, indicating their resilience. Here, adult male rats exposed to 7 days of social defeat were tested for fear extinction, retention of extinction, and persistence of retention using contextual fear and ethologically-relevant fear tests. Passively coping rats exhibited elevated freezing in response to the previously extinguished context. Analyses of cFos expressing cells across select brain regions showed high correlations within dorsal hippocampal subregions, while passively coping rats had high correlations between the dorsal hippocampus CA1 and the central and basolateral subregions of the amygdala. Importantly, although control and actively coping rats showed similar levels of behavioral extinction, there was little similarity between activated structures, suggesting stress resilience in response to chronic social defeat involves an adaptive differential recruitment of brain circuits to successfully extinguish fear memories.

ImportanceThe COVID-19 pandemic has led to 775 million documented cases and over 7 million deaths worldwide as of March 2024 and is an ongoing health crisis. To limit viral spread within households and in the community, public health officials have recommended self-isolation, self-quarantine of exposed household contacts, and mask use. Yet, risk of household transmission (HHT) may be underestimated due to low frequency of sampling, and risk factors for HHT are not well understood.ObjectivesTo estimate the secondary attack rate of SARS-CoV-2 within households and to define the risk factors for new infections in household members who are in close contact with the index case.Design, setting, and participantsIn this prospective cohort study, from March 2020-December 2021 we enrolled 60 households with index cases who tested positive for SARS-CoV-2. All household contacts and index cases were tested daily for SARS-CoV-2 via reverse transcription polymerase chain reaction (RT-PCR) using self-collected anterior nares specimens. Households were followed until all study participants in the household tested negative for SARS-CoV-2 for seven consecutive days. We collected sex, age, race/ethnicity, comorbidities, and relationship to index case for secondary contacts, household level characteristics including primary income, household density, and square feet per person on property. We compared the sociodemographic variables between COVID-19 positive and negative household members and between households where secondary transmission did and did not occur.Main outcomes and measuresDaily anterior nares swabs were tested for SARS-CoV-2 using RT-PCR, in order to assess duration of nasal shedding of SARS-CoV-2, as well as risk of transmission to secondary household contacts.ResultsOf the 163 participants in this study, 84 (51.5%) were women; median age (IQR) was 36.0 (17.0-54.0) years of age; 78 (47.8%) were white and 48 (29.5%) were Hispanic/LatinX. Of the fifty households with household contacts, at least one secondary case occurred in twenty-six households (52.0%) and forty-five household contacts (43.7%) were infected. Secondary attack rate was lowest among children of index cases (6/23, 26.1%). Modified Poisson regression identified that the risk of transmission to household contacts increases significantly with age (Risk ratio for each increase in years of age = 1.01, 95% CI = 1.00-1.02). Mixed effects regression models identified that participants with chronic diseases, such as asthma, diabetes, cancer, or cardiac disease, had higher Cts at baseline when compared to participants without chronic diseases (6.62, 95% CI: 1.46-11.77, p = 0.02) and show a slower rate of increase in Ct over time (-0.43, 95% CI: -0.77 to -0.09, p = 0.02).Conclusions and relevanceThis study suggests that HHT represents a key source of community-based infection of SARS-CoV-2. Allocation of resources for contact investigations and prevention interventions should focus on the individuals at highest risk of infection in households, especially those with higher density homes.

Purpose: ARID1B is one of the most frequently mutated genes in intellectual disability cohorts. Thus, far few adult-aged patients with ARID1B-related disorder have been described, which limits our understanding of the disease’s natural history and our ability to counsel patients and their families. Methods: Data on patients aged 18+ years with ARID1B-related disorder were collected through an online questionnaire completed by clinicians and parents. Results: Eighty-seven adult patients with ARID1B were included. Cognitive functioning ranged from borderline to severe intellectual disability. Patients identified through the genetic workup of their child were either mosaic or had a variant in exon 1. New clinical features identified in this population are loss of skill (16/64, 25%) and recurrent patella luxation (12/45, 32%). Self-sustainability data showed that 88% (45/51) could eat independently, and 16% (7/45) could travel alone by public transport. Facial photo analysis showed that patients’ photographs taken at different ages clustered consistently, separate from matched controls. Conclusion: The ARID1B spectrum is broad, and as patients age, there is a significant shift in the medical aspects requiring attention. To address the changing medical needs with increasing age, we have formulated recommendations to promote timely intervention in an attempt to mitigate disease progression.

Abstract A series of epidemiological studies have shown the limited life expectancy of patients suffering from idiopathic normal pressure hydrocephalus (iNPH). In most cases, comorbid medical conditions are the cause of death, rather than iNPH. Though it has also been shown that shunting improves both life quality and lifetime. We sought to investigate the utility of the Charlson comorbidity index (CCI) for improved preoperative risk–benefit assessment of shunt surgery in individual iNPH cases. 208 shunted iNPH cases were prospectively investigated. Two in-person follow up visits at 3 and 12 months assessed postoperative clinical status. The correlation of the age adjusted CCI with survival was investigated over the median observation time of 2.37 years (IQR 1.16–4.15). Kaplan Meier statistics revealed that patients with a CCI score of 0–5 have a 5-year survival rate of 87%, compared to only 55% in patients with CCI > 5. Cox multivariate statistics revealed that the CCI was an independent predictor of survival, while common preoperative iNPH scores (modified Rankin Scale (mRS), gait score, and continence score) are not. As expected, mRS, gait, and continence scores improved during the postoperative follow up period, though relative improvement on any of these was not predicted by baseline CCI. The CCI is an easily applicable preoperative predictor of survival time in shunted iNPH patients. The lack of a correlation between the CCI and functional outcome means that even patients with multiple comorbidities and limited remaining lifetime may appreciate benefit from shunt surgery.

OBJECTIVES/GOALS: Optimize an Individual Retention Conversation (IRC) toolkit aimed at enhancing trust amongst CRPs and leadership via a 2-phase project wherein 9 academic medical centers (AMCs) with significant CRP workforces developed and assessed a 16 question IRC guide and accompanying manager/leader instructional guide. #_msoanchor_1 METHODS/STUDY POPULATION: Significant interest in adapting the Stay Interview concept for the CRP workforce led to a 2-phase pilot to optimize the re-envisioned IRC toolkit. Representatives from nine AMCs and research sites volunteered to navigate their respective institutional IRB processes to initiate the assessment. Additional sites, such as Frontiers Clinical and Translational Institute (Frontiers) launched variations of the IRCs outside of the structured QI project to meet the needs of their institutional environments and reported feedback to the larger group. Feedback on both the standardized IRC, as well as Frontiers’ tailored version, will be presented. This will serve as an entryway into Phase 2, a multi-institutional mixed methods evaluation project open to all AMC members of ACTS and the CRPT SIG. RESULTS/ANTICIPATED RESULTS: To date, 7 institutions have initiated IRCs with test groups at their institutions. Each institution had unique requirements, but all IRBs deemed Phase 1 to be exempt/not human research. Preliminary data suggest not only that the IRC process is valuable to both employee and their manager/unit leadership, but also that the simple act of conducting IRCs was found to be unique and meaningful to employees. For example, in their tailored IRC process, Frontiers found that the 90% of their team found the process to be beneficial (n=9). DISCUSSION/SIGNIFICANCE: By acknowledging issues, understanding motivations, and increasing engagement, IRCs foster positive change, allowing team leaders to take immediate action on important issues. By doing so, retention and engagement of team members, and the CRP workforce as a whole, is likely to grow and strengthen, as supported by results from our initial test pilots.

Background: People with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) experience core symptoms of post-exertional malaise, unrefreshing sleep, and cognitive impairment. Despite numbering 0.2-0.4% of the population, no laboratory test is available for their diagnosis, no effective therapy exists for their treatment, and no scientific breakthrough regarding pathogenesis has been made. It remains unknown, despite decades of small-scale studies, whether individuals experience different types of ME/CFS separated by onset-type, sex or age. Methods: DecodeME is a large population-based study of ME/CFS that recruited 17,074 participants in the first 3 months following full launch. Detailed questionnaire responses from UK-based participants who all reported being diagnosed with ME/CFS by a health professional provided an unparalleled opportunity to investigate, using logistic regression, whether ME/CFS severity or onset type is significantly associated with sex, age, illness duration, comorbid conditions or symptoms. Results: The well-established sex-bias among ME/CFS patients is evident in the initial DecodeME cohort: 83.5% of participants were females. What was not known previously was that females tend to have more comorbidities than males. Moreover, being female, being older and being over 10 years from ME/CFS onset are significantly associated with greater severity. Five different ME/CFS onset types were examined in the self-reported data: those with ME/CFS onset (i) after glandular fever (infectious mononucleosis); (ii) after COVID-19 infection; (iii) after other infections; (iv) without an infection at onset; and, (v) where the occurrence of an infection at or preceding onset is not known. Among other findings, ME/CFS onset with unknown infection status was significantly associated with active fibromyalgia. Conclusions: DecodeME participants differ in symptoms, comorbid conditions and/or illness severity when stratified by their sex-at-birth and/or infection around the time of ME/CFS onset.

Introduction Approximately 15%–20% of the adult population self-report symptoms of addictive eating. There are currently limited options for management. Motivational interviewing-based interventions, containing personalised coping skills training, have been found to be effective for behaviour change in addictive disorders (eg, alcohol). This project builds upon foundations of an addictive eating feasibility study previously conducted and co-design process involving consumers. The primary aim of this study is to examine the efficacy of a telehealth intervention targeting addictive eating symptoms in Australian adults compared with passive intervention and control groups.Methods and analysis This three-arm randomised controlled trial will recruit participants 18–85 years, endorsing ≥3 symptoms on the Yale Food Addiction Scale (YFAS) 2.0, with body mass index >18.5 kg/m2. Addictive eating symptoms are assessed at baseline (pre-intervention), 3 months (post-intervention) and 6 months. Other outcomes include dietary intake and quality, depression, anxiety, stress, quality of life, physical activity and sleep hygiene. Using a multicomponent clinician-led approach, the active intervention consists of five telehealth sessions (15–45 min each) delivered by a dietitian over 3 months. The intervention uses personalised feedback, skill-building exercises, reflective activities and goal setting. Participants are provided with a workbook and website access. The passive intervention group receives the intervention via a self-guided approach with access to the workbook and website (no telehealth). The control group receives personalised written dietary feedback at baseline and participants advised to follow their usual dietary pattern for 6 months. The control group will be offered the passive intervention after 6 months. The primary endpoint is YFAS symptom scores at 3 months. A cost–consequence analysis will determine intervention costs alongside mean change outcomes.Ethics and dissemination Human Research Ethics Committee of University of Newcastle, Australia provided approval (H-2021-0100). Findings will be disseminated via publication in peer-reviewed journals, conference presentations, community presentations and student theses.Trial registration number Australia New Zealand Clinical Trials Registry (ACTRN12621001079831).

Study Design Retrospective study. Purpose To identify the rate of positive acid-fast bacillus (AFB) and fungal cultures during spine debridement, determine whether these infections are more common in certain spine segments, identify comorbidities associated with these infections, and determine whether the universal performance of fungal and AFB cultures during spine debridement is cost effective. Overview of Literature Spine infections are associated with significant morbidity and costs. Spine fungal and AFB infections are rare, but their incidence has not been well documented. As such, guidance regarding sample procurement for AFB and fungal cultures is lacking. Methods A retrospective review of medical record data from patients undergoing spine irrigation and debridement (I&D) at the University of Missouri over a 10-year period was performed. Results For patients undergoing spine I&D, there was a 4% incidence of fungal infection and 0.49% rate of AFB infection. Steroid use was associated with a higher likelihood (odds ratio, 5.62; 95% confidence interval, 1.33–23.75) of positive fungal or AFB cultures. Although not significant, patients undergoing multiple I&D procedures had higher rates of positive fungal cultures during each subsequent I&D. Over a 10-year period, if fungal cultures are obtained for each patient, it would cost our healthcare system $12,151.58. This is compared to an average cost of $177,297.64 per missed fungal infection requiring subsequent treatment. Conclusions Spine fungal infections occur infrequently at a rate of 4%. Physicians should strongly consider obtaining samples for fungal cultures in patients undergoing spine I&D, especially those using steroids and those undergoing multiple I&Ds. Our AFB culture rates mirror the false positive rates seen in previous orthopedic literature. It is unlikely to be cost effective to send for AFB cultures in areas with low endemic rates of AFB.

Abstract Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3′-phosphatase and DNA 5′-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. Functional and biochemical studies demonstrated these PNKP mutations significantly diminished DNA kinase/phosphatase activities, altered its cellular distribution, caused defective repair of DNA single/double stranded breaks, and were associated with a higher propensity for oncogenic transformation. Our findings indicate that specific PNKP mutations may contribute to tumor initiation within susceptible cells in the CNS by limiting DNA damage repair and increasing rates of spontaneous mutations resulting in pediatric glioma associated driver mutations such as ATRX and TP53.

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that α-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative phosphorylation. Collectively, our data argue that α-fetoprotein may be secreted by bioenergetically stressed tissue to suppress the immune system, an effect that may explain the recurrent or chronic infections that are observed in a subset of mitochondrial diseases or in other disorders with secondary mitochondrial dysfunction.

OBJECTIVES/GOALS: The training needs of clinical & translational scientists are evolving. Implementation of new curriculum content requires assessment of need, fit with current curriculum, incentives and barriers to implementation. We used implementation science methods to plan the implementation of a dissemination and implementation science training toolkit. METHODS/STUDY POPULATION: The Tufts Clinical & Translational Science (CTS) Graduate Program is the training core of the Tufts CTSI and its associated TL1. To assess barriers and facilitators to implementing the University of Washington’s Dissemination and Implementation (D&I) Science Toolkit for TL1 Programs into the Tufts CTS Graduate Program, we used the Consolidated Framework for Implementation Research (CFIR). We developed an interview guide based on CFIR constructs or categories of factors that might influence implementation of the D&I Toolkit and interviewed 8 stakeholders including leadership, trainees and faculty. We compared D&I Toolkit content to the current curriculum on stakeholder engagement (SE) and research study quality improvement (QI) to identify how the D&I Toolkit could be adapted to fit trainee and program needs. RESULTS/ANTICIPATED RESULTS: Stakeholder interviews and review of the current curriculum identified facilitators and barriers to implementing the D&I Toolkit in the Tufts CTS Graduate Program. The program has a strong SE focus and fosters the use of research study QI methods. Interviews identified student and faculty desire to implement the D&I content yet time constraints and overlap with the current curriculum were identified. The following plan to adapt the D&I Toolkit content to fit contextual factors was developed and executed: 1. Adapt didactic content to fit into a 90-min session. 2. Highlight the synergy between the current SE curriculum and the role of stakeholders in D&I science. 3. Modify course materials to highlight examples of disseminating local research results. 4. Limit the experiential learning component to a SE plan. DISCUSSION/SIGNIFICANCE: TL1 training programs must balance competing demands in selecting curriculum content. The CFIR framework was used to systematically assess implementation barriers by engaging program faculty, students and leaders to identify implementation strategies. This process could be useful when evaluating the addition of other educational content.

Introduction Pulmonary arterial hypertension (PAH) remains a serious and life-threatening illness. Thyroid dysfunction is relatively understudied in individuals with PAH but is known to affect cardiac function and vascular tone in other diseases. The aim of this observational study was to evaluate the association between thyroid-stimulating hormone (TSH), mortal and non-mortal outcomes in individuals with PAH.Methods The Seattle Right Ventricle Translational Science (Servetus) Study is an observational cohort that enrolled participants with PAH between 2014 and 2016 and then followed them for 3 years. TSH was measured irrespective of a clinical suspicion of thyroid disease for all participants in the cohort. Linear regression was used to estimate the relationships between TSH and right ventricular basal diameter, tricuspid annular plane systolic excursion and 6-minute walk distance. Logistic regression was used to estimate the relationship with New York Heart Association Functional Class, and Cox proportional hazards were used to estimate the relationship with mortality. Staged models included unadjusted models and models accounting for age, sex at birth and aetiology of pulmonary hypertension with or without further adjustment for N-terminal-pro hormone brain natriuretic peptide.Results Among 112 participants with PAH, TSH was strongly associated with mortality irrespective of adjustment. There was no clear consistent association between TSH and other markers of severity in a cohort with PAH.Discussion This report reinforces the important observation that TSH is associated with survival in patients with PAH, and future study of thyroid dysfunction as a potential remediable contributor to mortality in PAH is warranted.

Introduction Codesign is a meaningful end-user engagement in research design. The integrated knowledge translation (IKT) framework involves adopting a collaborative research approach to produce and apply knowledge to address real-world needs, resulting in useful and useable recommendations that will more likely be applied in policy and practice. In the field of food addiction (FA), there are limited treatment options that have been reported to show improvements in FA symptoms.Objectives The primary aim of this paper is to describe the step-by-step codesign and refinement of a complex intervention delivered via telehealth for adults with FA using an IKT approach. The secondary aim is to describe our intervention in detail according to the TIDieR checklist.Design This study applies the IKT process and describes the codesign and refinement of an intervention through a series of online meetings, workshops and interviews.Participants This study included researchers, clinicians, consumers and health professionals.Primary outcome measure The primary outcome was a refined intervention for use in adults with symptoms of FA for a research trial.Results A total of six female health professionals and five consumers (n=4 female) with lived overeating experience participated in two interviews lasting 60 min each. This process resulted in the identification of eight barriers and three facilitators to providing and receiving treatment for FA, eight components needed or missing from current treatments, telehealth as a feasible delivery platform, and refinement of key elements to ensure the intervention met the needs of both health professionals and possible patients.Conclusion Using an IKT approach allowed for a range of viewpoints and enabled multiple professions and disciplines to engage in a semiformalised way to bring expertise to formulate a possible intervention for FA. Mapping the intervention plan to the TIDieR checklist for complex interventions, allowed for detailed description of the intervention and the identification of a number of areas that needed to be refined before development of the finalised intervention protocol.

Abstract The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1–38), interacts with the AD-related variant, Aβ(1–42), and the predominant physiological variant, Aβ(1–40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1–38) interacts differently with Aβ(1–40) and Aβ(1–42) and, in general, Aβ(1–38) interferes with the conversion of Aβ(1–42) to a β-sheet-rich aggregate. Functionally, Aβ(1–38) reverses the negative impact of Aβ(1–42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1–42) phenotype in Caenorhabditis elegans. Aβ(1–38) also reverses any loss of MTT conversion induced by Aβ(1–40) and Aβ(1–42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1–38) and Aβ(1–42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1–42)/Aβ(1–38) [and Aβ(1–42)/Aβ(1–40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that Aβ(1–38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(1–42).

The combination of panobinostat, bortezomib and dexamethasone (PanBorDex) is available as a treatment option for relapsed refractory multiple myeloma (RRMM) based on the PANORAMA-1 trial which investigated this triplet in early relapse. In routine clinical care, PanBorDex is used primarily in later relapses and is commonly administered in attenuated dosing schedules to mitigate the treatment-related toxicity. We set out to evaluate efficacy and safety outcomes with PanBorDex later in the disease course and evaluate the role of attenuated dosing schedules. This was a retrospective evaluation of patients treated in routine clinical practice between 2016-2019 across seven heamatology centres in the UK; patients who received at least one dose of PanBorDex were eligible for inclusion. The dosing schedule of panobinostat (10mg, 15mg or 20mg, twice or three times a week) and bortezomib (0.7mg/m2, 1mg/m2 or 1.3mg/m2 once or twice weekly) was as per treating physician choice. Patients received treatment until disease progression or unacceptable toxicity. The primary outcome is response rates according to IMWG criteria. Key secondary endpoints include progression-free survival (PFS) and overall survival (OS). Other secondary endpoints include rates of adverse events according to CTCAE criteria. In total, 61 patients were eligible for inclusion and received PanBorDex primarily as ≥5th line of treatment. One third of patients received PanBorDex at full dose, for the remaining two thirds, treatment was given in reduced dose intensities. The overall response rate was 44.2%, including 14.7% very good partial response (VGPR) rates; 68.8% of patients derived clinical benefit with stable disease or better. The median PFS was 3.4 months; non-refractory patients and those who achieved VGPR benefited from prolonged PFS of 11.4 months and 17.7 months, respectively. The median OS was 9.5 months. The triplet was associated with 45% and 18% incidence of grade 3-4 thrombocytopenia and diarrhea, respectively.

Abstract This report highlights the clinical features seen in duplication of 8q22.1q23.1 inherited from balanced father. It stresses the importance of obtaining a karyotype to identify the location of a large copy number variant for accurate recurrence risk estimation.

Abstract Background Childhood adiposity has increased dramatically in the last few decades and is an important predictor of adulthood chronic disease. Later eating rhythm, termed night eating (NE), is increasingly prevalent in adults; however, the prevalence of NE in children and relationship between NE and adiposity in children still remains uncertain. The aim of this work is to review the association between adiposity in children and adolescents and NE, in terms of calorie intake, timing and meal frequency in the evening/night. Methods The Cochrane library, CINAHL, Embase, MEDLINE (via OVID) and Web of Science databases will be searched from inception to November 2019 for randomised controlled trials (RCTs) and observational studies (cohort, cross-sectional and case-control studies) which investigate the association between later vs. earlier timing of food intake at night or relatively more vs. less energy intake in any eating occasions or time period after 4 pm on adiposity in children and adolescents (4–18 years). The outcomes will be body mass index (BMI)/BMI standard deviation score (BMI-SDS or BMI Z-score), waist circumference (WC), fat mass index (FMI)/percentage of body fat (%BF) or waist to hip ratio (WHR). No language restriction will be applied. Screening for eligibility from the title and abstracts and data extraction from the full texts will be carried out by two reviewers independently. References listed in the included studies will be hand-searched for any additional articles. The quality of included RCT studies will be assessed using Revised Cochrane Risk of Bias tool (RoB 2), and of observational studies using Newcastle Ottawa scale. A qualitative synthesis of the results will be presented, and meta-analysis will be conducted, where appropriate. Discussion The planned systematic review will investigate the association between later eating rhythm and adiposity in children and adolescents. Understanding the best meal size, timing of energy intake and meal frequency across the evening time for maintaining healthy weight in children is important in order to give parents the best advice to help prevent adulthood obesity and associated chronic diseases in their children. Systematic review registration PROSPERO CRD42019134187.

Eukaryotic cells deploy autophagy to eliminate invading microbes. In turn, pathogens have evolved effector proteins to counteract antimicrobial autophagy. How adapted pathogens co-opt autophagy for their own benefit is poorly understood. The Irish famine pathogen Phytophthora infestans secretes the effector protein PexRD54 that selectively activates an unknown plant autophagy pathway that antagonizes antimicrobial autophagy at the pathogen interface. Here, we show that PexRD54 induces autophagosome formation by bridging vesicles decorated by the small GTPase Rab8a with autophagic compartments labeled by the core autophagy protein ATG8CL. Rab8a is required for pathogen-triggered and starvation-induced but not antimicrobial autophagy, revealing specific trafficking pathways underpin selective autophagy. By subverting Rab8a-mediated vesicle trafficking, PexRD54 utilizes lipid droplets to facilitate biogenesis of autophagosomes diverted to pathogen feeding sites. Altogether, we show that PexRD54 mimics starvation-induced autophagy to subvert endomembrane trafficking at the host-pathogen interface, revealing how effectors bridge distinct host compartments to expedite colonization.

Rationale Pulmonary hypertension (PH) is associated with significant perioperative morbidity and mortality. We hypothesised that pulmonary arterial hypertension (PAH) composite risk assessment scores could estimate perioperative risk for PH patients when adjusted for inherent procedural risk. Methods We identified patients in the Johns Hopkins PH Center Registry that had noncardiac surgery (including endoscopies) between September 2015 and January 2020. We collected information on preoperative patient-level and procedural variables and used logistic regression to evaluate associations with a composite outcome of death within 30 days or serious postoperative complication. We generated composite patient-level risk assessment scores for each subject and used logistic regression to estimate the association with adverse surgical outcomes. We adjusted multivariable models for inherent procedural risk of major cardiovascular events and used these models to generate a numerical PH perioperative risk (PHPR) score. Results Among 150 subjects, 19 (12.7%) reached the primary outcome, including 7 deaths (4.7%). Individual patient-level and procedural variables were associated with the primary outcome (all p10%) risk of reaching the primary outcome. Conclusion Composite PAH risk assessment scores can predict perioperative risk for PH patients after accounting for inherent procedural risk. Validation of the PHPR score in a multicentre, prospective cohort is warranted.

Ovarian cancer (OC) is associated with a dismal prognosis and lack of curative treatment. Increased understanding of OC biology has led to the development of several targeted therapies, including antiangiogenic agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Cell cycle inhibitors and endocrine therapy such as selective estrogen receptor down regulators are currently under development. In this article, we provide an overview of the current and emerging targeted therapies in OC.

The COVID-19 pandemic has disproportionately impacted racial and ethnic minority communities, particularly African American and Latino communities. The impacts of social determinants of health, structural racism, misinformation, and mistrust have contributed to a decreased COVID-19 vaccine uptake. Effective methods of addressing and combatting these barriers are essential. Accurate and targeted messaging delivered by trusted voices from community-based organizations, government health systems and organizations, and healthcare and academic systems is imperative. Outreach and communication should be culturally sensitive, provided in the preferred language of the community, flexible, and tailored for in-person and virtual outlets. This communication must also increase trust, combat misinformation, and inspire COVID-19 vaccine confidence. In this manuscript, we outline a framework for inspiring COVID-19 vaccine confidence in African American and Latino communities. These methods of targeted outreach should be considered and implemented for urgent and nonurgent community public health efforts beyond the COVID-19 pandemic (e.g., monkeypox) and as a framework to inspire vaccine confidence in those living in racial and ethnic minority communities globally.

The mitochondrial carrier family protein SLC25A3 transports both copper and phosphate in mammals, yet in Saccharomyces cerevisiae the transport of these substrates is partitioned across two paralogs: PIC2 and MIR1. To understand the ancestral state of copper and phosphate transport in mitochondria, we explored the evolutionary relationships of PIC2 and MIR1 orthologs across the eukaryotic tree of life. Phylogenetic analyses revealed that PIC2-like and MIR1-like orthologs are present in all major eukaryotic supergroups, indicating an ancient gene duplication created these paralogs. To link this phylogenetic signal to protein function, we used structural modeling and site-directed mutagenesis to identify residues involved in copper and phosphate transport. Based on these analyses, we generated an L175A variant of mouse SLC25A3 that retains the ability to transport copper but not phosphate. This work highlights the utility of using an evolutionary framework to uncover amino acids involved in substrate recognition by mitochondrial carrier family proteins.

Software is as integral as a research paper, monograph, or dataset in terms of facilitating the full understanding and dissemination of research. This article provides broadly applicable guidance on software citation for the communities and institutions publishing academic journals and conference proceedings. We expect those communities and institutions to produce versions of this document with software examples and citation styles that are appropriate for their intended audience. This article (and those community-specific versions) are aimed at authors citing software, including software developed by the authors or by others. We also include brief instructions on how software can be made citable, directing readers to more comprehensive guidance published elsewhere. The guidance presented in this article helps to support proper attribution and credit, reproducibility, collaboration and reuse, and encourages building on the work of others to further research.

Purpose The long-term goal of the Study of Mothers’ and Infants’ Life Events Affecting Oral Health (SMILE) birth cohort study is to identify and evaluate the relative importance and timing of critical factors that shape the oral health of young children. It will then evaluate those factors in their inter-relationship with socioeconomic influences.Participants SMILE is a single-centre study conducted in Adelaide, Australia. All newborns at the main three public hospitals between July 2013 and August 2014 were eligible for inclusion. The final recruited sample at birth was 2181 mother/infant dyads. Participants were followed up with questionnaires when the child was 3 and 6 months of age, and 1, 2 and 5 years of age. Oral epidemiological examinations and anthropometric assessments were conducted at age 2 and 5 years.Findings to date SMILE has contributed comprehensive data on dietary patterns of young children. Intakes of free sugars, core and discretionary foods and drinks have been detailed. There was a sharp increase in free sugars intake with age. Determinants of dietary patterns, oral health status and body weight during the first 5 years of life have been evaluated. Socioeconomic characteristics such as maternal education and household income and area-level socioeconomic profile influenced dietary patterns and oral health behaviours and status.Future plan Funding has been obtained to conduct oral epidemiological examinations and anthropometric assessments at age 7–8 years. Plans are being developed to follow the cohort into adolescent years.

BackgroundOccupational exercise training programs can improve overall health and fitness in firefighters, but evidence beyond clinical and performance outcomes is needed before fire departments invest in and successfully adopt health promotion programs. ObjectiveThis mixed methods pilot study sought to pair clinical and performance outcomes with participants’ qualitative feedback (eg, participants’ enjoyment, lifestyle behavior changes, and team structure) with the goal of informing recommendations for future programs. MethodsProfessional firefighters participated in a 14-week occupational exercise training program with assessments conducted pre- and posttraining. Clinical outcomes included weight, BMI, body fat percentage, resting heart rate, systolic blood pressure, and diastolic blood pressure. Performance outcomes included the sharpened Romberg balance test, 1-repetition maximum leg press and bench press, graded exercise test (estimated VO2max), knee range of motion, shoulder flexibility, and hamstring flexibility. Self-administered surveys (Short Form-36, International Physical Activity Questionnaire, Barriers Self-Efficacy Scale, and Barriers to Being Active Quiz) were completed. In 3 private focus groups of 3 to 4 participants, firefighters' experiences in the training program and their health behaviors were explored. ResultsMale firefighters (n=14; age: mean 36.4, SD 2.6 years) completed 20 training sessions. There were no significant changes to weight (P=.20), BMI (P=.15), body fat percentage (P=.16), systolic blood pressure (P=.12), estimated VO2max (P=.34), balance (P=.24), knee range of motion (left: P=.35; right: P=.31), or hamstring flexibility (P=.14). There was a significant decrease in diastolic blood pressure (P=.04) and significant increases in shoulder flexibility (P

Evidence shows that White and non-Hispanic individuals are overrepresented in clinical trials. The development of new vaccines and drugs, however, necessitates that clinical research trials include representative participants, particularly in light of evidence showing that underrepresented minorities may have a different response to certain medications and vaccines. Racial and ethnic disparities among clinical trials are multilayered and complex, and this requires action. The results of this study indicate that significant racial and ethnic disparities consistently exist among the most recent early SARS-CoV-2 vaccine clinical trials as compared to the pandemic H1N1 vaccine clinical trials of 2009. New strategies, policies, training programs, and reforms are required to address these disparities among clinical trials.

BackgroundActigraphs are wrist-worn devices that record tri-axial accelerometry data used clinically and in research studies. The expense of research-grade actigraphs, however, limit their widespread adoption, especially in clinical settings. Tri-axial accelerometer-based consumer wearable devices have gained worldwide popularity and hold potential for a cost-effective alternative. The lack of independent validation of minute-to-minute accelerometer data with polysomnographic data or even research-grade actigraphs, as well as access to raw data has hindered the utility and acceptance of consumer-grade actigraphs.MethodsSleep clinic patients wore a consumer-grade wearable (Huami Arc) on their non-dominant wrist while undergoing an overnight polysomnography (PSG) study. The sample was split into two, 20 in a training group and 21 in a testing group. In addition to the Arc, the testing group also wore a research-grade actigraph (Philips Actiwatch Spectrum). Sleep was scored for each 60-s epoch on both devices using the Cole-Kripke algorithm.ResultsBased on analysis of our training group, Arc and PSG data were aligned best when a threshold of 10 units was used to examine the Arc data. Using this threshold value in our testing group, the Arc has an accuracy of 90.3%±4.3%, sleep sensitivity (or wake specificity) of 95.5%±3.5%, and sleep specificity (wake sensitivity) of 55.6%±22.7%. Compared to PSG, Actiwatch has an accuracy of 88.7%±4.5%, sleep sensitivity of 92.6%±5.2%, and sleep specificity of 60.5%±20.2%, comparable to that observed in the Arc.ConclusionsAn optimized sleep/wake threshold value was identified for a consumer-grade wearable Arc trained by PSG data. By applying this sleep/wake threshold value for Arc generated accelerometer data, when compared to PSG, sleep and wake estimates were adequate and comparable to those generated by a clinical-grade actigraph. As with other actigraphs, sleep specificity plateaus due to limitations in distinguishing wake without movement from sleep. Further studies are needed to evaluate the Arc's ability to differentiate between sleep and wake using other sources of data available from the Arc, such as high resolution accelerometry and photoplethysmography.

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

BACKGROUND: The roots of advanced practice nursing (APN) can be traced back to the 1890s, but the nurse practitioner (NP) emerged in Western countries during the 1960s in response to the unmet healthcare needs of populations in rural areas. These early NPs utilized the medical model of care to assess, diagnose and treat. Nursing has since grown as a profession, with its own unique and distinguishable, holistic, science-based knowledge, which is complementary within the multidisciplinary team. Today, APNs demonstrate nursing expertise in clinical practice, education, research and leadership, and are no longer perceived as “physician replacements” or assistants. Saudi Arabia has yet to define, legislate or regulate APN. AIMS: This article aims to disseminate information from a Saudi APN thought leadership meeting, to chronicle the history of APN within Saudi Arabia, while identifying strategies for moving forward. CONCLUSION: It is important to build an APN model based on Saudi healthcare culture and patient population needs, while recognizing global historical underpinnings. Ensuring that nursing continues to distinguish itself from other healthcare professions, while securing a seat at the multidisciplinary healthcare table will be instrumental in advancing the practice of nursing.

In 2021, a large urban university-based hospital transitioned to a new two-floor emergency department. Despite the new environment, there were usability and workflow challenges with the space. The authors of this paper created a multidisciplinary, human-centered design collaborative of clinicians, university faculty, and students in an effort to increase emergency department efficiency. After thorough design-research and clinician-focused collaboration, the authors and design team identified the need to improve medical supply retrieval time, which directly impacts patient care and clinician satisfaction. The primary interventions consisted of a redesign that is as follows: (a) created standardized icons related to organ system, (b) increased visibility of supply labels, and (c) reorganized supplies based on usage data. Although a successful project, it was not without several barriers discussed in this article, including design researcher and clinician-level setting and engagement, academic/institutional policies, and conflicting schedules. In addition, the lessons learned from implementing human-centered design concepts into clinical workflow sets forth future research opportunities and inspiration for other institutions to collaborate. [ABSTRACT FROM AUTHOR]

BackgroundUnderstanding the role of the gut microbiome is pivotal for the future development of therapies for the prevention and management of autoimmune conditions such as type 1 diabetes when sampling during early life may be particularly important. The current standard methods for collecting gut microbiome samples for research is to extract fresh samples or freeze samples immediately after collection. This is often impractical however for population-based studies. The aim of this study was to determine the optimal method for the stabilization of stool bacterial DNA obtained from nappies and transported by post in ambient conditions to the research centre for a national birth cohort study.MethodsFour methods to collect samples were compared to immediate freezing of samples: 1) collecting faeces onto a swab which was immediately frozen, 2) using a commercially available kit with stabilisation solution (OMNIgene•GUT kit) at ambient temperature, 3) collecting onto a swab and 4) collecting into a sterile plain tube. Samples 3) and 4) were returned to the laboratory by post at ambient temperatures. A Bland Altman analysis was used to assess the agreement between the different methods and the frozen standard.ResultsStool samples were collected by parents. For samples transported in ambient conditions, the limits of agreement showed that the OMNIgene•GUT kit had the narrowest 95% limits of agreement with the frozen standard as measured by the number of operational taxonomic units and the Shannon diversity index.ConclusionsAll methods assessed for preserving samples collected from nappies at a distance and delivered by post for gut microbiome analysis showed variation / disagreement from the frozen standard. Overall, the OMNIgene•GUT kit preserved the samples with minimal changes compared to other methods and was practical for parents to use.

During plant cell invasion, the oomycete Phytophthora infestans remains enveloped by host-derived membranes whose functional properties are poorly understood. P. infestans secretes a myriad of effector proteins through these interfaces for plant colonization. Recently we showed that the effector protein PexRD54 reprograms host-selective autophagy by antagonising antimicrobial-autophagy receptor Joka2/NBR1 for ATG8CL binding (Dagdas et al., 2016). Here, we show that during infection, ATG8CL/Joka2 labelled defense-related autophagosomes are diverted toward the perimicrobial host membrane to restrict pathogen growth. PexRD54 also localizes to autophagosomes across the perimicrobial membrane, consistent with the view that the pathogen remodels host-microbe interface by co-opting the host autophagy machinery. Furthermore, we show that the host-pathogen interface is a hotspot for autophagosome biogenesis. Notably, overexpression of the early autophagosome biogenesis protein ATG9 enhances plant immunity. Our results implicate selective autophagy in polarized immune responses of plants and point to more complex functions for autophagy than the widely known degradative roles.

Helicobacter pylori requires genetic agility to infect new hosts and establish long-term colonization of changing gastric environments. In this study, we analyzed H. pylori genetic adaptation in the Mongolian gerbil model. This model is of particular interest because H. pylori-infected gerbils develop a high level of gastric inflammation and often develop gastric adenocarcinoma or gastric ulceration. We analyzed the whole genome sequences of H. pylori strains cultured from experimentally infected gerbils, in comparison to the genome sequence of the input strain. The mean annualized single nucleotide polymorphism (SNP) rate per site was 1.5e−5, which is similar to the rates detected previously in H. pylori-infected humans. Many of the mutations occurred within or upstream of genes associated with iron-related functions (fur, tonB1, fecA2, fecA3, and frpB3) or encoding outer membrane proteins (alpA, oipA, fecA2, fecA3, frpB3 and cagY). Most of the SNPs within coding regions (86%) were non-synonymous mutations. Several deletion or insertion mutations led to disruption of open reading frames, suggesting that the corresponding gene products are not required or are deleterious during chronic H. pylori colonization of the gerbil stomach. Five variants (three SNPs and two deletions) were detected in isolates from multiple animals, which suggests that these mutations conferred a selective advantage. One of the mutations (FurR88H) detected in isolates from multiple animals was previously shown to confer increased resistance to oxidative stress, and we now show that this SNP also confers a survival advantage when H. pylori is co-cultured with neutrophils. Collectively, these analyses allow the identification of mutations that are positively selected during H. pylori colonization of the gerbil model.