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BackgroundDiabetes prevalence and incidence vary by neighborhood socioeconomic environment (NSEE) and geographic region in the United States. Identifying modifiable community factors driving type 2 diabetes disparities is essential to inform policy interventions that reduce the risk of type 2 diabetes. ObjectiveThis paper aims to describe the Diabetes Location, Environmental Attributes, and Disparities (LEAD) Network, a group funded by the Centers for Disease Control and Prevention to apply harmonized epidemiologic approaches across unique and geographically expansive data to identify community factors that contribute to type 2 diabetes risk. MethodsThe Diabetes LEAD Network is a collaboration of 3 study sites and a data coordinating center (Drexel University). The Geisinger and Johns Hopkins University study population includes 578,485 individuals receiving primary care at Geisinger, a health system serving a population representative of 37 counties in Pennsylvania. The New York University School of Medicine study population is a baseline cohort of 6,082,146 veterans who do not have diabetes and are receiving primary care through Veterans Affairs from every US county. The University of Alabama at Birmingham study population includes 11,199 participants who did not have diabetes at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort study with oversampling of participants from the Stroke Belt region. ResultsThe Network has established a shared set of aims: evaluate mediation of the association of the NSEE with type 2 diabetes onset, evaluate effect modification of the association of NSEE with type 2 diabetes onset, assess the differential item functioning of community measures by geographic region and community type, and evaluate the impact of the spatial scale used to measure community factors. The Network has developed standardized approaches for measurement. ConclusionsThe Network will provide insight into the community factors driving geographical disparities in type 2 diabetes risk and disseminate findings to stakeholders, providing guidance on policies to ameliorate geographic disparities in type 2 diabetes in the United States. International Registered Report Identifier (IRRID)DERR1-10.2196/21377

Abstract The CARLO (cold ablation robot-guided laser osteotome) is a compact device with integrated multiple sensory, steering and safety checking elements. A multi-center study was performed to evaluate the CARLO device for the linear part of midface osteotomy in 28 patients. Feasibility, success rate, safety, performance and experience of the surgeons were assessed and evaluated. All 28 procedures were completed with CARLO without falling back to the conventional methods, giving a technical success rate of 100%. For 27 (96%) cases, procedural success was achieved with cutting lines deviation less than 2 mm. For 25 procedures, the CARLO-cutting was conducted smoothly. In the other 3 cases, some minor difficulties related to the reference markers were reported. For 18 procedures, no change for the cutting path was necessary. For the other 10 cases, cut path was adapted. Intraoperative re-planning was possible, easy and quick without significant delay of the procedures. No CARLO-related adverse events were recorded. Especially, there was no unexpected and unusual bleeding during the CARLO-conducted osteotomy. The time needed for the registration ranged from 1 to 12 min (median = 4). The CARLO-cutting lasted for 5 to 21 min (median = 7). The present study demonstrated feasibility, simplicity, safety, reliability and accuracy of CARLO for the linear part of midface osteotomy.

Abstract Young healthcare professionals and medical graduates often fall short in the practical experience necessary for handling medical emergencies. This can not only lead to strained feelings of inadequacy and insecurity among future physicians and less experienced healthcare providers in general, but also to detrimental outcomes for patients as emergency medicine demands rapid decision-making with low tolerance for errors. New didactic modalities and approaches may be needed to effectively address this shortcoming. Immersive technologies are powerful novel educational tools with untapped potential in medical training, and may be particularly suitable for simulation trainings in the high-stakes field of emergency medicine. Herein, we systematically explored the educational potential of extended reality (XR) technology, particularly virtual reality (VR), in the management of patients presenting as medical emergencies, combining the use of the STEP-VR application with an untethered hardware setup. Importantly, we aimed at studying multiple, large cohorts of senior medical students involving a total of 529 participants and collecting data over a period of two years. We assessed students’ acceptance of the training through a modified questionnaire measuring device handling, content complexity, degree of immersion, learning success, and seminar design. Our results show high, sustained acceptance and ease of use across different student cohorts and subgroups, with most students finding XR/VR engaging and beneficial for acquiring emergency medicine skills. Importantly, the prevalence of simulation sickness was minimal. Moreover, no major effect of the head-mounted displays (HMDs) price range was noted with regard to the learning experience. The results underscore the potential of XR/VR capabilities in effectively enhancing medical education, particularly in areas of high-stakes clinical scenarios and emergency care, by providing realistic and reproducible immersive training environments. In summary, our findings suggest that XR/VR-based training approaches could significantly contribute to preparing future physicians for the complexities of emergency medical care, encouraging the integration of such technologies into medical curricula. However, careful consideration must be given to its suitability for all students and the practical challenges of its implementation, highlighting the need for further research to harness its full potential for medical education.

Abstract Nanomechanical oscillators are an alternative platform for computation in harsh environments. However, external perturbations arising from such environments may hinder information processing by introducing errors into the computing system. Here, we simulate the dynamics of three coupled Duffing oscillators whose multiple equilibrium states can be used for information processing and storage. Our analysis reveals that, within experimentally relevant parameters, error correcting dynamics can emerge, wherein the system’s state is robust against random external impulses. We find that oscillators in this configuration have several surprising and attractive features, including dynamic isolation of resonators exposed to extreme impulses and the ability to correct simultaneous errors.

Abstract People with epilepsy frequently under- or inaccurately report their seizures, which poses a challenge for evaluating their treatment. The introduction of epilepsy health apps provides a novel approach that could improve seizure documentation. This study assessed the documentation performance of an app-based seizure diary and a conventional paper seizure diary. At two tertiary epilepsy centers patients were asked to use one of two offered methods to report their seizures (paper or app diary) during their stay in the epilepsy monitoring unit. The performances of both methods were assessed based on the gold standard of video-EEG annotations. In total 89 adults (54 paper and 35 app users) with focal epilepsy were included in the analysis, of which 58 (33 paper and 25 app users) experienced at least one seizure and made at least one seizure diary entry. We observed a high precision of 85.7% for the app group, whereas the paper group’s precision was lower due to overreporting (66.9%). Sensitivity was similar for both methods. Our findings imply that performance of seizure self-reporting is patient-dependent but is more precise for patients who are willing to use digital apps. This may be relevant for treatment decisions and future clinical trial design.

Abstract The identification of targetomes remains a challenge given the pleiotropic effect of miRNAs, the limited effects of miRNAs on individual targets, and the sheer number of estimated miRNA–target gene interactions (MTIs), which is around 44,571,700. Currently, targetome identification for single miRNAs relies on computational evidence and functional studies covering smaller numbers of targets. To ensure that the targetome analysis could be experimentally verified by functional assays, we employed a systematic approach and explored the targetomes of four miRNAs (miR-129-5p, miR-129-1-3p, miR-133b, and miR-873-5p) by analyzing 410 predicted target genes, both of which were previously associated with Parkinson’s disease (PD). After performing 13,536 transfections, we validated 442 of the 705 putative MTIs (62,7%) through dual luciferase reporter assays. These analyses increased the number of validated MTIs by at least 2.1-fold for miR-133b and by a maximum of 24.3-fold for miR-873-5p. Our study contributes to the experimental capture of miRNA targetomes by addressing i) the ratio of experimentally verified MTIs to predicted MTIs, ii) the sizes of disease-related miRNA targetomes, and iii) the density of MTI networks. A web service to support the analyses on the MTI level is available online ( https://ccb-web.cs.uni-saarland.de/utr-seremato ), and all the data have been added to the miRATBase database ( https://ccb-web.cs.uni-saarland.de/miratbase ).

Purpose Prospective, multicentric observational cohort study in Switzerland investigating measures to prevent mother-to-child transmission in pregnant women with HIV (WWH) and assessing health and development of their exposed children as well as of children with HIV (CWH) in general.Participants Between January 1986 and December 2022, a total of 1446 mother–child pairs were enrolled. During the same period, the study also registered 187 CWH and 521 HIV-exposed but uninfected children (HEU), for whom detailed maternal information was not available. Consequently, the cohort comprises a total of 2154 children.Findings to date During these 37 years, research by the Swiss Mother and Child HIV Cohort Study (MoCHiV) and its international collaborators has strongly influenced the prevention of vertical transmission of HIV (eg, introduction and discontinuation of elective caesarean section, neonatal postexposure prophylaxis and breastfeeding). Contributions have also been made to the management of diagnostics (eg, p24 antigen assay) and the effects of antiretroviral treatment (eg, prematurity, growth) in HEU and CWH.Future plans Most children present within the cohort are now HEU, highlighting the need to investigate other vertically transmitted pathogens such as hepatitis B and C viruses, cytomegalovirus or Treponema pallidum. In addition, analyses are planned on the longitudinal health status of CWH (eg, resistance and prolonged exposure to antiretroviral therapy), on social aspects including stigma in CWH and HEU, and on interventions to further optimise antenatal and postpartum care in WWH.

BackgroundPatients with open fractures often experience complications during their injury. The treatments incur high costs. Interdisciplinary cooperation between different medical disciplines may improve treatment outcomes. Such cooperation has not yet been envisaged in the German health care system. ObjectiveThe aim of the study is to improve the treatment of fractures with open soft tissue damage or postoperative complications in terms of duration and sustainability in a region in northwest Germany. Largely standardized diagnostics and therapy are intended to optimize processes in hospitals. In addition, a reduction in the duration of treatment and treatment costs is to be achieved. MethodsUsing a digital platform, physicians from 31 hospitals present patient cases to an interdisciplinary group of experts from the fields of plastic surgery, infectiology, hygiene, and others. The group of experts from the environment of the University Hospital Münster promptly makes a joint treatment recommendation for the individual case. The plan is to examine 3300 patients with open fractures or surgical complications. As consortium partners, there are also 3 statutory health insurance companies. The extent to which the therapy recommendations are effective and contribute to cost reduction in the health care system will be empirically investigated in a stepped-wedge cluster-randomized design. In addition, medical and nonmedical professional groups involved in the project will be asked about their work in the project (in total, 248 clinic employees). The primary outcome is the complication rate of open fractures or the occurrence of postoperative complications. As secondary outcomes, the number of antibiotics administered, limb function, and quality of life will be assessed. The health economic evaluation refers to the costs of health services and absenteeism. For the work-related evaluation, workload, work engagement, work-related resources, readiness for technology, and ergonomic aspects of the new telemedical technology will be collected. In addition, clinic employees will give their assessments of the success of the project in a structured telephone interview based on scaled and open-ended questions. ResultsThe project started in June 2022; data collection started in April 2023. As of mid-June 2024, data from 425 patients had been included. In total, 146 members of staff had taken part in the questionnaire survey and 15 had taken part in the interviews. ConclusionsStandardized treatment pathways in the standard care of patients with open fractures and postoperative infections will be established to reduce complications, improve chances of recovery, and reduce costs. Unnecessary and redundant treatment steps will be avoided through standardized diagnostics and therapy. The interdisciplinary treatment perspective allows for a more individualized therapy. In the medium term, outpatient or inpatient treatment centers specialized in the patient group could be set up where the new diagnostic and therapeutic pathways could be competently applied. Trial RegistrationGerman Clinical Trials Register DRKS00031308; https://drks.de/search/de/trial/DRKS00031308 International Registered Report Identifier (IRRID)DERR1-10.2196/57820

INTRODUCTION: Quantifying antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and neutralising antibodies may help to understand protection at the individual and population levels. Determination of neutralising antibodies using classical virus neutralisation tests (VNT) is considered the gold standard, but they are costly and time-intensive. Enzyme-linked immunosorbent assay (ELISA)-based surrogate VNTs (sVNT) or anti-SARS-CoV-2 spike protein receptor binding domain immunoglobulins (anti-S-RBD Ig) may be suitable alternatives to VNTs. We aimed to (a) explore the correlations between anti-S-RBD Ig, VNT, and sVNT measurements and (b) describe humoral immunity against SARS-CoV-2 after vaccination, natural infection, and vaccine breakthrough infection in healthy blood donors. METHODS: We measured total anti-SARS-CoV-2 Ig in 5714 serum samples from 2748 healthy individuals visiting the Swiss Red Cross Blood Donation Centre in Basel from 03/2020 to 04/2022. We used the Elecsys® Anti-SARS-CoV-2 immunoassay (Roche) against the N- and S-receptor binding domain (RBD) proteins. In a subset of 548 samples from 123 donors, we conducted sVNTs against the Wuhan wild-type SARS-CoV-2 (SARS-CoV-2 Neutralizing Antibodies Detection Kit; Adipogen™). In 100 samples from 40 donors, we correlated sVNT and VNTs against the wild-type (D614G WU1) virus. Surveys were sent to the blood donors to collect data on their SARS-CoV-2 infection and vaccination status. Using this data, donors were categorised as “vaccination only”, “infection before vaccination”, “post-vaccine breakthrough infection”, and “natural infection only”. RESULTS: Our longitudinal observation study cohort consisted of 50.7% males with a median age of 31 years (range 18–75 y). Anti-SARS-CoV-2 N protein positivity rates per month indicate 57.1% (88/154) of the cohort was infected up to 04/2022. No differences in seropositivity were found between sexes, age groups, blood types (AB0 or RhD), and cytomegalovirus serostatus. We observed a high correlation between anti-S-RBD Ig and inhibition percentage (Spearman’s ρ = 0.92, Kendall’s τ = 0.77, p

Abstract In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before and after a five-day psilocybin-assisted meditation retreat using a recently established approach, based on the Mapper algorithm from topological data analysis. After generating subject-specific maps for two groups (psilocybin vs. placebo, 18 subjects/group) of experienced meditators, organizational principles were uncovered using graph topological tools, including the optimal transport (OT) distance, a geometrically rich measure of similarity between brain activity patterns. This revealed characteristics of the topology (i.e. shape) in space (i.e. abstract space of voxels) and time dimension of whole-brain activity patterns during different styles of meditation and psilocybin-induced alterations. Most interestingly, we found that (psilocybin-induced) positive derealization, which fosters insightfulness specifically when accompanied by enhanced open-monitoring meditation, was linked to the OT distance between open-monitoring and resting state. Our findings suggest that enhanced meta-awareness through meditation practice in experienced meditators combined with potential psilocybin-induced positive alterations in perception mediate insightfulness. Together, these findings provide a novel perspective on meditation and psychedelics that may reveal potential novel brain markers for positive synergistic effects between mindfulness practices and psilocybin.

Abstract Patients with intestinal failure who receive long-term parenteral nutrition (PN) often develop intestinal failure-associated liver disease (IFALD). Although there are identified risk factors, the early pathogenesis is poorly understood and treatment options are limited. Here, we perform a transcriptomic analysis of liver tissue in a large animal IFALD model to generate mechanistic insights and identify therapeutic targets. Preterm Yorkshire piglets were provided PN or bottle-fed with sow-milk replacer for 14 days. Compared to bottle-fed controls, piglets receiving PN developed biochemical cholestasis by day of life 15 (total bilirubin 0.2 vs. 2.9 mg/dL, P = 0.01). RNA-Seq of liver tissue was performed. Ingenuity Pathway Analysis identified 747 differentially expressed genes (343 upregulated and 404 downregulated) with an adjusted P |1|. Enriched canonical pathways were identified, demonstrating broad activation of inflammatory pathways and inhibition of cell cycle progression. Potential therapeutics including infliximab, glucocorticoids, statins, and obeticholic acid were identified as predicted upstream master regulators that may reverse the PN-induced gene dysregulation. The early driver of IFALD in neonates may be inflammation with an immature liver; identified therapeutics that target the inflammatory response in the liver should be investigated as potential treatments.

Abstract Social difficulties during interactions with others are central to autism spectrum disorder (ASD). Understanding the links between these social difficulties and their underlying neural processes is a primary aim focused on improved diagnosis and treatment. In keeping with this goal, we have developed a multivariate classification method based on neural data acquired by functional near infrared spectroscopy, fNIRS, during live eye-to-eye contact with adults who were either typically developed (TD) or individuals with ASD. The ASD diagnosis was based on the gold-standard Autism Diagnostic Observation Schedule (ADOS) which also provides an index of symptom severity. Using a nested cross-validation method, a support vector machine (SVM) was trained to discriminate between ASD and TD groups based on the neural responses during eye-to-eye contact. ADOS scores were not applied in the classification training. To test the hypothesis that SVM identifies neural activity patterns related to one of the neural mechanisms underlying the behavioral symptoms of ASD, we determined the correlation coefficient between the SVM scores and the individual ADOS scores. Consistent with the hypothesis, the correlation between observed and predicted ADOS scores was 0.72 (p

Abstract Introduction Typically, oncology is not a structured part of the curriculum in Brazilian medical schools. Furthermore, sarcomas, which are uncommon tumors, are seldom covered in depth. A lack of comprehensive education on sarcomas might result in medical professionals being ill-equipped to care for patients with this condition. Objectives To assess medical students' understanding and awareness of sarcomas and the specific principles related to these tumors. Materials and methods A quantitative, cross-sectional study was conducted using a questionnaire, applied to medical students, focusing on the epidemiology, pathophysiology, and treatments of bone and soft tissue sarcomas. In all tests, the significance level adopted was 5%. The SPSS version 25.0 software was used. Results Of the 825 questionnaires distributed, 325 were returned. Educational sessions on sarcomas did not appear to significantly improve the student's knowledge. Only 29.5% of students identified the lack of pain as an indicator of potential malignancy in soft tissue sarcomas, while 73.8% correctly recognized pain as a symptom of bone sarcomas. Limb amputation as the optimal surgical method for patient recovery was incorrectly reported by 39.1% of the sample. Conclusion A great part of the surveyed population does not have adequate knowledge about the basic concepts associated with limb sarcomas. The minority of them are satisfied with the knowledge gained during their medical education about these tumors. Inadequate medical academic training may initially lead to the wrong clinical management of patients with bone and soft tissue tumor lesions. An educational effort is needed to enhance oncology education for medical students, especially concerning sarcomas.

Background: The most effective method for improving the prognosis of lung cancer is the application of low-dose computed tomography (LDCT) for pulmonary nodule screening in populations at high risk. Timely diagnosis and treatment of early-stage lung cancer can contribute to higher long-term survival rates. However, it remains difficult to differentiate malignant from benign pulmonary nodules measuring 8–15 mm, and avoid overtreatment on the one hand and delayed diagnosis on the other hand. In this consensus paper, we aimed to clarify the definition of “high-risk indeterminate pulmonary nodules (IPNs)” and discuss appropriate evaluation and management to facilitate timely diagnosis of lung cancer to improve lung cancer outcome. Direction for future research was discussed. Methods: A multi-disciplinary panel of doctors and IT experts from Asia, Canada and the U.S. were invited to participate. Published evidence and consensus guidelines were used to develop this consensus was clarified. Their evaluation and management were discussed. Findings: The experts believed that the prevalence of pulmonary nodules was very high, and it that was difficult to diagnose early-stage lung cancer due to the small size of the nodules, often leading to delayed diagnosis or overtreatment. To address this issue and to improve long-term outcome, the panel considered important to revise the classification of high-risk IPNs, (1) as pulmonary nodules that cannot be clearly diagnosed with non-surgical biopsy procedures, but is highly suspicious for early-stage lung cancer. The panel also recommends the most responsible should arrange imaging evaluations and follow-ups, taking new technologies into account. Artificial intelligence (AI) assessment based on the Medical Internet of Things (MIoT) can be combined with expert opinion to form a human–computer multidisciplinary team (MDT) that can fully implement the three core procedures of the MIoT, namely, comprehensive perception, reliable transmission, and intelligent processing. This will help to upgrade the non-standard diagnosis and treatment, the so-called “handicraft workshop model”, to a modern assembly-line model that meets international standards. The MIoT technology, which has the potential to realize “simplification of complex problems, digitalization of simple problems, programming of digital problems, and systematization of programming problems”, can promote the homogeneous evaluation of pulmonary nodules by enhancing both the sensitivity and the specificity of detecting early-stage lung cancer, in order to avoid delayed diagnosis and overtreatment. Conclusion: To optimize the evaluation of early-stage lung cancer, and to avoid delayed diagnosis and overtreatment, it is necessary to propose and promote the concept of “high-risk IPNs”. The application of current technologies, AI, and a human–computer MDT, will facilitate improvement in nodule evaluation, transforming the current diagnosis and treatment model, which is akin to production in handicraft workshops, into a modern assembly-line model that meets international standards, and will ultimately result in better prognosis.

Introduction: Pennsylvania opened its first medical marijuana (MMJ) dispensary in 2018. Qualifying conditions include six conditions determined to have no or insufficient evidence to support or refute MMJ effectiveness. We conducted a study to describe MMJ dispensary access in Pennsylvania and to determine whether dispensary proximity was associated with MMJ certifications and community demographics. Methods: Using data from the Pennsylvania Department of Health, we geocoded MMJ dispensary locations and linked them to US Census Bureau data. We created dispensary access measures from the population-weighted centroid of Zip Code Tabulation Areas (ZCTAs): distance to nearest dispensary and density of dispensaries within a 15-min drive. We evaluated associations between dispensary access and the proportion of adults who received MMJ certification and the proportion of certifications for low evidence conditions (amyotrophic lateral sclerosis, epilepsy, glaucoma, Huntington’s disease, opioid use disorder, and Parkinson’s disease) using negative binomial modeling, adjusting for community features. To evaluate associations racial and ethnic composition of communities and distance to nearest dispensary, we used logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI), adjusting for median income. Results: Distance and density of MMJ dispensaries were associated with the proportion of the ZCTA population certified and the proportion of certifications for insufficient evidence conditions. Compared to ZCTAs with no dispensary within 15 min, the proportion of adults certified increased by up to 31% and the proportion of certifications for insufficient evidence decreased by up to 22% for ZCTAs with two dispensaries. From 2018 to 2021, the odds of being within five miles of a dispensary was up to 20 times higher in ZCTAs with the highest proportions of individuals who were not White (2019: OR: 20.14, CI: 10.7–37.8) and more than double in ZCTAs with the highest proportion of Hispanic individuals (2018: OR: 2.81, CI: 1.51–5.24), compared to ZCTAs with the lowest proportions. Conclusions: Greater dispensary access was associated with the proportions of certified residents and certifications for low evidence conditions. Whether these patterns are due to differences in accessibility or demand is unknown. Associations between community demographics and dispensary proximity may indicate MMJ access differences.

During January–August 2021, the Community Prevalence of SARS-CoV-2 Study used time/location sampling to recruit a cross-sectional, population-based cohort to estimate SARS-CoV-2 seroprevalence and nasal swab sample PCR positivity across 15 US communities. Survey-weighted estimates of SARS-CoV-2 infection and vaccine willingness among participants at each site were compared within demographic groups by using linear regression models with inverse variance weighting. Among 22,284 persons >2 months of age and older, median prevalence of infection (prior, active, or both) was 12.9% across sites and similar across age groups. Within each site, average prevalence of infection was 3 percentage points higher for Black than White persons and average vaccine willingness was 10 percentage points lower for Black than White persons and 7 percentage points lower for Black persons than for persons in other racial groups. The higher prevalence of SARS-CoV-2 infection among groups with lower vaccine willingness highlights the disparate effect of COVID-19 and its complications.

Abstract Background Macrophage activation syndrome is a rare disorder leading to unregulated immune activity manifesting with nonspecific constitutional symptoms, laboratory abnormalities, and multiorgan involvement. We report the case of a patient who presented with acute hepatitis secondary to macrophage activation syndrome diagnosed by liver biopsy and successfully treated with intravenous immune globulin, anakinra, and rituximab. Case presentation A 42-year-old Laotian woman with adult-onset immunodeficiency with anti-interferon gamma antibodies presented with a fever, headache, generalized myalgia, dark urine, and reduced appetite in the setting of family members at home with similar symptoms. Her laboratory workup was notable for evidence of acute hepatitis without acute liver failure. After an unrevealing comprehensive infectious and noninvasive rheumatologic workup was completed, a liver biopsy was performed ultimately revealing the diagnosis of macrophage activation syndrome. She was successfully treated with intravenous immune globulin, anakinra, and rituximab. Conclusion This case highlights the importance of maintaining macrophage activation syndrome on the differential of a patient with acute hepatitis of unknown etiology in the correct clinical context and the value of a liver biopsy in making a diagnosis when noninvasive testing is unrevealing.

Background Worldwide, 1–2% of children are born premature and at risk for developing bronchopulmonary dysplasia (BPD). Preterm-born adults are at risk for early cardiovascular disease. The role of BPD is unclear. This study aims to examine cardiorespiratory function during submaximal exercise in young adult survivors of extreme prematurity, with or without BPD. Methods 40 preterm-born young adults, 20 with BPD (median gestational age 27 weeks, interquartile range (IQR) 26–28 weeks) and 20 without BPD (median gestational age 28 weeks, IQR 27–29 weeks) were prospectively compared to age-matched at term-born adults (median gestational age 39 weeks, IQR 38–40 weeks). Participants underwent exercise testing and cardiovascular magnetic resonance with submaximal exercise. Results Resting heart rate in BPD subjects was higher than in at term-born subjects (69±10 mL versus 61±7 mL, p=0.01). Peak oxygen uptake during maximal cardiopulmonary exercise testing was decreased in BPD subjects (91±18% versus 106±17% of predicted, p=0.01). In BPD subjects, cardiac stroke volume change with exercise was impaired compared to at term-born subjects (11±13% versus 25±10%; p

Objectives Various studies have highlighted how consuming adequate dietary fibre (DF) foods could confer multiple potential health benefits to humans, though data suggested that the average intake of the population is below the recommendations. The aim of this study, which involved probabilistic, mathematical and statistical modelling, was to understand, for the first time, how fibre fortification in a broad array of food categories could impact the diet and health status of Chinese consumers.Design A simulation-based approach was used to examine the potential impact of fibre fortification. The China Health and Nutrition Survey dataset was used to evaluate intakes of DF together with a dietary intake mathematical model. Commercially manufactured foods and beverages eligible for fibre fortification were identified and a total of 296 food and beverages were selected for fibre fortification calculation. Foods and beverages eligible for fibre fortification and the concentration of fibre used at intervention were identified based on Chinese legislations and regulations of nutrition label claims. Populations who meet the dietary reference values of fibre fortification have their health outcomes such as weight, cardiovascular disease (CVD) and type 2 diabetes risk quantified prefibre and postfibre reformulation as per published studies.Results The simulated fibre fortification intervention model has shown that the mean DF intake increased by 13.28%, from 12.8 g/day of baseline to 14.5 g/day, leading to an increase of 48% (from 6.85% to 10.13%) and 54% (from 14.22% to 21.84%) of the adult and children population, respectively, achieving the recommended fibre guidelines. Additionally, 234 diabetes cases per day (85 340 cases per year) as well as 73 065 deaths secondary to CVD could also potentially be averted or delayed with the increase of DF intake via fibre fortification.Conclusions This study provides a practical application implicating the potential public health benefits that could be achieved with food product reformulation.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

Abstract In magnetic resonance imaging (MRI), the perception of substandard image quality may prompt repetition of the respective image acquisition protocol. Subsequently selecting the preferred high-quality image data from a series of acquisitions can be challenging. An automated workflow may facilitate and improve this selection. We therefore aimed to investigate the applicability of an automated image quality assessment for the prediction of the subjectively preferred image acquisition. Our analysis included data from 11,347 participants with whole-body MRI examinations performed as part of the ongoing prospective multi-center German National Cohort (NAKO) study. Trained radiologic technologists repeated any of the twelve examination protocols due to induced setup errors and/or subjectively unsatisfactory image quality and chose a preferred acquisition from the resultant series. Up to 11 quantitative image quality parameters were automatically derived from all acquisitions. Regularized regression and standard estimates of diagnostic accuracy were calculated. Controlling for setup variations in 2342 series of two or more acquisitions, technologists preferred the repetition over the initial acquisition in 1116 of 1396 series in which the initial setup was retained (79.9%, range across protocols: 73–100%). Image quality parameters then commonly showed statistically significant differences between chosen and discarded acquisitions. In regularized regression across all protocols, ‘structured noise maximum’ was the strongest predictor for the technologists’ choice, followed by ‘N/2 ghosting average’. Combinations of the automatically derived parameters provided an area under the ROC curve between 0.51 and 0.74 for the prediction of the technologists’ choice. It is concluded that automated image quality assessment can, despite considerable performance differences between protocols and anatomical regions, contribute substantially to identifying the subjective preference in a series of MRI acquisitions and thus provide effective decision support to readers.

Abstract Deprescribing of inappropriate long-term proton pump inhibitors (PPI) is challenging and there is a lack of useful methods for general practitioners to tackle this. The objective of this randomized controlled trial was to evaluate the effectiveness of the electronic decision aid tool arriba-PPI on reduction of long-term PPI intake. Participants (64.5 ± 12.9 years; 54.4% women) with a PPI intake of at least 6 months were randomized to receive either consultation with arriba-PPI from their general practitioner (n = 1256) or treatment as usual (n = 1131). PPI prescriptions were monitored 6 months before, 6 and 12 months after study initiation. In 49.2% of the consultations with arriba-PPI, the general practitioners and their patients made the decision to reduce or discontinue PPI intake. At 6 months, there was a significant reduction by 22.3% (95% CI 18.55 to 25.98; p

Abstract Background The greatest change in the treatment of people living with type 1 diabetes in the last decade has been the explosion of technology assisting in all aspects of diabetes therapy, from glucose monitoring to insulin delivery and decision making. As such, the aim of our systematic review was to assess the utility of these technologies as well as identify any precision medicine-directed findings to personalize care. Methods Screening of 835 peer-reviewed articles was followed by systematic review of 70 of them (focusing on randomized trials and extension studies with ≥50 participants from the past 10 years). Results We find that novel technologies, ranging from continuous glucose monitoring systems, insulin pumps and decision support tools to the most advanced hybrid closed loop systems, improve important measures like HbA1c, time in range, and glycemic variability, while reducing hypoglycemia risk. Several studies included person-reported outcomes, allowing assessment of the burden or benefit of the technology in the lives of those with type 1 diabetes, demonstrating positive results or, at a minimum, no increase in self-care burden compared with standard care. Important limitations of the trials to date are their small size, the scarcity of pre-planned or powered analyses in sub-populations such as children, racial/ethnic minorities, people with advanced complications, and variations in baseline glycemic levels. In addition, confounders including education with device initiation, concomitant behavioral modifications, and frequent contact with the healthcare team are rarely described in enough detail to assess their impact. Conclusions Our review highlights the potential of technology in the treatment of people living with type 1 diabetes and provides suggestions for optimization of outcomes and areas of further study for precision medicine-directed technology use in type 1 diabetes.

OBJECTIVES/GOALS: We endeavor to investigated the hypothesis that muscle protein synthesis (MPS) is stimulated more after consumption of a 4-ounce beef patty as compared to 4- and 8-ounces of a soy protein based meat alternative (SPBMA) and if a greater stimulation is related to differences in the responses of plasma essential amino acid (EAA) concentrations. METHODS/STUDY POPULATION: Participants were aged 18 to 40 years of age with a BMI between 20 and 32 kg/m2. Written informed consent was obtained from all participants, and approved by UAMS IRB. Participants were assigned to one of three intervention groups via a single-blinded permuted block randomization, stratified for sex: 4 oz beef patty; 4 oz SPBMA; 2 x 4 oz (8oz) SPBMA. The impossible burgerTM was selected as it is primarily soy protein, a high-quality plant protein, and specifically designed to mimic a beef burger. Stable isotope were infused to assess protein metabolism. Appropriate muscle and blood samples were obtained. Enrichment and plasma EAA concentrations were measured with mass spectrometry. ANOVA’s on the change from basal to postprandial were used to identify group difference, significance was accepted at p < 0.05. RESULTS/ANTICIPATED RESULTS: The MPS increase from basal to postprandial indicated a significant main effect of group (p = 0.026), with the beef group (0.020 ± 0.016%/hour) being significantly greater than the 4oz SPBMA (0.003 ± 0.010%/hour; p = 0.021) but not the 8oz PBMA group (0.013 ± 0.016%/hour; p = 0.454). Similar results were observed for whole-body protein synthesis, where the beef group (p = 0.042) and 8oz SPBMA (p = 0.033) were significantly greater than the 4oz SPBMA (p = 0.021). Whole-body protein balance was significantly greater in the 8oz SPBMA as compared to 4oz of beef and SPBMA. Lastly, we observed a significantly relationship (p = 0.046; r = 0.411) between the maximal plasma EAA concentration and change in MPS, indicating the greater rate of MPS following 4oz of beef is mediated by an higher increase in plasma EAA concentrations. DISCUSSION/SIGNIFICANCE: In conclusion, 4oz of beef stimulates muscle protein FSR more than 4oz of a SPBMA. A common SPBMA can stimulate increase in protein metabolism, however, greater amounts are required as compared to beef protein. Further, the change in the muscle protein FSR response was significantly correlated with the maximal EAA concentration.

Abstract Objectives This release note describes the Maize GxE project datasets within the Genomes to Fields (G2F) Initiative. The Maize GxE project aims to understand genotype by environment (GxE) interactions and use the information collected to improve resource allocation efficiency and increase genotype predictability and stability, particularly in scenarios of variable environmental patterns. Hybrids and inbreds are evaluated across multiple environments and phenotypic, genotypic, environmental, and metadata information are made publicly available. Data description The datasets include phenotypic data of the hybrids and inbreds evaluated in 30 locations across the US and one location in Germany in 2020 and 2021, soil and climatic measurements and metadata information for all environments (combination of year and location), ReadMe, and description files for each data type. A set of common hybrids is present in each environment to connect with previous evaluations. Each environment had a collaborator responsible for collecting and submitting the data, the GxE coordination team combined all the collected information and removed obvious erroneous data. Collaborators received the combined data to use, verify and declare that the data generated in their own environments was accurate. Combined data is released to the public with minimal filtering to maintain fidelity to the original data.

BackgroundThe COVID-19 pandemic exerted extraordinary pressure on health care workers (HCWs), imperiling their well-being and mental health. In response to the urgent demand to provide barrier-free support for the health care workforce, Pause-4-Providers implemented 30-minute live web-based drop-in mindfulness sessions for HCWs. ObjectiveThis study aims to evaluate the use, feasibility, satisfaction, and acceptability of a novel mindfulness program aimed at enhancing the well-being of HCWs during the COVID-19 pandemic. MethodsAccrual for the study continued throughout the first 3 pandemic waves, and attendees of ≥1 session were invited to participate. The evaluation framework included descriptive characteristics, including participant demographics, resilience at work, and single-item burnout scores; feedback questionnaires on reasons attended, benefits, and satisfaction; qualitative interviews to further understand participant experience, satisfaction, benefits, enablers, and barriers; and the number of participants in each session summarized according to the pandemic wave. ResultsWe collected descriptive statistics from 50 consenting HCWs. Approximately half of the participants (24/50, 48%) attended >1 session. The study participants were predominantly female individuals (40/50, 80%) and comprised physicians (17/50, 34%), nurses (9/50, 18%), and other HCWs (24/50, 48%), who were largely from Ontario (41/50, 82%). Of 50 attendees, 26 (52%) endorsed feeling burned out. The highest attendance was in May 2020 and January 2021, corresponding to the first and second pandemic waves. The participants endorsed high levels of satisfaction (43/47, 92%). The most cited reasons for attending the program were to relax (38/48, 79%), manage stress or anxiety (36/48, 75%), wish for loving kindness or self-compassion (30/48, 64%), learn mindfulness (30/48, 64%), and seek help with emotional reactivity (25/48, 53%). Qualitative interviews with 15 out of 50 (30%) participants identified positive personal and professional impacts. Personal impacts revealed that participation helped HCWs to relax, manage stress, care for themselves, sleep better, reduce isolation, and feel recognized. Professional impacts included having a toolbox of mindfulness techniques, using mindfulness moments, and being calmer at work. Some participants noted that they shared techniques with their colleagues. The reported barriers included participants’ needing time to prioritize themselves, fatigue, forgetting to apply skills on the job, and finding a private place to participate. ConclusionsThe Pause-4-Providers participants reported that the web-based groups were accessible; appreciated the format, content, and faculty; and had high levels of satisfaction with the program. Both novel format (eg, drop-in, live, web-based, anonymous, brief, and shared activity with other HCWs) and content (eg, themed mindfulness practices including micropractices, with workplace applications) were enablers to participation. This study of HCW support sessions was limited by the low number of consenting participants and the rolling enrollment project design; however, the findings suggest that a drop-in web-based mindfulness program has the potential to support the well-being of HCWs.

Background: Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown. Methods: Pregnant mice were subjected to acute or chronic hypoxia (12.5% O2) resulting in reduced fetal weight. Placenta oxygen transport was assessed by blood oxygenation level dependent (BOLD) contrast magnetic resonance imaging (MRI). The placentae were analyzed via immunohistochemistry and in situ hybridization. Human placentae were selected from FGR and matched controls and analyzed by immunohistochemistry (IHC). Maternal and cord sera were analyzed by mass spectrometry. Results: We show that murine acute and chronic gestational hypoxia recapitulates FGR phenotype and affects placental structure and morphology. Gestational hypoxia decreased labyrinth area, increased the incidence of red blood cells (RBCs) in the labyrinth while expanding the placental spiral arteries (SpA) diameter. Hypoxic placentae exhibited higher hemoglobin-oxygen affinity compared to the control. Placental abundance of Bisphosphoglycerate mutase (BPGM) was upregulated in the syncytiotrophoblast and spiral artery trophoblast cells (SpA TGCs) in the murine gestational hypoxia groups compared to the control. Hif1α levels were higher in the acute hypoxia group compared to the control. In contrast, human FGR placentae exhibited reduced BPGM levels in the syncytiotrophoblast layer compared to placentae from healthy uncomplicated pregnancies. Levels of 2,3 BPG, the product of BPGM, were lower in cord serum of human FGR placentae compared to control. Polar expression of BPGM was found in both human and mouse placentae syncytiotrophoblast, with higher expression facing the maternal circulation. Moreover, in the murine SpA TGCs expression of BPGM was concentrated exclusively in the apical cell side, in direct proximity to the maternal circulation. Conclusions: This study suggests a possible involvement of placental BPGM in maternal-fetal oxygen transfer, and in the pathophysiology of FGR. Funding: This work was supported by the Weizmann Krenter Foundation and the Weizmann – Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.

BackgroundResearchers have increasingly recognized the importance of structural and social determinants of health (SSDOH) as key drivers of a multitude of diseases and health outcomes. The Multi-Ethnic Study of Atherosclerosis (MESA) is an ongoing, longitudinal cohort study of subclinical cardiovascular disease (CVD) that has followed geographically and racially/ethnically diverse participants starting in 2000. Since its inception, MESA has incorporated numerous SSDOH assessments and instruments to study in relation to CVD and aging outcomes. In this paper, we describe the SSDOH data available in MESA, systematically review published papers using MESA that were focused on SSDOH and provide a roadmap for future SSDOH-related studies.Methods and findingsThe study team reviewed all published papers using MESA data (n = 2,125) through January 23, 2023. Two individuals systematically reviewed titles, abstracts, and full text to determine the final number of papers (n = 431) that focused on at least one SSDOH variable as an exposure, outcome, or stratifying/effect modifier variable of main interest (discrepancies resolved by a third individual). Fifty-seven percent of the papers focused on racialized/ethnic groups or other macrosocial/structural factors (e.g., segregation), 16% focused on individual-level inequalities (e.g. income), 14% focused on the built environment (e.g., walking destinations), 10% focused on social context (e.g., neighborhood socioeconomic status), 34% focused on stressors (e.g., discrimination, air pollution), and 4% focused on social support/integration (e.g., social participation). Forty-seven (11%) of the papers combined MESA with other cohorts for cross-cohort comparisons and replication/validation (e.g., validating algorithms).ConclusionsOverall, MESA has made significant contributions to the field and the published literature, with 20% of its published papers focused on SSDOH. Future SSDOH studies using MESA would benefit by using recently added instruments/data (e.g., early life educational quality), linking SSDOH to biomarkers to determine underlying causal mechanisms linking SSDOH to CVD and aging outcomes, and by focusing on intersectionality, understudied SSDOH (i.e., social support, social context), and understudied outcomes in relation to SSDOH (i.e., sleep, respiratory health, cognition/dementia).

Introduction Traditional survey-based surveillance is costly, limited in its ability to distinguish diabetes types and time-consuming, resulting in reporting delays. The Diabetes in Children, Adolescents and Young Adults (DiCAYA) Network seeks to advance diabetes surveillance efforts in youth and young adults through the use of large-volume electronic health record (EHR) data. The network has two primary aims, namely: (1) to refine and validate EHR-based computable phenotype algorithms for accurate identification of type 1 and type 2 diabetes among youth and young adults and (2) to estimate the incidence and prevalence of type 1 and type 2 diabetes among youth and young adults and trends therein. The network aims to augment diabetes surveillance capacity in the USA and assess performance of EHR-based surveillance. This paper describes the DiCAYA Network and how these aims will be achieved.Methods and analysis The DiCAYA Network is spread across eight geographically diverse US-based centres and a coordinating centre. Three centres conduct diabetes surveillance in youth aged 0–17 years only (component A), three centres conduct surveillance in young adults aged 18–44 years only (component B) and two centres conduct surveillance in components A and B. The network will assess the validity of computable phenotype definitions to determine diabetes status and type based on sensitivity, specificity, positive predictive value and negative predictive value of the phenotypes against the gold standard of manually abstracted medical charts. Prevalence and incidence rates will be presented as unadjusted estimates and as race/ethnicity, sex and age-adjusted estimates using Poisson regression.Ethics and dissemination The DiCAYA Network is well positioned to advance diabetes surveillance methods. The network will disseminate EHR-based surveillance methodology that can be broadly adopted and will report diabetes prevalence and incidence for key demographic subgroups of youth and young adults in a large set of regions across the USA.

Summary: Background: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. Methods: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. Findings: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with

In patients with lung cancer (LC), understanding factors that impact the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike antibody (SAb) titers over time is critical, but challenging, due to evolving treatments, infections, vaccinations, and health status. The objective was to develop a time-dependent regression model elucidating individual contributions of factors influencing SAb levels in LC patients using a prospective, longitudinal, multi-institutional cohort study initiated in January 2021. The study evaluated 296 LC patients—median age 69; 55% female; 50% stage IV. Blood samples were collected every three months to measure SAb levels using FDA-approved ELISA. Asymptomatic and unreported infections were documented through measurement of anti-nucleocapsid Ab levels (Meso Scale Discovery). Associations between clinical characteristics and titers were evaluated using a time-dependent linear regression model with a generalized estimating equation (GEE), considering time-independent variables (age, sex, ethnicity, smoking history, histology, and stage) and time-dependent variables (booster vaccinations, SARS-CoV-2 infections, cancer treatment, steroid use, and influenza vaccination). Significant time-dependent effects increasing titer levels were observed for prior SARS-CoV-2 infection (p < 0.001) and vaccination/boosters (p < 0.001). Steroid use (p = 0.043) and chemotherapy (p = 0.033) reduced titer levels. Influenza vaccination was associated with increased SAb levels (p < 0.001), independent of SARS-CoV-2 vaccine boosters. Prior smoking significantly decreased titers in females (p = 0.001). Age showed no association with titers. This GEE-based linear regression model unveiled the nuanced impact of multiple variables on patient anti-spike Ab levels over time. After controlling for the major influences of vaccine and SARS-CoV-2 infections, chemotherapy and steroid use were found to have negatively affected titers. Smoking in females significantly decreased titers. Surprisingly, influenza vaccinations were also significantly associated, likely indirectly, with improved SARS-CoV-2 titers.

OBJECTIVES/GOALS: Since 2017, we have used the Design Lab methodology to support investigators taking innovative approaches to clinical effectiveness trial design. To date we have held 12 Design Labs and this year we are creating a handbook that will support dissemination of this approach across the Clinical and Translational Science Award consortium. METHODS/STUDY POPULATION: The Clinical Trial Design Lab brings together a multi-stakeholder group to consider innovative and impactful clinical trial designs. An investigative team is selected from a competitive pool of applicants, after which expert-led consultations support the investigator team to think about evidence generation in the context of the full treatment development pathway. Teams map the stakeholders at each step of this pathway (e.g. clinicians, patients, researchers, funders, industry experts, policy experts, regulatory experts, payers) and consider innovative design solutions. These consultations prepare investigators for an event that involves all stakeholders in a structured and facilitated discussion about trial designs that generate the best evidence and increase potential for health impact. RESULTS/ANTICIPATED RESULTS: The result of our work will be a set of Design Lab principles, a handbook with templates that support stakeholder mapping and structured discussions, and educational resources to accompany the handbook. The work is supported by a literature review that characterizes the multi-component processes included in the Design Lab, situates them within the larger context of team science interventions, and lays groundwork for the development of process metrics and impact evaluation criteria to assess the Design Lab method. In this poster presentation, we will share our multi-component broadly engaged team science approach, provide a brief outline of the principles and educational resources, and include an early version of the evaluation criteria. DISCUSSION/SIGNIFICANCE: Broadly engaged team science supports innovative thinking about study design and is especially important in the development of clinical trials. We have grown the Design Lab program of work over the past seven years and are now able to characterize our team science methodology and support others to use this approach to innovate for health impact.

OBJECTIVES/GOALS: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by dysregulated collagen accumulation in the lung parenchyma. Our goal is to investigate the role of O-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) in pulmonary fibrosis to ultimately discover novel therapies for fibrosis resolution. METHODS/STUDY POPULATION: Lung tissue from IPF and non-IPF donors was subjected to immunohistochemistry (IHC) to assess O-GlcNAc levels. Primary human lung fibroblasts were treated with OGT or O-GlcNAcase (OGA) inhibitors followed by transforming growth factor-beta 1 (TGF-β1) stimulation to assess O-GlcNAc regulation of fibroblast-to-myofibroblast transition (FMT) markers [alpha smooth muscle actin (α-SMA) and type 1 and type 3 collagen (COL1α1, COL3α1)] In Drosophila melanogaster, OGT knockdown (KD)/overexpression (OE) was conditionally induced to assess pericardin, a type IV collagen-like protein, regulation by immunofluorescence. Lastly, a mouse model of bleomycin-induced pulmonary fibrosis was examined following OGT KD and assessed for fibrosis resolution via histology, hydroxyproline assay, and western blotting. RESULTS/ANTICIPATED RESULTS: O-GlcNAc staining was increased in IPF lung tissue compared to non-IPF control lungs. In primary human lung fibroblasts, TGF-α1 administration resulted in increased FMT markers (α-SMA, COL1α1, and COL3α1), which were reduced or increased by OGT or OGA inhibition, respectively. Genetic manipulation in the Drosophila models showed decreased pericardin expression with OGT KD compared to the wild-type, whereas OGT OE increased pericardin compared to control. Additionally, OGT KD in bleomycin treated aged mice resulted in reduced collagen levels at the transcript and protein level and concurrent fibrosis resolution as assessed by Masson’s trichrome staining and total hydroxyproline analysis. Collectively, showing OGT/O-GlcNAc regulating collagen in fibrosis resolution. DISCUSSION/SIGNIFICANCE: These data suggest that the OGT/O-GlcNAc axis regulates collagen deposition in pulmonary fibrosis, and we show that O-GlcNAc is implicated in the pathogenesis of IPF. We identified OGT as a therapeutic target to overcome current drug limitations, opening new horizons for biomedical treatment.

Abstract Objectives The Genomes to Fields (G2F) 2022 Maize Genotype by Environment (GxE) Prediction Competition aimed to develop models for predicting grain yield for the 2022 Maize GxE project field trials, leveraging the datasets previously generated by this project and other publicly available data. Data description This resource used data from the Maize GxE project within the G2F Initiative [1]. The dataset included phenotypic and genotypic data of the hybrids evaluated in 45 locations from 2014 to 2022. Also, soil, weather, environmental covariates data and metadata information for all environments (combination of year and location). Competitors also had access to ReadMe files which described all the files provided. The Maize GxE is a collaborative project and all the data generated becomes publicly available [2]. The dataset used in the 2022 Prediction Competition was curated and lightly filtered for quality and to ensure naming uniformity across years.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Abstract An elevation in serum phosphate—also called hyperphosphatemia—is associated with reduced kidney function in chronic kidney disease (CKD). Reports show CKD patients are more likely to develop lung disease and have poorer kidney function that positively correlates with pulmonary obstruction. However, the underlying mechanisms are not well understood. Here, we report that two murine models of CKD, which both exhibit increased serum levels of phosphate and fibroblast growth factor (FGF) 23, a regulator of phosphate homeostasis, develop concomitant airway inflammation. Our in vitro studies point towards a similar increase of phosphate-induced inflammatory markers in human bronchial epithelial cells. FGF23 stimulation alone does not induce a proinflammatory response in the non-COPD bronchial epithelium and phosphate does not cause endogenous FGF23 release. Upregulation of the phosphate-induced proinflammatory cytokines is accompanied by activation of the extracellular-signal regulated kinase (ERK) pathway. Moreover, the addition of cigarette smoke extract (CSE) during phosphate treatments exacerbates inflammation as well as ERK activation, whereas co-treatment with FGF23 attenuates both the phosphate as well as the combined phosphate- and CS-induced inflammatory response, independent of ERK activation. Together, these data demonstrate a novel pathway that potentially explains pathological kidney-lung crosstalk with phosphate as a key mediator.

Abstract In this work, we present a novel approach to photothermal super resolution based thermographic resolution of internal defects using two-dimensional pixel pattern-based active photothermal laser heating in conjunction with subsequent numerical reconstruction to achieve a high-resolution reconstruction of internal defect structures. With the proposed adoption of pixelated patterns generated using laser coupled high-power DLP projector technology the complexity for achieving true two-dimensional super resolution can be dramatically reduced taking a crucial step forward towards widespread practical viability. Furthermore, based on the latest developments in high-power DLP projectors, we present their first application for structured pulsed thermographic inspection of macroscopic metal samples. In addition, a forward solution to the underlying inverse problem is proposed along with an appropriate heuristic to find the regularization parameters necessary for the numerical inversion in a laboratory setting. This allows the generation of synthetic measurement data, opening the door for the application of machine learning based methods for future improvements towards full automation of the method. Finally, the proposed method is experimentally validated and shown to outperform several established conventional thermographic testing techniques while conservatively improving the required measurement times by a factor of 8 compared to currently available photothermal super resolution techniques.

Abstract Long interspersed element 1 (LINE-1) open reading frame 1 protein (ORF1p) expression is a common feature of many cancer types, including high-grade serous ovarian carcinoma (HGSOC). Here, we report that ORF1p is not only expressed but also released by ovarian cancer and primary tumor cells. Immuno-multiple reaction monitoring-mass spectrometry assays showed that released ORF1p is confidently detectable in conditioned media, ascites, and patients’ plasma, implicating ORF1p as a potential biomarker. Interestingly, ORF1p expression is detectable in fallopian tube (FT) epithelial precursors of HGSOC but not in benign FT, suggesting that ORF1p expression in an early event in HGSOC development. Finally, treatment of FT cells with DNA methyltransferase inhibitors led to robust expression and release of ORF1p, validating the regulatory role of DNA methylation in LINE-1 repression in non-tumorigenic tissue.

Objectives: We compared clinical outcomes after acquiring a FreeStyle Libre© Flash Continuous Glucose Monitoring System (FSL) or Dexcom (DEX) continuous glucose monitoring (CGM) device in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D) treated with intensive insulin therapy. Design and Methods: This retrospective analysis of the IBM® MarketScan® Research Databases and IBM® Explorys® Electronic Health Records Database assessed differences in acute diabetes-related events (ADE), all-cause hospitalizations (ACH) and glycated hemoglobin (HbA1c) in T1D and T2D populations 6 months post CGM acquisition. Analyses were conducted in two study cohorts (Cohort 1, n = 7,494; Cohort 2, n = 678). Participants were T1D or T2D, age ≥ 18 years, treated with short or rapid-acting insulin and naïve to CGM, who acquired a CGM system. Users were propensity score matched on demographics and clinical factors. Results: Cohort 1: Post-CGM ADE-free rates at 6 months ranged from 94.8 to 96.7% and ACH-free rates ranged from 90.4 to 95.4%, for both T1D and T2D groups, with no significant differences between CGM systems. Cohort 2: Significant HbA1c reductions were associated with use of the DEX and FSL devices in the T1D (-0.35% and -0.37%, respectively) and T2D (-0.73% and -0.79%, respectively) cohorts, both p

Among adolescents, sole use is the most common pattern of e-cigarette use. However, concurrent use of e-cigarettes with other tobacco products is not uncommon and may be associated with high-risk behaviors. We used data from 12,767 participants in the 2019 Youth Risk Behavior Survey to examine the patterns of tobacco product use among youth in the US. First, we examined the prevalence of e-cigarette-specific patterns of tobacco use (nonuse[no tobacco product use], sole use[sole e-cigarette use], dual-use[e-cigarette and one other tobacco product], and poly use[e-cigarette and two or more other tobacco products]). Then, using multivariable Poisson regression, we assessed how the tobacco use patterns were associated with the misuse of nine substances of abuse (alcohol, marijuana, cocaine, ecstasy, hallucinogens, heroin, inhalants, injectables, and methamphetamines).62.9% of youth reported nonuse of any tobacco product. The weighted prevalence of sole e-cigarette use, dual use, and poly use was 23.2%, 4.2%, and 3.3%, respectively. Across all the substances explored, the prevalence was highest among poly users, followed by dual users, sole users, and non-users. Compared to non-users, sole, dual, and poly users had 7.8(95 %CI:6.1–10.0), 14.3(95 %CI:10.8–18.8), and 19.7(95 %CI:15.0–25.9) times higher adjusted prevalence of reporting past-30-day binge drinking, after adjusting for age, sex, race/ethnicity, sexual orientation, and depressive symptoms. This pattern was seen across all the different substances explored. These findings highlight the high prevalence of substance misuse among youth who use tobacco products and the need to educate and counsel on substances of abuse among this population, particularly among poly-tobacco users.

Objectives US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined.Design This is an observational retrospective comparative cohort study.Setting Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites.Results Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45).Conclusions Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others.

Objectives To identify incident SARS-CoV-2 infections and inform effective mitigation strategies in university settings, we piloted an integrated symptom and exposure monitoring and testing system among a cohort of university students and employees.Design Prospective cohort study.Setting A public university in California from June to August 2020.Participants 2180 university students and 738 university employees.Primary outcome measures At baseline and endline, we tested participants for active SARS-CoV-2 infection via quantitative PCR (qPCR) test and collected blood samples for antibody testing. Participants received notifications to complete additional qPCR tests throughout the study if they reported symptoms or exposures in daily surveys or were selected for surveillance testing. Viral whole genome sequencing was performed on positive qPCR samples, and phylogenetic trees were constructed with these genomes and external genomes.Results Over the study period, 57 students (2.6%) and 3 employees (0.4%) were diagnosed with SARS-CoV-2 infection via qPCR test. Phylogenetic analyses revealed that a super-spreader event among undergraduates in congregate housing accounted for at least 48% of cases among study participants but did not spread beyond campus. Test positivity was higher among participants who self-reported symptoms (incidence rate ratio (IRR) 12.7; 95% CI 7.4 to 21.8) or had household exposures (IRR 10.3; 95% CI 4.8 to 22.0) that triggered notifications to test. Most (91%) participants with newly identified antibodies at endline had been diagnosed with incident infection via qPCR test during the study.Conclusions Our findings suggest that integrated monitoring systems can successfully identify and link at-risk students to SARS-CoV-2 testing. As the study took place before the evolution of highly transmissible variants and widespread availability of vaccines and rapid antigen tests, further research is necessary to adapt and evaluate similar systems in the present context.

BackgroundLung cancer is the leading cause of cancer-related death in the United States, with the majority of lung cancer occurrence diagnosed after the disease has already metastasized. Lung cancer screening (LCS) with low-dose computed tomography can diagnose early-stage disease, especially when eligible individuals participate in screening on a yearly basis. Unfortunately, annual adherence has emerged as a challenge for academic and community screening programs, endangering the individual and population health benefits of LCS. Reminder messages have effectively increased adherence rates in breast, colorectal, and cervical cancer screenings but have not been tested with LCS participants who experience unique barriers to screening associated with the stigma of smoking and social determinants of health. ObjectiveThis research aims to use a theory-informed, multiphase, and mixed methods approach with LCS experts and participants to develop a set of clear and engaging reminder messages to support LCS annual adherence. MethodsIn aim 1, survey data informed by the Cognitive-Social Health Information Processing model will be collected to assess how LCS participants process health information aimed at health protective behavior to develop content for reminder messages and pinpoint options for message targeting and tailoring. Aim 2 focuses on identifying themes for message imagery through a modified photovoice activity that asks participants to identify 3 images that represent LCS and then participate in an interview about the selection, likes, and dislikes of each photo. A pool of candidate messages for multiple delivery platforms will be developed in aim 3, using results from aim 1 for message content and aim 2 for imagery selection. The refinement of message content and imagery combinations will be completed through iterative feedback from LCS experts and participants. ResultsData collection began in July 2022 and will be completed by May 2023. The final reminder message candidates are expected to be completed by June 2023. ConclusionsThis project proposes a novel approach to facilitate adherence to annual LCS through the development of reminder messages that embrace content and imagery representative of the target population directly in the design process. Developing effective strategies to increase LCS adherence is instrumental in achieving optimal LCS outcomes at individual and population health levels. International Registered Report Identifier (IRRID)DERR1-10.2196/46657