Search

Objective: Hypoglycemia is a major concern in type 2 diabetes (T2DM), but little is known about its likelihood compared across common therapies. We compared the likelihood of hypoglycemia among metformin-treated patients with T2DM randomized to the addition of one of 4 common therapies., Research Design & Methods: Randomized, controlled trial of 5,047 participants with T2DM of <10 years' duration, hemoglobin A1c (HbA1c) 6.8-8.5% (50.8-69.4 mmol/mol). Randomization to addition of glargine U100, glimepiride, liraglutide, or sitagliptin over 5.0 ± 1.3 (mean ± SD) years. HbA1c was measured quarterly; if a level >7.5% (>58.5 mmol/mol) was confirmed, rescue glargine and/or aspart insulin was added. We conducted a per-protocol analysis of 4,830, who attended at least one post-baseline visit and took at least one dose of assigned study medication. We assessed severe hypoglycemia events reported throughout the entire study. At quarterly visits, all participants were asked about hypoglycemic symptoms within the last 30 days, and those in the glargine and glimepiride groups were asked for any measured glucose <70 mg/dL (3.9 mmol/L) within this time period., Results: While participants were taking their assigned medications, severe hypoglycemia occurred in 10 (0.8%), 16 (1.3%), 6 (0.5%), and 4 (0.3%), (p<0.05) and hypoglycemic symptoms in 659 (54.2%), 833 (68.3%), 375 (32.4%), and 361 (29.1%) of participants following randomization to glargine, glimepiride, liraglutide, and sitagliptin, respectively (p<0.001)., Conclusions: In metformin-treated patients with T2DM who add a second medication, hypoglycemia is most likely with addition of glimepiride, less with glargine, and least likely with liraglutide and sitagliptin., Trial Registration: ClinicalTrials.gov Identifier: NCT01794143., Competing Interests: Outside the submitted work, Dr. Elizabeth Seaquist reports grants or contracts from JDRF to her institution; consulting fees from Lily, NovoNordisk, Sanofi, and Zucara; honoraria from International Hypoglycemia study group; board membership with the American Diabetes Association; and receipt of sensors from Dexcom to her institution. Dr. Lawrence Phillips reports salary support from the Veterans Health Administration during the conduct of the study; grants from Janssen Pharmaceuticals, grants from Merck, Amylin, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, AbbVie, Vascular Pharmaceuticals, GlaxoSmithKline, Pfizer, AstraZeneca, Kowa, and Cystic Fibrosis Foundation; other support from DIASYST, outside the submitted work. Outside the submitted work, Dr. Richard M. Bergenstal reports consulting fees from Abbot Diabetes Care, Ascencia, Bigfoot Biomedical, Inc., DexCom, MannKind, Medtronic, Novo Nordisk, Sanofi, and United Health Care made to HealthPartners Institute; payments or honoraria from Sanofi and Vertex Pharmaceuticals made to Health Partners Institute; support for meetings or travel from Abbott Diabetes Care, Ascensia, CeQur, Eli Lilly, Embecta, MannKind, Novo Nordisk, Roche GmbH, Sanofi, Vertex Pharmaceuticals, and Zealand Pharma made to Health Partners Institute, and participation on a data safety monitoring or advisory board from Abbott Diabetes Care, CeQur, Eli Lilly, Embecta, Hygieia, Roche GmbH, and Zealand Pharma with payments made to HealthPartners Institute. Outside the submitted work, Dr. Jill Crandall reports non-financial support from Abbott. Outside the submitted work, Mary L Johnson reports research grants paid to Health Partners Institute from Sanofi, Novo Nordisk, and Lilly. Dr. Alokananda Ghosh, Dr. Naji Younes, Dr. John Lachin, Chelsea Baker, Dr. Robin S. Goland, Michaela R Gramzinski, Dr. Daniel S Hsia, Dr. Sophia H Hox, Dr. Philip Raskin, Dr. Willy M Valencia, and Andrea H Waltje have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Medulloblastoma is the most common malignant brain tumor in children. It has WNT-driven, SHH-driven/TP53 mutant, SHH-driven/TP53 wildtype, and non-WNT/non-SHH subgroups. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encodes a mitochondrial import inner membrane translocase subunit and is responsible for the translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines. The aim of our study was to investigate whether the chemotherapeutic effect of BT9 can be extended to pediatric medulloblastoma., Methods: DAOY (SHH driven/tp53 mutant) and D425 (non-SHH group 3) were treated with BT9. For in vitro analysis, cell proliferation, death, migration, invasion, and metabolic activity were assessed using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. A D425 orthotopic xenograft mouse model was used to evaluate BT9 efficacy in vivo., Results: BT9 treatment resulted in a significant decrease in cell proliferation (DAOY, 24 hours IC50: 3.6 μM, 48 hours IC50: 2.3 μM, 72 hours IC50: 2.1 μM; D425 24 hours IC50: 3.4 μM, 48 hours IC50: 2.2 μM, 72 hours IC50: 2.1 μM) and a significant increase in cell death (DAOY, 24 hours p = 0.0004, 48 hours p<0.0001; D425, 24 hours p = 0.0001, 48 hours p = 0.02). In DAOY cells, 3 μM BT9 delayed migration and significantly reduced DAOY and D425 cell invasion (p < 0.0001). It also modified mitochondrial respiratory function in both medulloblastoma cell lines. Compared to control, however, BT9 administration did not improve survival in a D425 orthotopic xenograft mouse model., Conclusions: Our in vitro data showed BT9 antitumor efficacy in DAOY and D425 cell lines, suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Motahari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: This study was conducted to assess the cost-effectiveness of prophylactic use of ramosetron compared to no antiemetic medications for the prevention of postoperative nausea and vomiting (PONV) from the healthcare payer and societal perspectives in South Korea., Method: A decision analytic model was constructed to assess the cost-effectiveness of prophylactic ramosetron use versus no antiemetic therapy at 24-hour and 48-hour periods post-surgery over a 5-day duration. The model was populated using costs and utility parameters from published studies as well as from surveys of an expert panel of physicians using structured questionnaires. The cost parameters included the costs of drugs, treatment, patient time, productivity loss, and transportation. Effectiveness was measured using quality adjusted life years (QALYs). The study outcome was the incremental cost-effectiveness ratio (ICER). The parameter uncertainties were addressed using deterministic and probabilistic scenario analyses., Results: The base-case analysis showed that, on average, patients treated with prophylactic ramosetron had lower costs from both the healthcare payer (US$16.88 vs US$17.33) and societal (US$16.89 vs US$18.72) perspectives and higher QALYs (0.0121 vs 0.0114) over the 5-day study duration compared to patients without any antiemetic medications. Deterministic and probabilistic sensitivity analyses were conducted to examine the robustness of results for the parameters included in the model. The acceptability curve probability showed that treating patients with ramosetron compared to no antiemetic medications was more than 99% cost-effective at a willingness-to pay threshold of US$5,000/QALY from both payer and societal perspectives., Conclusion: The results demonstrated that prophylactic use of ramosetron compared to no antiemetic therapy is highly cost-effective to prevent PONV for patients undergoing surgery from both healthcare payer and societal perspectives. The cost effectiveness is the result of the decrease in the incidence of PONV and the direct treatment costs of severe PONV with improved patient quality of life., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Suh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Retention to complete follow-up surveys in extensive longitudinal epidemiological cohort studies is vital yet challenging. All of Us developed pilot interventions to improve response rates for follow-up surveys., Study Design and Setting: The pilot interventions occurred from April 27, 2020, to August 3, 2020. The three arms were: (1) telephone appointment [staff members calling participants offering appointments to complete surveys over phone] (2) postal [mail reminder to complete surveys through U.S. Postal Service], and (3) combination of telephone appointment and postal. Controls received digital-only reminders [program-level digital recontact via email or through the participant portal]. Study sites chose their study arm and participants were not randomized., Results: A total of 50 sites piloted interventions with 17,593 participants, while 47,832 participants comprised controls during the same period. Of all participants, 6,828 (10.4%) completed any follow-up surveys (1448: telephone; 522: postal; 486: combination; 4372: controls). Follow-up survey completions were 24% higher in the telephone appointment arm than in controls in bivariate analyses. When controlling for confounders, telephone appointment and combination arms increased rates of completion similarly compared to controls, while the postal arm had no significant effect (odds ratio [95% Confidence Interval], telephone appointment:2.01[1.81-2.23]; combination:1.91[1.66-2.20]; postal:0.92[0.79-1.07]). Although the effects of the telephone appointment and combination arms were similar, differential effects were observed across sub-populations., Conclusion: Telephone appointments appeared to be the most successful intervention in our study. Lessons learned about retention interventions, and improvement in follow-up survey completion rates provide generalizable knowledge for similar cohort studies and demonstrate the potential value of precision reminders and engagement with sub-populations of a cohort., Competing Interests: NO authors have competing interests., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGF) play important role in breast tumor growth, invasion, metastasis, patient survival and drug resistance. The aim of this study was to evaluate the protein expression status of EGFR and VEGF-A, as well as their association with hormone receptor status and histopathological characteristics in the invasive type of female breast cancer among Ethiopians., Method: The primary breast tumor tissues were obtained from 85 Ethiopian invasive breast cancer cases that underwent modified radical mastectomy (MRM) from June 2014 to June 2015. Their FFPE blocks were analyzed for EGFR and VEGF protein expressions using immunohistochemical techniques. The expressions were also correlated with histopathologic features., Result: Epidermal growth factor receptor over-expression was observed in 22% of the tumor samples. VEGF-A expression was negative in 13.41%, low in 63.41%, moderate in 20.73%, and high in 2.44%. EGFR expression, but not VEGF-A, showed a significant inverse correlation with both estrogen receptor (ER) (P = 0.01) and progesterone receptor (PR) statuses (P = 0.04). EGFR and VEGF expressions did not show significant association with tumor size, grade, lymph node status or age at diagnosis., Conclusion: Epidermal growth factor receptor expression was most likely associated with ER and PR negative tumors. Assessments of multiple molecular markers aid to understand the biological behavior of the disease in Ethiopian population. It might also help to predict which group of patients might get more benefit from the selected treatment strategies and which are not., Competing Interests: Authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Purpose: To describe and explore variation in 'pandemic-related circumstances' among suicide decedents during the first year of the COVID-19 pandemic., Methods: We identified pandemic-related circumstances using decedents' text narratives in the 2020 National Violent Death Reporting System. We use time-series analysis to compare other psychosocial characteristics (e.g., mental health history, interpersonal difficulties, financial strain) of decedents pre-pandemic (2017/2018: n = 56,968 suicide and n = 7,551 undetermined deaths) to those in 2020 (n = 31,887 suicide and n = 4,100 undetermined). We characterize common themes in the narratives with pandemic-related circumstances using topic modeling, and explore variation in topics by age and other psychosocial circumstances., Results: In 2020, n = 2,502 (6.98%) narratives described pandemic-related circumstances. Compared to other deaths in 2020 and to the pre-pandemic period, decedents with pandemic-related circumstances were older and more highly educated. Common themes of pandemic-related circumstances narratives included: concerns about shutdown restrictions, financial losses, and infection risk. Relative to decedents of the same age that did not have pandemic-related circumstances in 2020, those with pandemic-related circumstances were more likely to also have financial (e.g., for 25-44 years, 43% vs. 12%) and mental health (76% vs. 66%) psychosocial circumstances, but had similar or lower prevalence of substance abuse (47% vs. 49%) and interpersonal (40% vs. 42%) circumstances., Conclusions: While descriptive, these findings help contextualize suicide mortality during the acute phase of the COVID-19 pandemic and can inform mental health promotion efforts during similar public health emergencies., Competing Interests: The authors have declared tht no competing interests exist., (Copyright: © 2024 Mezuk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lowering the levels of the cellular prion protein (PrPC) is widely considered a promising strategy for the treatment of prion diseases. Building on work that established immediate spatial proximity of PrPC and Na+, K+-ATPases (NKAs) in the brain, we recently showed that PrPC levels can be reduced by targeting NKAs with their natural cardiac glycoside (CG) inhibitors. We then introduced C4'-dehydro-oleandrin as a CG with improved pharmacological properties for this indication, showing that it reduced PrPC levels by 84% in immortalized human cells that had been differentiated to acquire neural or astrocytic characteristics. Here we report that our lead compound caused cell surface PrPC levels to drop also in other human cell models, even when the analyses of whole cell lysates suggested otherwise. Because mice are refractory to CGs, we explored guinea pigs as an alternative rodent model for the preclinical evaluation of C4'-dehydro-oleandrin. We found that guinea pig cell lines, primary cells, and brain slices were responsive to our lead compound, albeit it at 30-fold higher concentrations than human cells. Of potential significance for other PrPC lowering approaches, we observed that cells attempted to compensate for the loss of cell surface PrPC levels by increasing the expression of the prion gene, requiring daily administration of C4'-dehydro-oleandrin for a sustained PrPC lowering effect. Regrettably, when administered systemically in vivo, the levels of C4'-dehydro-oleandrin that reached the guinea pig brain remained insufficient for the PrPC lowering effect to manifest. A more suitable preclinical model is still needed to determine if C4'-dehydro-oleandrin can offer a cost-effective complementary strategy for pushing PrPC levels below a threshold required for long-term prion disease survival., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: GS and DW declare that they are co-inventors on patent applications named ‘Compounds for altering levels of one or more NKA alpha subunits and their use in treating prion diseases or brain diseases associated with cellular prion protein’ filed in the US and Canada as well as a European patent application named ‘Compounds and methods to treat prion and related diseases’ based on a PCT international filing (PCT/CA2022/050358). These patent applications describe the use of CGs for the purpose of reducing steady-state levels of PrPC. This potential conflict-of-interest does not affect the adherence of all authors to journal policies on the sharing of data and materials. This does not alter our adherence to PLoS One policies on sharing data and materials., (Copyright: © 2024 Eid et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The use of trait-based approaches to understand ecological communities has increased in the past two decades because of their promise to preserve more information about community structure than taxonomic methods and their potential to connect community responses to subsequent effects of ecosystem functioning. Though trait-based approaches are a powerful tool for describing ecological communities, many important properties of commonly-used trait metrics remain unexamined. Previous work with simulated communities and trait distributions shows sensitivity of functional diversity measures to the number and correlation of traits used to calculate them, but these relationships have yet to be studied in actual plant communities with a realistic distribution of trait values, ecologically meaningful covariation of traits, and a realistic number of traits available for analysis. To address this gap, we used data from six grassland plant communities in Minnesota and New Mexico, USA to test how the number of traits and the correlation between traits used in the calculation of eight functional diversity indices impact the magnitude of functional diversity metrics in real plant communities. We found that most metrics were sensitive to the number of traits used to calculate them, but functional dispersion (FDis), kernel density estimation dispersion (KDE dispersion), and Rao's quadratic entropy (Rao's Q) maintained consistent rankings of communities across the range of trait numbers. Despite sensitivity of metrics to trait correlation, there was no consistent pattern between communities as to how metrics were affected by the correlation of traits used to calculate them. We recommend that future use of evenness metrics include sensitivity analyses to ensure results are robust to the number of traits used to calculate them. In addition, we recommend use of FDis, KDE dispersion, and Rao's Q when ecologically applicable due to their ability to produce consistent rankings among communities across a range of the numbers of traits used to calculate them., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ohlert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Over the years, the driver-vehicle interface has been improved, but interacting with in-vehicle features can still increase distraction and affect road safety. This study aims to introduce brain-machine interface (BMI)- based solution to potentially enhance road safety. To achieve this goal, we evaluated visual stimuli properties (SPs) for a steady state visually evoked potentials (SSVEP)-based BMI system. We used a heads-up display (HUD) as the primary screen to present icons for controlling in-vehicle functions such as music, temperature, settings, and navigation. We investigated the effect of various SPs on SSVEP detection performance including the duty cycle and signal-to-noise ratio of visual stimuli, the size, color, and frequency of the icons, and array configuration and location. The experiments were conducted with 10 volunteers and the signals were analyzed using the canonical correlation analysis (CCA), filter bank CCA (FBCCA), and power spectral density analysis (PSDA). Our experimental results suggest that stimuli with a green color, a duty cycle of 50%, presented at a central location, with a size of 36 cm2 elicit a significantly stronger SSVEP response and enhanced SSVEP detection time. We also observed that lower SNR stimuli significantly affect SSVEP detection performance. There was no statistically significant difference observed in SSVEP response between the use of an LCD monitor and a HUD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hamidi Shishavan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Increasingly, studies use social media to recruit, enroll, and collect data from participants. This introduces a threat to data integrity: efforts to produce fraudulent data to receive participant compensation, e.g., gift cards. MOMENT is an online symptom-monitoring and self-care study that implemented safeguards to protect data integrity. Facebook, Twitter, and patient organizations were used to recruit participants with chronic health conditions in four countries (USA, Italy, The Netherlands, Sweden). Links to the REDCap baseline survey were posted to social media accounts. The initial study launch, where participants completed the baseline survey and were automatically re-directed to the LifeData ecological momentary assessment app, was overwhelmed with fraudulent responses. In response, safeguards (e.g., reCAPTCHA, attention checks) were implemented and baseline data was manually inspected prior to LifeData enrollment. The initial launch resulted in 411 responses in 48 hours, 265 of which (64.5%) successfully registered for the LifeData app and were considered enrolled. Ninety-nine percent of these were determined to be fraudulent. Following implementation of safeguards, the re-launch yielded 147 completed baselines in 3.5 months. Eighteen cases (12.2%) were found fraudulent and not invited to enroll. Most fraudulent cases in the re-launch (15 of 18) were identified by a single attention check question. In total, 96.1% of fraudulent responses were to the USA-based survey. Data integrity safeguards are necessary for research studies that recruit online and should be reported in manuscripts. Three safeguard strategies were effective in preventing and removing most of the fraudulent data in the MOMENT study. Additional strategies were also used and may be necessary in other contexts., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Belfiglio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Stable isotope data have made pivotal contributions to nearly every discipline of the physical and natural sciences. As the generation and application of stable isotope data continues to grow exponentially, so does the need for a unifying data repository to improve accessibility and promote collaborative engagement. This paper provides an overview of the design, development, and implementation of IsoBank (www.isobank.org), a community-driven initiative to create an open-access repository for stable isotope data implemented online in 2021. A central goal of IsoBank is to provide a web-accessible database supporting interdisciplinary stable isotope research and educational opportunities. To achieve this goal, we convened a multi-disciplinary group of over 40 analytical experts, stable isotope researchers, database managers, and web developers to collaboratively design the database. This paper outlines the main features of IsoBank and provides a focused description of the core metadata structure. We present plans for future database and tool development and engagement across the scientific community. These efforts will help facilitate interdisciplinary collaboration among the many users of stable isotopic data while also offering useful data resources and standardization of metadata reporting across eco-geoinformatics landscapes., Competing Interests: The authors declare no competing interests., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Children have alarmingly low levels of competency in fundamental motor skills (FMS) and high levels of physical inactivity. e:health interventions, interventions delivered electronically, are useful tools for intervention in the home through parents, but less is known about the effects of these interventions in early childhood education centers or settings. Therefore, we created the Motor skills At Playtime (MAP) e:health intervention (e:MAP) to be delivered in an early childhood education setting. The goals of this pilot study on e:MAP are to (1) determine the intervention effects on children's FMS and physical activity and (2) explore the teachers' perceptions and ability to facilitate e:MAP., Methods: This pilot study uses a pretest/posttest randomized cluster control design. We will recruit at least 64 children (3.5-5 years of age) enrolled in a single early childhood education center. Children will be randomly assigned at the level of the classroom to an e:MAP group (n~30) or a control group (n~30). Children in classrooms assigned to e:MAP will complete an 8-week intervention. We will collect measures of child FMS and physical activity, and teacher's perceptions of the program before (pretest) and after the intervention (posttest). FMS measures include process (Test of Gross Motor Development-3rd Edition) and product-oriented scores. Physical activity will be assessed using a 7-day accelerometer wear protocol. Teachers' perceptions will be assessed through a brief survey. Lastly, we will collect data on teachers' ability to facilitate e:MAP through a daily survey., Potential Significance: This study will yield novel insights into the effectiveness and feasibility of a health intervention in an early childhood education setting. Results from this work will expand our knowledge of how to harness e:health modalities, which have the potential to significantly expand the distribution and scalability of FMS interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Palmer, Wang. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias, but research on end-of-life experiences for people with DLB and their caregivers is limited., Method: Dyads of individuals with moderate-advanced DLB and their primary informal caregivers were recruited from specialty clinics, advocacy organizations, and research registries and followed prospectively every 6 months. The current study examines results of caregiver study visits 3 months after the death of the person with DLB. These visits included the Last Month of Life survey, study-specific questions, and a semi-structured interview querying end-of-life experiences., Results: Individuals with DLB (n = 50) died 3.24 ± 1.81 years after diagnosis, typically of disease-related complications. Only 44% of caregivers reported a helpful conversation with clinicians regarding what to expect at the end of life in DLB. Symptoms commonly worsening prior to death included: cognition and motor function, ADL dependence, behavioral features, daytime sleepiness, communication, appetite, and weight loss. Almost 90% of participants received hospice care, but 20% used hospice for <1 week. Most caregivers reported overall positive experiences in the last month of life, but this was not universal. Having information about DLB and what to expect, access to support, and hospice care were healthcare factors associated with positive and negative end of life experiences. Hospice experiences were driven by communication, care coordination, quality care, and caregiver education., Conclusion: Most caregivers of individuals who died with DLB reported positive end-of-life experiences. However, the study identified multiple opportunities for improvement relating to clinician counseling of patients/families, support/hospice referrals, and monitoring individuals with DLB to identify approaching end of life. Future research should quantitatively identify changes that herald end of life in DLB and develop tools that can assist clinicians in evaluating disease stage to better inform counseling and timely hospice referrals., Trial Registration: Trial registration information: NCT04829656., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: EW, BL, SMM, ZL, and HJF report no competing interests. HLP: HLP receives funding from the NIA (1P30AG053760) and is the local PI of a Lewy Body Dementia Association Research Center of Excellence. CM: CM receives research support from ACL/DHHS (90ALGG0014-01-00), NIA/NIH (2SB1AG037357-04A1, R01-AG-054435), HRSA (U1QHP287440400) and DoD (AZ190036). She is the local PI of a Lewy Body Dementia Association Research Center of Excellence. JAF: JAF receives research support from the NIA (U01NS100620, R01AG068128, R43AG65088). AL: AL receives research support from the NIA (P30AG62677, R43AG65088). She is a Program Coordinator for the local a Lewy Body Dementia Association Coordinating Center Research Center of Excellence. BFB: BFB has served as an investigator for clinical trials sponsored by Biogen, Alector, and EIP Pharma. He serves on the Scientific Advisory Board of the Lewy Body Dementia Association, Association for Frontotemporal Degeneration, and Tau Consortium. He is the site PI of a Lewy Body Dementia Association Research Center of Excellence program, as well as coordinating center PI of the program. He receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, and the Little Family Foundation. JEG: JEG is the creator of the QDRS and the LBCRS. He is supported by grants from the National Institutes of Health (R01 AG069765, R01 AG057681, R01 NS101483, P30 AG059295, U54 AG06354, R01 AG056531, U01 NS100610, R01 AG056610, R01 AG054425, R01 AG068128) and the Leo and Anne Albert Charitable Trust. He is the local PI of the Lewy Body Dementia Association Research Center of Excellence at the University of Miami and serves on the Scientific Advisory Board of the Lewy Body Dementia Association. AST: AST is an employee of the Lewy Body Dementia Association. MJA: MJA receives research support from the NIH (R01AG068128, P30AG066506, R01NS121099, R44AG062072), the Florida Department of Health (grants 20A08, 24A14, 24A15), and as the local PI of a Lewy Body Dementia Association Research Center of Excellence. She serves on the DSMBs for the Alzheimer’s Therapeutic Research Institute/Alzheimer’s Clinical Trial Consortium and the Alzheimer’s Disease Cooperative Study. She has provided educational content for Medscape, Vindico CME, and Prime Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Wollney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: The left-digit bias (LDB), a numerical-related cognitive bias, not only potentially influences decision-making among the general public but also that of medical practitioners. Few studies have investigated its role in out-of-hospital cardiac arrest (OHCA)., Methods: We retrospectively included all consecutive patients with OHCA witnessed by family members registered in the All-Japan Utstein Registry of the Fire and Disaster Management Agency between January 1, 2005, and December 31, 2020. Target outcomes were the percentage of bystander cardiopulmonary resuscitation (BCPR) performed by family members or paramedics and the percentage of prehospital physician-staffed advanced cardiac life support (ACLS). Using a nonparametric regression discontinuity methodology, we examined whether a significant change occurred in the percentages of BCPR and ACLS at the age thresholds of 60, 70, 80, and 90 years, which would indicate the presence of LDB., Results: Of the 1,930,273 OHCA cases in the All-Japan Utstein Registry, 384,200 (19.9%) cases witnessed by family members were analyzed. The mean age was 75.8 years (±SD 13.7), with 38.0% (n = 146,137) female. We identified no discontinuities in the percentages of chest compressions, mouth-to-mouth ventilation, or automated external defibrillator (AED) usage by family members for the age thresholds of 60, 70, 80, and 90 years. Moreover, no discontinuities existed in the percentages of chest compressions, advanced airway management, and AED usage by paramedics or prehospital ACLS by physicians for any of the age thresholds., Conclusions: In conclusion, our study did not find any evidence that age-related LDB affects medical decision-making in patients with OHCA., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Suzuki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Identifying causal sentences from nuclear incident reports is essential for advancing nuclear safety research and applications. Nonetheless, accurately locating and labeling causal sentences in text data is challenging, and might benefit from the usage of automated techniques. In this paper, we introduce LERCause, a labeled dataset combined with labeling methods meant to serve as a foundation for the classification of causal sentences in the domain of nuclear safety. We used three BERT models (BERT, BioBERT, and SciBERT) to 10,608 annotated sentences from the Licensee Event Report (LER) corpus for predicting sentence labels (Causal vs. non-Causal). We also used a keyword-based heuristic strategy, three standard machine learning methods (Logistic Regression, Gradient Boosting, and Support Vector Machine), and a deep learning approach (Convolutional Neural Network; CNN) for comparison. We found that the BERT-centric models outperformed all other tested models in terms of all evaluation metrics (accuracy, precision, recall, and F1 score). BioBERT resulted in the highest overall F1 score of 94.49% from the ten-fold cross-validation. Our dataset and coding framework can provide a robust baseline for assessing and comparing new causal sentences extraction techniques. As far as we know, our research breaks new ground by leveraging BERT-centric models for causal sentence classification in the nuclear safety domain and by openly distributing labeled data and code to enable reproducibility in subsequent research., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Clostridioides difficile infection (CDI) is a significant public health threat, associated with antibiotic-induced disruption of the normally protective gastrointestinal microbiota. CDI is thought to occur in two stages: acquisition of asymptomatic colonization from ingesting C. difficile bacteria followed by progression to symptomatic CDI caused by toxins produced during C. difficile overgrowth. The degree to which disruptive antibiotic exposure increases susceptibility at each stage is uncertain, which might contribute to divergent published projections of the impact of hospital antibiotic stewardship interventions on CDI. Here, we model C. difficile transmission and CDI among hospital inpatients, including exposure to high-CDI-risk antibiotics and their effects on each stage of CDI epidemiology. We derive the mathematical relationship, using a deterministic model, between those parameters and observed equilibrium levels of colonization, CDI, and risk ratio of CDI among certain antibiotic-exposed patients relative to patients with no recent antibiotic exposure. We then quantify the sensitivity of projected antibiotic stewardship intervention impacts to alternate assumptions. We find that two key parameters, the antibiotic effects on susceptibility to colonization and to CDI progression, are not identifiable given the data frequently available. Furthermore, the effects of antibiotic stewardship interventions are sensitive to their assumed values. Thus, discrepancies between different projections of antibiotic stewardship interventions may be largely due to model assumptions. Data supporting improved quantification of mechanistic antibiotic effects on CDI epidemiology are needed to understand stewardship effects better., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mitchell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The increased usage of navigation technologies has caused conflicts in local traffic management, resulting in congested residential areas among other challenges for residents. This paper uses content analysis to investigate such negative social externalities within local communities and neighbourhoods. Through a corpus of 90 news articles about traffic incidents caused by navigation technologies, we identified negative traffic and safety-related externalities, including congestion, damage, pollution, and accidents. We also report on countermeasures by local communities and governments, including street closures, speed limit reduction, and turn bans. Based on our results, we discuss the implications for designing mobile navigation technologies that reduce negative social externalities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Schade et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Breast Cancer and cardiovascular diseases are amongst the two leading causes of mortality in the United States, and the two conditions are connected in part because of recognized cardiotoxicity of cancer treatments. The aim of this study is to investigate the predictors risk factors for thirty-day readmission in female breast cancer survivors presenting with acute heart failure., Methods: This is a retrospective cohort study of acute heart failure (AHF) hospitalization in female patients with breast cancer in 2019 using the National Readmission Database (NRD), which is the largest publicly available all-payer inpatient readmission database in the United States. Our study sample included adult female patients aged 18 years and older. The primary outcome of interest was the rate of 30- day readmission., Results: In 2019, there were 8332 total index admissions for AHF in females with breast cancer and 7776 patients were discharged alive. The mean age was 74.4 years (95% CI: 74, 74.7). The percentage of readmission at 30 days among those discharged alive was 21.8% (n = 1699). Hypertensive heart disease with chronic kidney disease accounted for the majority of readmission in AHF with breast cancer followed by sepsis, acute kidney injury, respiratory failure, pneumonia, and atrial fibrillation. Demographic factors including higher burden of comorbidities predict readmission. The total in-hospital mortality in index admission was 6.67% (n = 556) and for readmitted patients was 8.77% (n = 149). The mean length of stay for index admission was 7.5 days (95% CI: 7.25, 7.75)., Conclusions: Readmission of female breast cancer survivors presenting with AHF is common and largely be attributed to high burden of comorbidities including hypertension, and chronic kidney disease. A focus on close outpatient follow-up will be beneficial in lowering readmissions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kambalapalli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Inducible laryngeal obstruction (ILO) accounts for or contributes to dyspnea in a noteworthy proportion of treatment seeking populations including those misdiagnosed with asthma. Despite increasing awareness of the disorder, literature exploring patient experience is limited. The aim of this work is to report patient perspectives on ILO and the way in which it impacts quality of life., Methods: This qualitative study utilized methods detailed in the literature on grounded theory and phenomenological research to analyze interviews collected from participants diagnosed with ILO. Interviews were conducted, audio recorded, and transcribed. Transcriptions underwent content-analysis using Burnard's 14 step method [15], which included review of content codes across multiple raters until consensus regarding analyses was reached., Results: Twenty-six participants were included in the study. Most participants were female (92%). Ages ranged from 18-72 with a mean age of 45 for female participants and 37 for male participants. Without specific prompting to do so, all participants offered descriptions of the specific symptoms they experienced and the triggers for their symptoms. In the content analysis process, "descriptions of symptoms and triggers" was thus labeled a theme that was present in all interviews. Seven additional themes were shared consistently and judged to encapsulate the interview material. These themes were: 2) diagnosis and treatment, 3) emotional impact of ILO, 4) perception of health and prognosis, 5) ameliorating factors, 6) influence of ILO on lifestyle, 7) the physical impact of ILO, and 8), social consequences of ILO. In addition, 54 subthemes were identified., Conclusions: Patients appear to place particular emphasis on the emotional and psychosocial consequences of ILO as well as factors that ameliorate the condition. As such, future efforts to treat ILO and to collect outcomes measures should account for these aspects of the patient experience., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 McConville, Thibeault. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To compare whole-body kinematics, leg muscle activity, and discomfort while performing a 10-min carrying task with and without a passive upper-body exoskeleton (CarrySuitⓇ), for both males and females., Background: Diverse commercial passive exoskeletons have appeared on the market claiming to assist lifting or carrying task. However, evidence of their impact on kinematics, muscle activity, and discomfort while performing these tasks are necessary to determine their benefits and/or limitations., Method: Sixteen females and fourteen males carried a 15kg load with and without a passive exoskeleton during 10-min over a round trip route, in two non-consecutive days. Whole-body kinematics and leg muscle activity were evaluated for each condition. In addition, leg discomfort ratings were quantified before and immediately after the task., Results: The gastrocnemius and vastus lateralis muscle activity remained constant over the task with the exoskeleton. Without the exoskeleton a small decrease of gastrocnemius median activation was observed regardless of sex, and a small increase in static vastus lateralis activation was observed only for females. Several differences in sagittal, frontal, and transverse movements' ranges of motion were found between conditions and over the task. With the exoskeleton, ROM in the sagittal plane increased over time for the right ankle and pelvis for both sexes, and knees for males only. Thorax ROMs in the three planes were higher for females only when using the exoskeleton. Leg discomfort was lower with the exoskeleton than without., Conclusion: The results revealed a positive impact on range of motion, leg muscle activity, and discomfort of the tested exoskeleton., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Garcia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Forests play a key role in the mitigation of global warming and provide many other vital ecosystem goods and services. However, as forest continues to vanish at an alarming rate from the surface of the planet, the world desperately needs knowledge on what contributes to forest preservation and restoration. Migration, a hallmark of globalization, is widely recognized as a main driver of forest recovery and poverty alleviation. Here, we show that remittance from migrants reinforces forest recovery that would otherwise be unlikely with mere migration, realizing the additionality of payments for ecosystem services for China's largest reforestation policy, the Conversion of Cropland to Forest Program (CCFP). Guided by the framework that integrates telecoupling and coupled natural and human systems, we investigate forest-livelihood dynamics under the CCFP through the lens of rural out-migration and remittance using both satellite remote sensing imagery and household survey data in two representative sites of rural China. Results show that payments from the CCFP significantly increases the probability of sending remittance by out-migrants to their origin households. We observe substantial forest regeneration and greening surrounding households receiving remittance but forest decline and browning in proximity to households with migrants but not receiving remittance, as measured by forest coverage and the Enhanced Vegetation Index derived from space-borne remotely sensed data. The primary mechanism is that remittance reduces the reliance of households on natural capital from forests, particularly fuelwood, allowing forests near the households to recover. The shares of the estimated ecological and economic additionality induced by remittance are 2.0% (1.4%∼3.8%) and 9.7% (5.0%∼15.2%), respectively, to the baseline of the reforested areas enrolled in CCFP and the payments received by the participating households. Remittance-facilitated forest regeneration amounts to 12.7% (6.0%∼18.0%) of the total new forest gained during the 2003-2013 in China. Our results demonstrate that remittance constitutes a telecoupling mechanism between rural areas and cities over long distances, influencing the local social-ecological gains that the forest policy intended to stimulate. Thus, supporting remittance-sending migrants in cities can be an effective global warming mitigation strategy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The Hedgehog (HH) pathway regulates embryonic development of anterior tongue taste fungiform papilla (FP) and the posterior circumvallate (CVP) and foliate (FOP) taste papillae. HH signaling also mediates taste organ maintenance and regeneration in adults. However, there are knowledge gaps in HH pathway component expression during postnatal taste organ differentiation and maturation. Importantly, the HH transcriptional effectors GLI1, GLI2 and GLI3 have not been investigated in early postnatal stages; the HH receptors PTCH1, GAS1, CDON and HHIP, required to either drive HH pathway activation or antagonism, also remain unexplored. Using lacZ reporter mouse models, we mapped expression of the HH ligand SHH, HH receptors, and GLI transcription factors in FP, CVP and FOP in early and late postnatal and adult stages. In adults we also studied the soft palate, and the geniculate and trigeminal ganglia, which extend afferent fibers to the anterior tongue. Shh and Gas1 are the only components that were consistently expressed within taste buds of all three papillae and the soft palate. In the first postnatal week, we observed broad expression of HH signaling components in FP and adjacent, non-taste filiform (FILIF) papillae in epithelium or stroma and tongue muscles. Notably, we observed elimination of Gli1 in FILIF and Gas1 in muscles, and downregulation of Ptch1 in lingual epithelium and of Cdon, Gas1 and Hhip in stroma from late postnatal stages. Further, HH receptor expression patterns in CVP and FOP epithelium differed from anterior FP. Among all the components, only known positive regulators of HH signaling, SHH, Ptch1, Gli1 and Gli2, were expressed in the ganglia. Our studies emphasize differential regulation of HH signaling in distinct postnatal developmental periods and in anterior versus posterior taste organs, and lay the foundation for functional studies to understand the roles of numerous HH signaling components in postnatal tongue development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kumari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To examine the association between recent experiences of discrimination and depressive symptom presentation and severity among a U.S. sample of older Black and African American adults. A cross-sectional survey of 124 Black and African American adults aged 50 and older in the United States was conducted assessing interpersonal discrimination and depressive symptoms. The Perceived Ethnic Discrimination Questionnaire assessed four forms of interpersonal discrimination. A measure of heightened vigilance to bias assessed anticipatory coping with discrimination experiences. Past-month affective and somatic symptoms of depression were assessed using the Depressive and Somatic Symptoms Scale. All forms of interpersonal racial discrimination were positively associated with greater affective symptom severity. Being avoided, devalued, and threatened or actively physically harmed were associated with greater somatic symptom severity. Vigilant coping was positively associated with affective symptom severity but not somatic symptom severity. Racial discrimination is linked to depression severity among older Black and African American and varies by symptom. This study helps inform work on processes linking discrimination with poorer psychological outcomes and will allow for more effective interventions and prevention efforts that are tailored to older minority populations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Malic Enzyme 1 (ME1) plays an integral role in fatty acid synthesis and cellular energetics through its production of NADPH and pyruvate. As such, it has been identified as a gene of interest in obesity, type 2 diabetes, and an array of epithelial cancers, with most work being performed in vitro. The current standard model for ME1 loss in vivo is the spontaneous Mod-1 null allele, which produces a canonically inactive form of ME1. Herein, we describe two new genetically engineered mouse models exhibiting ME1 loss at dynamic timepoints. Using murine embryonic stem cells and Flp/FRT and Cre/loxP class switch recombination, we established a germline Me1 knockout model (Me1 KO) and an inducible conditional knockout model (Me1 cKO), activated upon tamoxifen treatment in adulthood. Collectively, neither the Me1 KO nor Me1 cKO models exhibited deleterious phenotype under standard laboratory conditions. Knockout of ME1 was validated by immunohistochemistry and genotype confirmed by PCR. Transmission patterns favor Me1 loss in Me1 KO mice when maternally transmitted to male progeny. Hematological examination of these models through complete blood count and serum chemistry panels revealed no discrepancy with their wild-type counterparts. Orthotopic pancreatic tumors in Me1 cKO mice grow similarly to Me1 expressing mice. Similarly, no behavioral phenotype was observed in Me1 cKO mice when aged for 52 weeks. Histological analysis of several tissues revealed no pathological phenotype. These models provide a more modern approach to ME1 knockout in vivo while opening the door for further study into the role of ME1 loss under more biologically relevant, stressful conditions., Competing Interests: L.C.C. and C.A.L. are inventors on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting GOT1 or ME1 as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015). L.C.C. owns equity in, receives compensation from, and serves on the Scientific Advisory Boards of Faeth Therapeutics, Agios Pharmaceuticals, Volastra Therapeutics, and Larkspur Biosciences. L.C.C.’s laboratory has previously received financial support from Petra Pharmaceuticals. Agios Pharmaceuticals is identifying metabolic pathways of cancer cells and developing drugs to inhibit such enzymes to disrupt tumor cell growth and survival. In the last 3 years, C.A.L. has received consulting fees from Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures, and T-Knife Therapeutics. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Alektiar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The Belson site is located on an outwash plain draining the Early Algonquin stage of the central Great Lakes (coinciding with the Older Dryas stadial period around 14,000 Cal B.P) southwest across Lower Michigan into the Ohio tributaries. By 13,000 Cal B.P the St. Joseph River had incised multiple channels into this plain. On a terrace just north of a now-abandoned channel, a detailed surface study by Talbot from 2005-2018 showed several flake clusters largely of Attica chert, procured about 235 km southwest of Belson. A study of the surface sample was published by the authors in 2021 and indicated that the points were made with the Clovis technological pattern. Excavations in 2020-21 revealed hundreds of buried flakes and multiple tools in the lower, less-disturbed terrace sediment. Plotting of this material indicates successive occupations below the ploughed deposit and covering more than 30 m2. The buried assemblages are similar to the published surface assemblage with the addition of more small scrapers and manufacturing debris. Several of the buried tools have traces of proteins from a range of mammals, suggesting a broad-spectrum subsistence strategy. The documentation of a succession of little disturbed deposits with precisely recorded micro-debris will allow for testing of models describing settlement choice and developing dynamics of internal site organization. Initial analysis of recovered data provides support for an 'outcrop centered' model where high-quality chert outcrops serve as central places on the landscape. Samples of sediment and charcoal for identification and dating await study., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nash et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Most U.S. K-12 schools have adopted safety tactics and policies like arming teachers and installing metal detectors, to address intentional school gun violence. However, there is minimal research on their effectiveness. Furthermore, sociodemographic factors may influence their implementation. Controlled studies are necessary to investigate their impact on gun violence and related disciplinary outcomes., Objective: The paper outlines the protocol for a case-control study examining gun violence prevention policies in U.S. K-12 schools. The study aims to investigate if there is an association between the total number and type of specific safety tactics and policies and the occurrence of intentional shootings in K-12 public schools, student disciplinary outcomes, and if urbanicity, economic, and racial factors modify these associations., Methods: We will create a nationally representative dataset for this study and ascertain a full census of case schools (schools that experienced intentional gunfire on the campus during school hours since 2015) through national school shooting databases. Matched control schools will be randomly selected from U.S. Department of Education's national database of all public schools. We will analyze 27 school safety strategies organized into seven key exposure groupings., Results: Supported by the National Institutes for Child Health and Development (R01HD108027-01) and having received Institutional Review Board approval, our study is currently in the data collection phase. Our analytical plan will determine the association between the number and type of school safety tactics and policies with the occurrence of intentional shootings and suspensions and expulsions in a national sample of approximately 650 K-12 public schools. Additional analyses will investigate the effect modification of specific covariates., Conclusion: As the first national, controlled study, its results will provide novel and needed data on the effectiveness of school safety tactics and policies in preventing intentional shootings at K-12 public schools., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Buttar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Strategies to prevent or delay Alzheimer's disease and related dementias (AD/ADRD) are urgently needed, and blood pressure (BP) management is a promising strategy. Yet the effects of different BP control strategies across the life course on AD/ADRD are unknown. Randomized trials may be infeasible due to prolonged follow-up and large sample sizes. Simulation analysis is a practical approach to estimating these effects using the best available existing data. However, existing simulation frameworks cannot estimate the effects of BP control on both dementia and cardiovascular disease. This manuscript describes the design principles, implementation details, and population-level validation of a novel population-health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP-COG) study of the effect of BP levels over the life course on dementia and cardiovascular disease. MICROSIM is an agent-based Monte Carlo simulation designed using computer programming best practices. MICROSIM estimates annual vascular risk factor levels and transition probabilities in all-cause dementia, stroke, myocardial infarction, and mortality in a nationally representative sample of US adults 18+ using the National Health and Nutrition Examination Survey (NHANES). MICROSIM models changes in risk factors over time, cognition and dementia using changes from a pooled dataset of individual participant data from 6 US prospective cardiovascular cohort studies. Cardiovascular risks were estimated using a widely used risk model and BP treatment effects were derived from meta-analyses of randomized trials. MICROSIM is an extensible, open-source framework designed to estimate the population-level impact of different BP management strategies and reproduces US population-level estimates of BP and other vascular risk factors levels, their change over time, and incident all-cause dementia, stroke, myocardial infarction, and mortality., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Burke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Multimorbidity may confer higher risk for cognitive decline than any single constituent disease. This study aims to identify distinct trajectories of cognitive impairment probability among middle-aged and older adults, and to assess the effect of changes in mental-somatic multimorbidity on these distinct trajectories., Methods: Data from the Health and Retirement Study (1998-2016) were employed to estimate group-based trajectory models identifying distinct trajectories of cognitive impairment probability. Four time-varying mental-somatic multimorbidity combinations (somatic, stroke, depressive, stroke and depressive) were examined for their association with observed trajectories of cognitive impairment probability with age. Multinomial logistic regression analysis was conducted to quantify the association of sociodemographic and health-related factors with trajectory group membership., Results: Respondents (N = 20,070) had a mean age of 61.0 years (SD = 8.7) at baseline. Three distinct cognitive trajectories were identified using group-based trajectory modelling: (1) Low risk with late-life increase (62.6%), (2) Low initial risk with rapid increase (25.7%), and (3) High risk (11.7%). For adults following along Low risk with late-life increase, the odds of cognitive impairment for stroke and depressive multimorbidity (OR:3.92, 95%CI:2.91,5.28) were nearly two times higher than either stroke multimorbidity (OR:2.06, 95%CI:1.75,2.43) or depressive multimorbidity (OR:2.03, 95%CI:1.71,2.41). The odds of cognitive impairment for stroke and depressive multimorbidity in Low initial risk with rapid increase or High risk (OR:4.31, 95%CI:3.50,5.31; OR:3.43, 95%CI:2.07,5.66, respectively) were moderately higher than stroke multimorbidity (OR:2.71, 95%CI:2.35, 3.13; OR: 3.23, 95%CI:2.16, 4.81, respectively). In the multinomial logistic regression model, non-Hispanic Black and Hispanic respondents had higher odds of being in Low initial risk with rapid increase and High risk relative to non-Hispanic White adults., Conclusions: These findings show that depressive and stroke multimorbidity combinations have the greatest association with rapid cognitive declines and their prevention may postpone these declines, especially in socially disadvantaged and minoritized groups., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum identified lower levels of the host metabolite itaconate in those infected with NTM. Itaconate can inhibit the growth of M. tuberculosis (MTB) in vitro via the inhibition of the glyoxylate cycle enzyme (ICL), but its impact on NTM is unclear. To test itaconic acid's (IA) effect on NTM growth, laboratory and CF clinical strains of Mycobacterium abscessus and Mycobacterium avium were cultured in 7H9 minimal media supplemented with 1-10 mM of IA and short-chain fatty acids (SCFA). M. avium and M. abscessus grew when supplemented with SCFAs, whereas the addition of IA (≥ 10 mM) completely inhibited NTM growth. NTM supplemented with acetate or propionate and 5 mM IA displayed slower growth than NTM cultured with SCFA and ≤ 1 mM of IA. However, IA's inhibition of NTM was pH dependent; as similar and higher quantities (100 mM) of pH adjusted IA (pH 7) did not inhibit growth in vitro, while in an acidic minimal media (pH 6.1), 1 to 5 mM of non-pH adjusted IA inhibited growth. None of the examined isolates displayed the ability to utilize IA as a carbon source, and IA added to M. abscessus isocitrate lyase (ICL) decreased enzymatic activity. Lastly, the addition of cell-permeable 4-octyl itaconate (4-OI) to THP-1 cells enhanced NTM clearance, demonstrating a potential role for IA/itaconate in host defense against NTM infections., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Breen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The COVID-19 pandemic has not only caused tremendous loss of life and health but has also greatly disrupted the world economy. The impact of this disruption has been especially harsh in urban settings of developing countries. We estimated the impact of the pandemic on the occurrence of food insecurity in a cohort of women living in Mexico City, and the socioeconomic characteristics associated with food insecurity severity., Methods: We analyzed data longitudinally from 685 women in the Mexico City-based ELEMENT cohort. Food insecurity at the household level was gathered using the Latin American and Caribbean Food Security Scale and measured in-person during 2015 to 2019 before the pandemic and by telephone during 2020-2021, in the midst of the pandemic. Fluctuations in the average of food insecurity as a function of calendar time were modeled using kernel-weighted local polynomial regression. Fixed and random-effects ordinal logistic regression models of food insecurity were fitted, with timing of data collection (pre-pandemic vs. during pandemic) as the main predictor., Results: Food insecurity (at any level) increased from 41.6% during the pre-pandemic period to 53.8% in the pandemic stage. This increase was higher in the combined severe-moderate food insecurity levels: from 1.6% pre-pandemic to 16.8% during the pandemic. The odds of severe food insecurity were 3.4 times higher during the pandemic relative to pre-pandemic levels (p<0.01). Socioeconomic status quintile (Q) was significantly related to food insecurity (Q2 OR = 0.35 p<0.1, Q3 OR = 0.48 p = 0.014, Q4 OR = 0.24 p<0.01, and Q5 OR = 0.17 p<0.01), as well as lack of access to social security (OR = 1.69, p = 0.01), and schooling (OR = 0.37, p<0.01)., Conclusions: Food insecurity increased in Mexico City households in the ELEMENT cohort as a result of the COVID-19 pandemic. These results contribute to the body of evidence suggesting that governments should implement well-designed, focalized programs in the context of economic crisis such as the one caused by COVID-19 to prevent families from the expected adverse health and well-being consequences associated to food insecurity, especially for the most vulnerable., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bautista-Arredondo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Zinc Finger MIZ-Type Containing 1 (Zmiz1), also known as ZIMP10 or RAI17, is a transcription cofactor and member of the Protein Inhibitor of Activated STAT (PIAS) family of proteins. Zmiz1 is critical for a variety of biological processes including vascular development. However, its role in the lymphatic vasculature is unknown. In this study, we utilized human dermal lymphatic endothelial cells (HDLECs) and an inducible, lymphatic endothelial cell (LEC)-specific Zmiz1 knockout mouse model to investigate the role of Zmiz1 in LECs. Transcriptional profiling of ZMIZ1-deficient HDLECs revealed downregulation of genes crucial for lymphatic vessel development. Additionally, our findings demonstrated that loss of Zmiz1 results in reduced expression of proliferation and migration genes in HDLECs and reduced proliferation and migration in vitro. We also presented evidence that Zmiz1 regulates Prox1 expression in vitro and in vivo by modulating chromatin accessibility at Prox1 regulatory regions. Furthermore, we observed that loss of Zmiz1 in mesenteric lymphatic vessels significantly reduced valve density. Collectively, our results highlight a novel role of Zmiz1 in LECs and as a transcriptional regulator of Prox1, shedding light on a previously unknown regulatory factor in lymphatic vascular biology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 K. C. et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Zebrafish are an established and widely used animal model, yet there is limited understanding of their welfare needs. Despite an increasing number of studies on zebrafish enrichment, in-tank environmental enrichment remains unpopular among researchers. This is due to perceived concerns over health/hygiene when it comes to introducing enrichment into the tank, although actual evidence for this is sparse. To accommodate this belief, regardless of veracity, we tested the potential benefits of enrichments presented outside the tank. Thus, we investigated the preferences and physiological stress of zebrafish with pictures of pebbles placed underneath the tank. We hypothesized that zebrafish would show a preference for enriched environments and have lower stress levels than barren housed zebrafish. In our first experiment, we housed zebrafish in a standard rack system and recorded their preference for visual access to a pebble picture, with two positive controls: visual access to conspecifics, and group housing. Using a crossover repeated-measures factorial design, we tested if the preference for visual access to pebbles was as strong as the preference for social contact. Zebrafish showed a strong preference for visual access to pebbles, equivalent to that for conspecifics. Then, in a second experiment, tank water cortisol was measured to assess chronic stress levels of zebrafish housed with or without a pebble picture under their tank, with group housing as a positive control. Cortisol levels were significantly reduced in zebrafish housed with pebble pictures, as were cortisol levels in group housed zebrafish. In fact, single housed zebrafish with pebble pictures showed the same cortisol levels as group housed zebrafish without pebble pictures. Thus, the use of an under-tank pebble picture was as beneficial as being group housed, effectively compensating for the stress of single housing. Pebble picture enrichment had an additive effect with group housing, where group housed zebrafish with pebble pictures had the lowest cortisol levels of any treatment group., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Byrd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults., Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science., Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions., Clinical Trials.gov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Brett Anderson reported receiving direct support for work not related to RECOVER work/publications from Genentech and the National Institute of Allergy and Immunology. Walter Dehority reported receiving grant support from Merck and participating in research for the Moderna COVID-19 pediatric vaccine trial and the Pfizer Paxlovid trial. Alex Fiks reported receiving support from NJM insurance and personal consulting fees not related to this paper from Rutgers University and the American Academy of Pediatrics. Ashraf Harahsheh reported serving as a scientific advisory board member unrelated to this paper for OP2 DRUGS. Lawrence Kleinman reported serving as an unpaid member of the Board of Directors for the DARTNet Institute, as a principle investigator at Quality Matters, Inc., and as the Vice Chair for the Borough of Metuchen Board of Health. Dr. Kleinman also reported grant support for work not related to RECOVER work/publications from NIH, HRSA, and the Robert Wood Johnson Foundation. Dr. Kleinman also reported minority individual stock ownership in Apple Computer, Sanofi SA, Experion, GlaxoSmithKline, Magyar Bank, Regeneron Pharmaceuticals, JP Morgan Chase, and Amgen Inc. Torri Metz reported participating as a Principle Investigator in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She is also a principle investigator for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Joshua Milner reported serving as a member of the Scientific Advisory Board for Blueprint Medicines, in a capacity unrelated to RECOVER work/publications. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Gross et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Federal scientific agencies seek to make an impact on the continued prevalence of sexual harassment in the scientific academic community beyond institutional self-regulation. The National Science Foundation's Article X, released in 2018, is one of the most significant and ambitious federal policy initiatives to address sexual harassment. The present article presents the results of the first study to examine scientists' knowledge and attitudes about this important recent policy. We found, although overall knowledge about Article X was fairly low, the majority of participants responded positively to it. Crucially, impressions of the policy varied based on past experience and demographic factors. Individuals who had experienced harassment in the past year were less likely to believe the policy would help reduce sexual harassment in the sciences compared to those who had not experienced harassment (OR = 0.47, 95% CI:0.23-0.97, p = .034) and had greater odds of endorsing that the policy failed to go far enough (OR = 2.77, 95% CI:1.15-6.66, p = .023). Associations between demographic factors and views of the policy were less pronounced, but it is notable that, compared to their White counterparts, Black participants were more likely to believe the policy went too far (OR = 5.87, 95% CI:1.04-33.17, p = .045). Additionally, concerns were raised about the institutional enforcement of these policies and the existence of sufficient protections for survivors. Our work has implications for NSF's continued evaluation of the efficacy of this program as well as for other federal agencies implementing or considering similar policies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Recent advances in interdisciplinary archaeological research in Arabia have focused on the evolution and historical development of regional human populations as well as the diverse patterns of cultural change, migration, and adaptations to environmental fluctuations. Obtaining a comprehensive understanding of cultural developments such as the emergence and lifeways of Neolithic groups has been hindered by the limited preservation of stratified archaeological assemblages and organic remains, a common challenge in arid environments. Underground settings like caves and lava tubes, which are prevalent in Arabia but which have seen limited scientific exploration, offer promising opportunities for addressing these issues. Here, we report on an archaeological excavation and a related survey at and around Umm Jirsan lava tube in the Harrat Khaybar, north-western Saudi Arabia. Our results reveal repeated phases of human occupation of the site ranging from at least the Neolithic through to the Chalcolithic/Bronze Age. Pastoralist use of the lava tube and surrounding landscape is attested in rock art and faunal records, suggesting that Umm Jirsan was situated along a pastoral route linking key oases. Isotopic data indicates that herbivores primarily grazed on wild grasses and shrubs rather than being provided with fodder, while humans had a diet consistently high in protein but with increasing consumption of C3 plants through-time, perhaps related to the emergence of oasis agriculture. While underground and naturally sheltered localities are globally prominent in archaeology and Quaternary science, our work represents the first such combined records for Saudi Arabia and highlight the potential for interdisciplinary studies in caves and lava tubes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Stewart et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The Awakening, Breathing Coordination, Delirium monitoring and Early mobility bundle (ABCDE) is associated with lower mortality for intensive care unit (ICU) patients. However, efforts to improve ABCDE are variably successful, possibly due to lack of clarity about who are the team members interacting when caring for each patient, each shift. Lack of patient shift-level information regarding who is interacting with whom limits the ability to tailor interventions to the specific ICU team to improve ABCDE., Objective: Determine the number and types of individuals (i.e., clinicians and family members) interacting in the care of mechanically ventilated (MV) patients, as reported by the patients' assigned physician, nurse, and respiratory therapist (RT) each shift, using a network science lens., Methods: We conducted a prospective, patient-shift-level survey in 2 medical ICUs. For each patient, we surveyed the assigned physician, nurse, and RT each day and night shift about who they interacted with when providing ABCDE for each patient-shift. We determined the number and types of interactions, reported by physicians, nurses, and RTs and day versus night shift., Results: From 1558 surveys from 404 clinicians who cared for 169 patients over 166 shifts (65% response rate), clinicians reported interacting with 2.6 individuals each shift (physicians: 2.65, nurses: 3.33, RTs: 1.86); this was fewer on night shift compared to day shift (1.99 versus 3.02). Most frequent interactions were with the bedside nurse, attending, resident, intern, and RT; family member interactions were reported in less than 1 in 5 surveys (12.2% of physician surveys, 19.7% of nurse surveys, 4.9% of RT surveys)., Interpretation: Clinicians reported interacting with 3-4 clinicians each shift, and fewer on nights. Nurses interacted with the most clincians and family members. Interventions targeting shift-level teams, focusing on nurses and family members, may be a way to improve ABCDE delivery and ICU teamwork., Competing Interests: Authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The chemokines of the immune system act as first responders by operating as chemoattractants, directing immune cells to specific locations of inflamed tissues. This promiscuous network is comprised of 50 ligands and 18 receptors where the ligands may interact with the receptors in various oligomeric states i.e., monomers, homodimers, and heterodimers. Chemokine receptors are G-protein coupled receptors (GPCRs) present in the membrane of immune cells. The migration of immune cells occurs in response to a concentration gradient of the ligands. Chemotaxis of neutrophils is directed by CXC-ligand (CXCL) activation of the membrane bound CXC chemokine receptor 2 (CXCR2). CXCR2 plays an important role in human health and is linked to disorders such as autoimmune disorders, inflammation, and cancer. Yet, despite their important role, little is known about the biophysical characteristics controlling ligand:ligand and ligand:receptor interaction essential for biological activity. In this work, we study the homodimers of three of the CXCR2 cognate ligands, CXCL1, CXCL5, and CXCL8. The ligands share high structural integrity but a low sequence identity. We show that the sequence diversity has evolved different binding affinities and stabilities for the CXC-ligands resulting in diverse agonist/antagonist behavior. Furthermore, CXC-ligands fold through a three-state mechanism, populating a folded monomeric state before associating into an active dimer., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Martin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Working with research animals can be both rewarding and challenging. The rewarding part of the work is associated with understanding the necessity for animal research to improve the health of humans and animals and the knowledge that one can provide care and compassion for the animals. Challenges with animal research include witnessing stress/pain in animals necessitated by scientific requirements, end of study euthanasia, and societal stigmatization about animal research. These challenges could be compounded with more general workplace stresses, in turn, impacting job retention and satisfaction. However, these factors have yet to be formally evaluated. Therefore, the purpose of this survey was to comprehensively evaluate professional quality of life's correlation with key workplace metrics., Methods: Six institutions were recruited to participate in a longitudinal intervention trial on compassion fatigue resiliency. This manuscript reports key baseline metrics from this survey. A cross-sectional mixed methods survey was developed to evaluate professional quality of life, job satisfaction, retention, and factors influencing compassion fatigue resiliency. Quantitative data were analyzed via general linear models and qualitative data were analyzed by theme., Results: Baseline data was collected from 198 participants. Personnel who reported higher compassion satisfaction also reported higher retention and job satisfaction. Conversely, personnel who reported higher burnout also reported lower job satisfaction. In response to open-ended questions, participants said their compassion fatigue was impacted by institutional culture (70% of participants), animal research (58%), general mental health (41%), and specific compassion fatigue support (24%)., Conclusions: In conclusion, these results show that professional quality of life is related to important operational metrics of job satisfaction and retention. Furthermore, compassion fatigue is impacted by factors beyond working with research animals, including institutional culture and general mental health support. Overall, this project provides rationale and insight for institutional support of compassion fatigue resiliency., Competing Interests: All authors are employed by the institution noted in their affiliation except for Lauren Young who was a student during data collection and initial writing and then transitioned to a full-time role with the 3Rs Collaborative during manuscript revision. All authors are also members of the 3Rs Collaborative’s Compassion Fatigue Initiative. Elizabeth Nunamaker and Sally Thompson-Iritani also sat on the board of directors and leadership team of the 3Rs Collaborative during publication. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Young et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Deep learning shows promise for automating detection and classification of wildlife from digital aerial imagery to support cost-efficient remote sensing solutions for wildlife population monitoring. To support in-flight orthorectification and machine learning processing to detect and classify wildlife from imagery in near real-time, we evaluated deep learning methods that address hardware limitations and the need for processing efficiencies to support the envisioned in-flight workflow. We developed an annotated dataset for a suite of marine birds from high-resolution digital aerial imagery collected over open water environments to train the models. The proposed 3-stage workflow for automated, in-flight data processing includes: 1) image filtering based on the probability of any bird occurrence, 2) bird instance detection, and 3) bird instance classification. For image filtering, we compared the performance of a binary classifier with Mask Region-based Convolutional Neural Network (Mask R-CNN) as a means of sub-setting large volumes of imagery based on the probability of at least one bird occurrence in an image. On both the validation and test datasets, the binary classifier achieved higher performance than Mask R-CNN for predicting bird occurrence at the image-level. We recommend the binary classifier over Mask R-CNN for workflow first-stage filtering. For bird instance detection, we leveraged Mask R-CNN as our detection framework and proposed an iterative refinement method to bootstrap our predicted detections from loose ground-truth annotations. We also discuss future work to address the taxonomic classification phase of the envisioned workflow., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Breastfeeding brings about a positive impact on both child and maternal health in the short and long terms. However, adolescent mothers have a lower breastfeeding initiation rate and a shorter breastfeeding duration than adult mothers. Although mobile applications have been found to be the most widely used platform for breastfeeding support, there is still a lack of design specific for adolescents., Aim: To explore the experiences, perspectives and needs of adolescent mothers and professional nurses using smartphone applications for breastfeeding support and the influence of this technology on healthcare in Thailand., Methods: This formative qualitative research of the 'Development of smartphone application for promoting breastfeeding and learning of infant responsiveness for Thai teenage pregnant women' study intends to design a smartphone application and develop an implementation plan. A purposive sample was used to elicit experiences from adolescent mothers and nurses. Data were collected from 48 adolescent mothers through in-depth interviews with six focus group discussions and 12 nurses, following the data saturation principle. Thematic analysis was conducted, and potential factors and needs were mapped to the capability, opportunity, and motivation model of behaviour change (COM-B)., Results: Most adolescent mothers perceived the usefulness of smartphone apps as breastfeeding support resources. The qualitative findings of adolescent mothers were grouped into the following three themes: a friendly breastfeeding tool; allows them to manage their breastfeeding activities; and enhances the accessibility and equality of breastfeeding support. The professional nurses perceived the benefits of using smartphone applications in their work, which included the following three themes: reducing workload and making their work easier; preparation is always better; and increasing the standards of breastfeeding support., Conclusion: Adolescent mothers and professional nurses showed favourable attitudes toward smartphone apps for breastfeeding support. These smartphone apps should be tailored to these groups to achieve optimal BF outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The activities of the phospholipase C gamma (PLCγ) 1 and 2 enzymes are essential for numerous cellular processes. Unsurprisingly, dysregulation of PLCγ1 or PLCγ2 activity is associated with multiple maladies including immune disorders, cancers, and neurodegenerative diseases. Therefore, the modulation of either of these two enzymes has been suggested as a therapeutic strategy to combat these diseases. To aid in the discovery of PLCγ family enzyme modulators that could be developed into therapeutic agents, we have synthesized a high-throughput screening-amenable micellular fluorogenic substrate called C16CF3-coumarin. Herein, the ability of PLCγ1 and PLCγ2 to enzymatically process C16CF3-coumarin was confirmed, the micellular assay conditions were optimized, and the kinetics of the reaction were determined. A proof-of-principle pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC1280) was performed. This new substrate allows for an additional screening methodology to identify modulators of the PLCγ family of enzymes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Visvanathan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Major depressive disorder (MDD), a prevalent mental health issue, affects more than 8% of the US population, and almost 17% in the young group of 18-25 years old. Since Covid-19, its prevalence has become even more significant. However, the remission (being free of depression) rates of first-line antidepressant treatments on MDD are only about 30%. To improve treatment outcomes, researchers have built various predictive models for treatment responses and yet none of them have been adopted in clinical use. One reason is that most predictive models are based on data from subjective questionnaires, which are less reliable. Neuroimaging data are promising objective prognostic factors, but they are expensive to obtain and hence predictive models using neuroimaging data are limited and such studies were usually in small scale (N<100). In this paper, we proposed an advanced machine learning (ML) pipeline for small training dataset with large number of features. We implemented multiple imputation for missing data and repeated K-fold cross validation (CV) to robustly estimate predictive performances. Different feature selection methods and stacking methods using 6 general ML models including random forest, gradient boosting decision tree, XGBoost, penalized logistic regression, support vector machine (SVM), and neural network were examined to evaluate the model performances. All predictive models were compared using model performance metrics such as accuracy, balanced accuracy, area under ROC curve (AUC), sensitivity and specificity. Our proposed ML pipeline was applied to a training dataset and obtained an accuracy and AUC above 0.80. But such high performance failed while applying our ML pipeline using an external validation dataset from the EMBARC study which is a multi-center study. We further examined the possible reasons especially the site heterogeneity issue., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Mortality is the most devastating complication of percutaneous coronary interventions (PCI). Identifying the most common causes and mechanisms of death after PCI in contemporary practice is an important step in further reducing periprocedural mortality., Objectives: To systematically analyze the cause and circumstances of in-hospital mortality in a large, multi-center, statewide cohort., Methods: In-hospital deaths after PCI occurring at 39 hospitals included in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) between 2012 and 2014 were retrospectively reviewed using validated methods. A priori PCI-related mortality risk was estimated using the validated BMC2 model., Results: A total of 1,163 deaths after PCI were included in the study. Mean age was 71±13 years, and 507 (44%) were women. Left ventricular failure was the most common cause of death (52% of cases). The circumstance of death was most commonly related to prior acute cardiovascular condition (61% of cases). Procedural complications were considered contributing to mortality in 235 (20%) cases. Death was rated as not preventable or slightly preventable in 1,045 (89.9%) cases. The majority of the deaths occurred in intermediate or high-risk patients, but 328 (28.2%) deaths occurred in low-risk patients (<5% predicted risk of mortality). PCI was considered rarely appropriate in 30% of preventable deaths., Conclusions: In-hospital mortality after PCI is rare, and primarily related to pre-existing critical acute cardiovascular condition. However, approximately 10% of deaths were preventable. Further research is needed to characterize preventable deaths, in order to develop strategies to improve procedural safety., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. Azzalini received consulting fees from Teleflex, Abiomed, GE Healthcare, Asahi Intecc, Philips, Abbott Vascular, Reflow Medical, and Cardiovascular Systems, Inc.; is on the advisory board of GE Healthcare; and owns equity in Reflow Medical. Devraj Sukul reports no relevant financial disclosures. Hitinder Gurm receives research support from Blue Cross and Blue Shield of Michigan. He is the co-founder of, owns equity in, and is a consultant to Amplitude Vascular Systems. He also owns equity in Jiaxing Bossh Medical Technology Partnership and is a consultant for Osprey Medical. He is the chair of the Clinical Events Committee for the PERFORMANCE trial sponsored by Contego Medical. All other authors have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Moroni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Advancing human induced pluripotent stem cell derived cardiomyocyte (hiPSC-CM) technology will lead to significant progress ranging from disease modeling, to drug discovery, to regenerative tissue engineering. Yet, alongside these potential opportunities comes a critical challenge: attaining mature hiPSC-CM tissues. At present, there are multiple techniques to promote maturity of hiPSC-CMs including physical platforms and cell culture protocols. However, when it comes to making quantitative comparisons of functional behavior, there are limited options for reliably and reproducibly computing functional metrics that are suitable for direct cross-system comparison. In addition, the current standard functional metrics obtained from time-lapse images of cardiac microbundle contraction reported in the field (i.e., post forces, average tissue stress) do not take full advantage of the available information present in these data (i.e., full-field tissue displacements and strains). Thus, we present "MicroBundleCompute," a computational framework for automatic quantification of morphology-based mechanical metrics from movies of cardiac microbundles. Briefly, this computational framework offers tools for automatic tissue segmentation, tracking, and analysis of brightfield and phase contrast movies of beating cardiac microbundles. It is straightforward to implement, runs without user intervention, requires minimal input parameter setting selection, and is computationally inexpensive. In this paper, we describe the methods underlying this computational framework, show the results of our extensive validation studies, and demonstrate the utility of exploring heterogeneous tissue deformations and strains as functional metrics. With this manuscript, we disseminate "MicroBundleCompute" as an open-source computational tool with the aim of making automated quantitative analysis of beating cardiac microbundles more accessible to the community., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kobeissi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Comprehensive abortion care is an emerging intervention being integrated into nursing and midwifery curricula. Yet, no studies have been conducted in Rwanda to determine whether faculty perceive themselves as capable of teaching comprehensive abortion care. This study aims to evaluate the perceived self-efficacy to teach comprehensive abortion care among nursing and midwifery faculty in higher learning institutions in Rwanda., Materials and Methods: The University of Rwanda College of Medicine and Health Sciences Institutional Review Board approved this study (UR-CMHS-IRB No 335/CMHSIRB/2022). In quantitative, a self-administered questionnaire was administered to 98 study participants. Data were entered into Statistical Package for the Social Sciences (SPSS) version 26 and analyzed using Chi-square test with a p-value of 0.05 set as the significance level. In the qualitative part, an interview guide was developed based on quantitative data to understand comprehensive abortion care teaching fully. Data were collected from four focus group discussions with eight participants in each group, entered in Dedoose, and analyzed thematically., Results: Among the 98 study participants who were invited to participate in this study, only 85 filled out the questionnaires. This translates into 86.7% of the response rate. More than half 58.8% had adequate self-efficacy in teaching comprehensive abortion care. A Chi-square test has revealed that being a male, being a midwife, and having more years of working experience in nursing education were significantly associated with self-efficacy in teaching comprehensive abortion care (p value <0.05). In the qualitative phase, 32 study participants participated in four focus group discussions and four themes were identified: a) variability in confidence levels to teach comprehensive abortion care; b) readiness about teaching comprehensive abortion care; c) facilitators of teaching comprehensive abortion care; and d) contextual challenges to teach comprehensive abortion care., Conclusions: The findings revealed that faculty's self-efficacy in teaching comprehensive abortion care was not adequate. Personal and religious beliefs and institutional barriers were also reported to hinder self-efficacy in teaching comprehensive abortion care. Therefore, intensive comprehensive abortion care training for nursing and midwifery faculty in higher learning institutions should be provided, including values clarification and attitude transformation training for attitudes and beliefs. It is also critical for higher learning institutions to develop strategies for overcoming the challenges faculty face when teaching comprehensive abortion care., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nkurunziza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

There are cases in which CKD progression is difficult to evaluate, because the changes in estimated glomerular filtration rate (eGFR) and proteinuria sometimes show opposite directions as CKD progresses. Indices and models that enable the easy and accurate risk prediction of end-stage-kidney disease (ESKD) are indispensable to CKD therapy. In this study, we investigated whether a CKD stage coordinate transformed into a vector field (CKD potential model) accurately predicts ESKD risk. Meta-analysis of large-scale cohort studies of CKD patients in PubMed was conducted to develop the model. The distance from CKD stage G2 A1 to a patient's data on eGFR and proteinuria was defined as r. We developed the CKD potential model on the basis of the data from the meta-analysis of three previous cohort studies: ESKD risk = exp(r). Then, the model was validated using data from a cohort study of CKD patients in Japan followed up for three years (n = 1,564). Moreover, the directional derivative of the model was developed as an index of CKD progression velocity. For ESKD prediction in three years, areas under the receiver operating characteristic curves (AUCs) were adjusted for baseline characteristics. Cox proportional hazards models with spline terms showed the exponential association between r and ESKD risk (p<0.0001). The CKD potential model more accurately predicted ESKD with an adjusted AUC of 0.81 (95% CI 0.76, 0.87) than eGFR (p<0.0001). Moreover, the directional derivative of the model showed a larger adjusted AUC for the prediction of ESKD than the percent eGFR change and eGFR slope (p<0.0001). Then, a chart of the transformed CKD stage was developed for implementation in clinical settings. This study indicated that the transformed CKD stage as a vector field enables the easy and accurate estimation of ESKD risk and CKD progression and suggested that vector analysis is a useful tool for clinical studies of CKD and its related diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kanda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Understanding the functional effects of sequence variation is crucial in genomics. Individual human genomes contain millions of variants that contribute to phenotypic variability and disease risks at the population level. Because variants rarely act in isolation, we must consider potential interactions of neighboring variants to accurately predict functional effects. We can accomplish this using haplotagging, which matches sequencing reads to their parental haplotypes using alleles observed at known heterozygous variants. However, few published tools for haplotagging exist and these share several technical and usability-related shortcomings that limit applicability, in particular a lack of insight or control over error rates, and lack of key metrics on the underlying sources of haplotagging error. Here we present HaplotagLR: a user-friendly tool that haplotags long sequencing reads based on a multinomial model and existing phased variant lists. HaplotagLR is user-configurable and includes a basic error model to control the empirical FDR in its output. We show that HaplotagLR outperforms the leading haplotagging method in simulated datasets, especially at high levels of specificity, and displays 7% greater sensitivity in haplotagging real data. HaplotagLR advances both the immediate utility of haplotagging and paves the way for further improvements to this important method., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Holmes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Cash transfers are a promising but understudied intervention that may protect cognitive function in adults. Although South Africa has a rapidly ageing population, little is known about the nature of association between cash transfers and cognitive function in this setting., Objectives: We leveraged age-eligibility expansions to South Africa's Child Support Grant (CSG) to investigate the association between duration of CSG eligibility and cognitive function of biological mothers of child beneficiaries in South Africa., Methods: We analysed 2014/2015 baseline data from 944 women, aged 40-59 years with at least one CSG-eligible child, enrolled in the population-representative HAALSI cohort in Agincourt, South Africa. Duration of CSG eligibility for each mother was calculated based on the birth dates of all their children and the CSG age-eligibility expansion years (2003-2012). Cognitive function was measured using a cognitive battery administered at the HAALSI baseline interview. Linear regression was used to estimate the association between duration of CSG eligibility, dichotomized as low (≤10 years) and high (>10 years) eligibility, and cognitive function z-scores of the mothers., Results: High vs. low duration of CSG eligibility, was associated with higher cognitive function z-scores in the full sample [β: 0.15 SD units; 95% CI: 0.04, 0.26; p-value = 0.01]. In mothers with one to four lifetime children, but not five or more, high vs. low duration of CSG eligibility, was associated with higher cognitive function z-scores [β: 0.19 SD units; 95% CI: 0.05, 0.34, p-value = 0.02]., Conclusion: Government cash transfers given to support raising children may confer substantial protective effects on the subsequent cognitive function of mothers. Further studies are needed to understand how parity may influence this relationship. Our findings bring evidence to policymakers for designing income supplementation programmes to promote healthy cognitive ageing in low-income settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chakraborty et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)