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BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimers disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

Purpose: This study investigated the longitudinal, cross-linguistic developmental relationships of phonological awareness (PA), letter identification (letter ID), and morphological awareness (MA) in 71 heritage Spanish-English dual language learners (DLLs) in kindergarten and second grade. Method: Multiple linear regression was used to test if kindergarten Spanish and English PA (sound elision and sound matching) and letter ID significantly predicted later English MA (oral derived word stress judgment, oral derivational morpheme blending, written derived word decomposition, and morphologically complex word spelling) performance in second grade. Results: Cross-linguistically, the PA skill of sound matching in kindergarten was the most reliable predictor of MA in second grade for Spanish-English DLLs. Spanish PA explained the majority of variation in oral MA skills in English. English PA was only uniquely predictive of written MA skills in English. Conclusions: Both the cognitive operation of sound sequence manipulation in PA (elision or matching) and the modality of morpheme representation in MA (oral or written) appear to mediate the transfer of metalinguistic knowledge in Spanish-English DLL development in early elementary school. Results are discussed within the context of classroom practices.

OBJECTIVE: Bans on evictions were implemented to reduce the spread of COVID-19 and to protect vulnerable populations during a public health crisis. Our objective was to examine how three bans on eviction enforcement impacted eviction filings from March 2020 through January 2022 in Ontario, Canada. METHODS: Data were derived from eviction application records kept by the Ontario Landlord and Tenant Board. We used segmented regression analysis to model changes in the average weekly filing rates for evictions due to non-payment of rent (L1 filings) and reasons other than non-payment of rent (L2 filings). RESULTS: The average number of weekly L1 and L2 applications dropped by 67.5 (95% CI: 55.2, 79.9) and 31.7 (95% CI: 26.7, 36.6) filings per 100,000 rental dwellings, respectively, following the first ban on eviction enforcement (p

Abstract Background Among individuals with heart failure (HF), racial differences in comorbidities may be mediated by social determinants of health (SDOH). Methods Black and White US community-dwelling participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study aged ≥ 45 years with an adjudicated HF hospitalization between 2003 and 2017 were included in this cross-sectional analysis. We assessed whether higher prevalence of comorbidities in Black participants compared to White participants were mediated by SDOH in socioeconomic, environment/housing, social support, and healthcare access domains, using the inverse odds weighting method. Results Black (n = 240) compared to White (n = 293) participants with HF with preserved ejection fraction (HFpEF) had higher prevalence of diabetes [1.38 (95% CI 1.18–1.61)], chronic kidney disease [1.21 (95% CI 1.01–1.45)], and anemia [1.33 (95% CI 1.02–1.75)] and lower prevalence of atrial fibrillation [0.80 (95% CI (0.65–0.98)]. Black (n = 314) compared to White (n = 367) participants with HF with reduced ejection fraction (HFrEF) had higher prevalence of hypertension [1.04 (95% CI 1.02–1.07)] and diabetes [1.26 (95% CI 1.09–1.45)] and lower prevalence of coronary artery disease [0.86 (95% CI 0.78–0.94)] and atrial fibrillation [0.70 (95% CI 0.58–0.83)]. Socioeconomic status explained 14.5%, 26.5% and 40% of excess diabetes, anemia, and chronic kidney disease among Black adults with HFpEF; however; mediation was not statistically significant and no other SDOH substantially mediated differences in comorbidity prevalence. Conclusions Socioeconomic status partially mediated excess diabetes, anemia, and chronic kidney disease experienced by Black adults with HFpEF, but differences in other comorbidities were not explained by other SDOH examined.

Abolition is, put simply, creating paths to freedom. In education, that can be freedom of expression, thought, and so much more. While the work of educational abolition is for all [...]

Introduction Exposure to traffic-related air pollution (TRAP) is associated with adverse health outcomes, including elevated blood pressure (BP). (1-3) However, unlike fine particulate matter [PM [less than or equal to]2:5 [...]

The aim of this paper is to compare the power measurement capabilities in millimetre- and sub-millimetre-wave frequency bands of several national metrology institutes and one research institute. The first comparison, in WR-6.5 waveguide (110 GHz to 170 GHz), involved NPL, TUBITAK UME and PTB. The second comparison, in WR-1.5 waveguide (500 GHz to 750 GHz), involved NPL, METAS, TUBITAK UME, LNE, WAT, GUM and VDI. Two types of travelling standards were used for these comparisons: a thermoelectric power sensor in the WR-6.5 band and a calorimetric power sensor in the WR-6.5 and WR-1.5 bands. The thermoelectric power sensor was characterised by the participants against their own standards and a generalised effective efficiency was calculated. The calorimetric power sensor operating in the WR-6.5 band was measured to observe its behaviour during the comparison and was also measured in the WR-1.5 band after being fitted with a suitable waveguide taper and used in conjunction with a frequency multiplier. The participants measured the output of the calorimetric power sensor and their own power sensor standard. A normalised power ratio method was used as a comparison parameter for the WR-1.5 band measurements. In addition, a pyroelectric power standard was used by METAS to measure absolute power, and a frequency of 650 GHz was used as a link between the absolute power and the power ratios. Finally, all but two of the measurement points compared between the participants achieved agreement in terms of En scores less than 1. For the first time, an interlaboratory comparison of power measurements at sub-millimetre frequencies has been performed and, overall, good agreement was achieved between the different laboratories.

Abstract Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

Abstract Many species around the world have collapsed, yet only some have recovered. A key question is what happens to populations post collapse. Traditionally, marine fish collapses are linked to overfishing, poor climate, and recruitment. We test whether the effect on biomass change from these drivers remains the same after a collapse. We used a regression model to analyse the effect of harvesting, recruitment, and climate variability on biomass change before and after a collapse across 54 marine fish populations around the world. The most salient result was the change in fishing effect that became weaker after a collapse. The change in sea temperature and recruitment effects were more variable across systems. The strongest changes were in the pelagic habitats. The resultant change in the sensitivity to external drivers indicates that whilst biomass may be rebuilt, the responses to variables known to affect stocks may have changed after a collapse. Our results show that a general model applied to many stocks provides useful insights, but that not all stocks respond similarly to a collapse calling for stock-specific models. Stocks respond to environmental drivers differently after a collapse, so caution is needed when using pre-collapse knowledge to advise on population dynamics and management.

Abstract In natural environments, head movements are required to search for objects outside the field of view (FoV). Here we investigate the power of a salient target in an extended visual search array to facilitate faster detection once this item comes into the FoV by a head movement. We conducted two virtual reality experiments using spatially clustered sets of stimuli to observe target detection and head and eye movements during visual search. Participants completed search tasks with three conditions: (1) target in the initial FoV, (2) head movement needed to bring the target into the FoV, (3) same as condition 2 but the periphery was initially hidden and appeared after the head movement had brought the location of the target set into the FoV. We measured search time until participants found a more salient (O) or less salient (T) target among distractors (L). On average O’s were found faster than T’s. Gaze analysis showed that saliency facilitation occurred due to the target guiding the search only if it was within the initial FoV. When targets required a head movement to enter the FoV, participants followed the same search strategy as in trials without a visible target in the periphery. Moreover, faster search times for salient targets were only caused by the time required to find the target once the target set was reached. This suggests that the effect of stimulus saliency differs between visual search on fixed displays and when we are actively searching through an extended visual field.

Background Cognitive impairment is common among adults with heart failure (HF) and associated with poor outcomes. However, less is known about the trajectory of cognitive decline after a first HF hospitalization. We examined the rate of cognitive decline among adults with incident HF hospitalization compared with those without HF hospitalization. Methods and Results The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a prospective longitudinal study of 23 894 participants aged ≥45 years free of HF at baseline. HF hospitalization was expert adjudicated. Changes in global cognitive function (primary outcome) were assessed with the Six‐Item Screener (range, 0–6). Secondary outcomes included change in Word List Learning (range, 0–30), Word List Delayed Recall (WLD; range, 0–10), and Animal Fluency Test (range, 0+). Segmented linear mixed‐effects regression models were used. Over 5 years, mean scores across all 4 cognitive tests declined for all participants regardless of HF status. Those with incident HF hospitalization experienced faster declines in the Six‐Item Screener versus those who were HF free (difference, −0.031 [95% CI, −0.047 to −0.016]; P

Background Self‐care for adults with hypertension includes adherence to lifestyle behaviors and medication. For unpaid caregivers with hypertension, the burden of family caregiving may adversely impact self‐care. We examined the association between caregiver strain and hypertension self‐care among caregivers with hypertension. Methods and Results We included participants of the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study who identified as caregivers and had hypertension. Caregiver strain, assessed by self‐report, was categorized as “none/some” or “high.” Hypertension self‐care was assessed individually across 5 domains (Dietary Approaches to Stop Hypertension [DASH] diet, physical activity, alcohol use, cigarette smoking, and medication adherence) and a composite self‐care score summing performance across them. The association between caregiver strain and hypertension self‐care was examined with multivariable linear regression. Among the 2128 caregivers with hypertension, 18.1% reported high caregiver strain. Caregivers with high strain versus those with none/some were less adherent to the DASH diet (50.8% versus 38.9%, P

BACKGROUND/OBJECTIVES: CAN-THUMBS UP is designed as a comprehensive and innovative fully remote program to 1) develop an interactive and compelling online Brain Health Support Program intervention, with potential to positively influence dementia literacy, self-efficacy and lifestyle risk factors; 2) enroll and retain a community-dwelling Platform Trial Cohort of individuals at risk of dementia who will participate in the intervention; 3) support an open platform trial to test a variety of multidomain interventions that might further benefit individuals at risk of dementia. This manuscript presents the Brain Health Support Program Study protocol. DESIGN/SETTING: Twelve-month prospective multi-center longitudinal study to evaluate a fully remote web-based educational intervention. Participants will subsequently be part of a Platform Trial Cohort and may be eligible to participate in further dementia prevention clinical trials. PARTICIPANTS: Three hundred fifty older adults who are cognitively unimpaired or have mild cognitive impairment, with at least 1 well established dementia risk factor. INTERVENTION: Participants engage in the Brain Health Support Program intervention for 45-weeks and complete pre/post intervention measures. This intervention is designed to convey best available evidence for dementia prevention, consists of 181 chapters within 8 modules that are progressively delivered, and is available online in English and French. The program has been developed as a collaborative effort by investigators with recognized expertise in the programs content areas, along with input from older-adult citizen advisors. MEASUREMENTS: This study utilizes adapted remote assessments with accessible technologies (e.g. videoconferencing, cognitive testing via computer and mobile phone, wearable devices to track physical activity and sleep, self-administered saliva sample collection). The primary outcome is change in dementia literacy, as measured by the Alzheimers Disease Knowledge Scale. Secondary outcomes include change in self-efficacy; engagement using the online program; user satisfaction ratings; and evaluation of usability and acceptance. Exploratory outcomes include changes in attitudes toward dementia, modifiable risk factors, performance on the Neuropsychological Test Battery, performance on self-administered online cognitive assessments, and levels of physical activity and sleep; success of the national recruitment plan; and the distribution of age adjusted polygenic hazard scores. CONCLUSIONS: This fully remote study provides an accessible approach to research with all study activities being completed in the participants home environment. This approach may reduce barriers to participation, provide an easier and less demanding participant experience, and reach a broader geography with recruitment from all regions of Canada. CAN-THUMBS UP represents a Canadian contribution to the global World-Wide FINGERS program (alz.org/wwfingers).

ContextThe COVID-19 pandemic caused significant shocks to U.S. food systems at multiple scales. While disturbances to long-distance supply chains received substantial attention in national media, local supply chains experienced mixed impacts. As broad closures of schools, restaurants, and other businesses sourcing from local farmers removed key marketing channels for many direct market farmers, consumer interest in Community Supported Agriculture (CSA), farmers markets, and on-farm and online direct farm sales increased.ObjectiveIn this paper, we examine the resilience and vulnerability of farmers during the March 2020 through December 2020 period of the COVID-19 pandemic. We focus on California farmers and ranchers engaged in direct market sales.MethodsThrough a widely disseminated survey, we collected responses from 364 farmers and used these data to answer the following questions about direct market farmers in California: 1) What were direct market farmers' experiences of the pandemic from March 2020 through December 2020? 2) Which factors (e.g., relationships, institutions, market channels) did farmers report enhanced their resilience during the pandemic? 3) Which individual and operational factors were significantly associated with resilience during the pandemic? And finally, 4) how do the farmer-reported factors compare to the statistically significant factors associated with resilience? We created three dependent variables-ability to respond to the pandemic, concern about pandemic impacts, and change in profitability-to operationalize several aspects of resilience and examine their association with individual and operational characteristics through a series of ordered logistic regression models.Results and conclusionsAcross both the quantitative models and the farmer reported factors, we found that farmers who increased their use of online sales and marketing during the first year of the pandemic, had larger-scale farms, and had more on-farm crop and livestock diversity were more resilient to the shocks of the pandemic. We also found that greater use of non-direct-to-consumer market channels was associated with less resilience. The characteristics of the farming operations played a relatively larger role in predicting resilience compared to the individual characteristics of the farmers surveyed.SignificanceThis study gives a detailed picture of how California direct market farmers fared during the pandemic and the characteristics associated with greater resilience. As short and long-term disruptions become increasingly common in agriculture, policies and programs can leverage support to direct market farmers, particularly direct-to-consumer farmers, as a strategy to strengthen farmer resilience.

BackgroundManagement of adults with atrial fibrillation (AF) or atrial flutter in the emergency department (ED) includes rate reduction, cardioversion, and stroke prevention. Different approaches to these components of care may lead to variation in frequency of hospitalization and stroke prevention actions, with significant implications for patient experience, cost of care, and risk of complications. Standardization using evidence-based recommendations could reduce variation in management, preventable hospitalizations, and stroke risk.MethodsWe describe the rationale for our ED-based AF treatment recommendations. We also describe the development of an electronic clinical decision support system (CDSS) to deliver these recommendations to emergency physicians at the point of care. We implemented the CDSS at three pilot sites to assess feasibility and solicit user feedback. We will evaluate the impact of the CDSS on hospitalization and stroke prevention actions using a stepped-wedge cluster randomized pragmatic clinical trial across 13 community EDs in Northern California.DiscussionWe hypothesize that the CDSS intervention will reduce hospitalization of adults with isolated AF or atrial flutter presenting to the ED and increase anticoagulation prescription in eligible patients at the time of ED discharge and within 30 days. If our hypotheses are confirmed, the treatment protocol and CDSS could be recommended to other EDs to improve management of adults with AF or atrial flutter.Trial registrationClinicalTrials.gov NCT05009225 .  Registered on 17 August 2021.

Introduction: Ectopic pregnancy is the most common cause of maternal mortality in the first trimester. Bilateral tubal pregnancy is the rarest subset with an estimated incidence of one in 725 to 1,580 ectopic pregnancies. Of the cases of bilateral tubal pregnancy reported in the literature, most were associated with the use of assisted reproductive techniques. Here we present the case of a patient, without a prior history of reproductive technology use, who underwent treatment for a tubal pregnancy and was subsequently found to have a second, contralateral tubal pregnancy 11 days later.Case Report: A 35-year-old female gravida eight para two with a history of left tubal pregnancy and salpingectomy 11 days prior, presented to the emergency department (ED) with two days of left lower and upper quadrant abdominal pain. The patient’s last menstrual period had been several months prior. A physical examination revealed left lower quadrant abdominal tenderness, rebound, guarding, and left adnexal tenderness. Her vital signs were unremarkable, and her laboratory studies revealed normal white blood cell and hemoglobin values. Her human chorionic gonadotropin had tripled from her last presentation 11 days prior. Transvaginal ultrasound showed a possible ectopic pregnancy adjacent to the right ovary. She promptly underwent a right salpingectomy. Pathology findings confirmed a tubal pregnancy, and the patient’s postoperative course was uneventful.Conclusion: This case highlights the importance of maintaining a high index of suspicion for ectopic pregnancy in all biologically female patients of reproductive age who present to the ED with abdominal pain.

Significant socio-economic, health, and mental health disparities due to highly entrenched and systemic anti-Black racism in Canadian institutions, policies, and practices are now well documented in research and policy reports. Yet, few in-depth studies have addressed the mental health impacts of anti-Black racism on Canadian populations. This article is rooted in a community-based, qualitative research project with young first and second-generation Black Caribbean-Canadian mothers and is informed by Black Feminist epistemologies and intersectional theories and methodologies. Our research demonstrates how participants' childhood experiences with xenophobic and racist immigration policies and educational, child welfare, and childcare systems caused their future mental health challenges as young Black mothers, and how these struggles were exacerbated by their encounters with the racist, ageist, xenophobic medical, social, and mental health services they had to access as young mothers. Based on these findings, we recommend enhancements to current social policies to minimize the differential mental health impacts on young Black Canadian mothers. Les rapports de recherche et de politique documentent d'importantes disparites socio-economiques, sanitaires et mentales dues au racisme anti-Noir systemique et fortement enracine dans les institutions, les politiques et les pratiques canadiennes. Pourtant, peu d'etudes approfondies se sont penchees sur les effets du racisme antiNoirs sur la sante mentale des populations canadiennes. Cet article s'appuie sur un projet de recherche qualitative communautaire mene aupres de jeunes meres canadiennes noires des Caraibes de premiere et de deuxieme generation, et s'inspire des epistemologies feministes noires ainsi que des theories et methodologies intersectionnelles. Notre recherche demontre comment les experiences de l'enfance des participantes avec les politiques d'immigration xenophobes et racistes et les systemes d'education, de protection de l'enfance et de garde d'enfants ont cause leurs futurs problemes de sante mentale en tant que jeunes meres noires, et comment ces luttes ont ete exacerbees par leurs rencontres avec les services medicaux, sociaux et de sante mentale racistes, agistes et xenophobes auxquels elles ont du avoir acces en tant que jeunes meres. Sur la base de ces resultats, nous recommandons d'ameliorer les politiques sociales actuelles afin de minimiser les impacts differentiels sur la sante mentale des jeunes meres noires canadiennes., INTRODUCTION Black people (defined as those of African and Caribbean descent) now account for 3.5% of the Canadian population, with more than half of Canada's Black residents (52.4%) living in [...]

Between 2018 and 2024, we conducted systematic whole-genome sequencing and phylogenomic analysis on 263 V. cholerae O1 isolates from cholera patients across four provinces in the Democratic Republic of Congo (North-Kivu, South-Kivu, Tanganyika, and Kasai Oriental). These isolates were classified into the AFR10d and AFR10e sublineages of AFR10 lineage, originating from the third wave of the seventh El Tor cholera pandemic (7PET). Compared to the strains analysed between 2014 and 2017, both sublineages had few genetic changes in the core genome but recent isolates (2022-2024) had significant CTX prophage rearrangement. AFR10e spread across all four provinces, while AFR10d appeared to be extinct by the end of 2020. Since 2022, most V. cholerae O1 isolates exhibited significant CTX prophage rearrangements, including a tandem repeat of an environmental satellite phage RS1 downstream the ctxB toxin gene of the CTX-Φ-3 prophage on the large chromosome, as well as two or more arrayed copies of an environmental pre-CTX-Φ prophage precursor on the small chromosome. We used Illumina data for mapping and coverage estimation to identify isolates with unique CTX-Φ genomic features. Gene localization was then determined on MinION-derived assemblies, revealing an organization similar to that of non-O1 V. cholerae isolates found in Asia (O139 VC1374, and environmental O4 VCE232), but never described in V. cholerae O1 El Tor from the third wave. In conclusion, while the core genome of AFR10d and AFR10e showed minimal changes, significant alterations in the CTX-Φ and pre-CTX-Φ prophage content and organization were identified in AFR10e from 2022 onwards.