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Abstract Although histological and molecular classifications have been extensively studied for gastric cancer (GC), targeted therapies for GC remain limited. CDH1 mutations (MT) are characteristic of genomically stable GC and are associated with poor prognosis, but lack effective or targeted therapies. Here, we showed the overall mutation frequency of CDH1 was 9.7% (155 of 1596). CDH1-MT GC showed significantly lower rates of PD-L1 positivity (CPS score ≥1) than CDH1-wildtype (WT) GC (56.7% vs. 73.3%, p

The reliance by North American regulatory authorities on in vivo rodent bioassays—Protein Correct-Amino Acid Score (PDCAAS) in the U.S. and Protein Efficiency Ratio (PER) in Canada—to measure the protein quality for protein content claim substantiation represents a major barrier for innovation in the development and marketing of protein foods. Although FAO in 2013 proposed a new method (Digestible Indispensable Amino Acid Score, DIAAS), it is still not used for protein content claim substantiation in any jurisdiction. Together with public health efforts to increase the consumption of plant-based foods, removing hurdles is key to incentivizing the food industry to measure protein digestibility in making food formulation decisions as well as in claiming protein content on product labels. To address this issue, a pathway has been proposed to position alternative methods for in vitro protein digestibility in collaborative studies to generate the data necessary for method approval by a certifying body. The latter is critical to the potential recognition of these methods by both Health Canada and the US FDA. The purpose of this article is to briefly summarize the state-of-the-art in the field, to inform the research community of next steps, and to describe the path engaging collaborative laboratories in a proficiency test as the first step in moving forward toward acceptance of in vitro digestibility methods. Throughout, a consultative and iterative process will be utilized to ensure the program goals are met. Success will be achieved when the proposed path results in the acceptance of an in vitro methods for protein digestibility used for PDCAAS determinations, which will enable increased protein analyses and improved nutrition labeling of protein foods.

Background The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and to determine whether CCR5/CCL5 levels could impact treatment outcomes.Methods 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial.Results CCR5/CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5/CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5/CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5/CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone.Conclusions Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.

Background: Effective therapeutics for severe acute respiratory syndrome CoronaVirus-2 (SARS-CoV-2) infection are evolving. Under Emergency Use Authorization, COVID-19 convalescent plasma (CCP) was widely used in individuals hospitalized for COVID-19, but few randomized controlled trials supported its efficacy to limit respiratory failure or death. Methods: VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1) was a double-blind, multi-site, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of CCP with conventional therapy in hospitalized Veterans with SARS-CoV-2 infection and early respiratory compromise (requirement for oxygen). Participants (planned sample size 702) were randomized 1:1 to receive CCP with high titer neutralizing activity or 0.9% saline, stratified by site and age (≥65 versus

Abstract Objective To further clarify genotype:phenotype correlations associated with variants in KCNC1 encoding the voltage‐gated potassium (K+) channel subunit Kv3.1 and which are an emerging cause of a spectrum of neurological disease including intellectual disability, isolated myoclonus, progressive myoclonus epilepsy, and developmental and epileptic encephalopathy. Methods We describe the clinical and genetic characteristics of a series of three patients with de novo heterozygous missense variants in KCNC1 associated with nonspecific developmental delay/intellectual disability and central hypotonia without epilepsy or ataxia. All three variants lead to amino acids alterations with mild predicted differences in physicochemical properties yet are localized to the S6 pore region of the Kv3.1 protein between the selectivity filter and PXP motif important for K+ channel gating. We performed whole‐cell voltage clamp electrophysiological recording of wild‐type versus variants in a heterologous mammalian expression system. Results We demonstrate a prominent leftward (hyperpolarized) shift in the voltage dependence of activation and slowed deactivation of all variants in the clinically defined series. Interpretation Electrophysiological recordings are consistent with a gain of K+ channel function that is predicted to exert a loss of function on the excitability of Kv3‐expressing high frequency‐ firing neurons based on the unique electrophysiological properties of Kv3 channels. These results define a clinical‐genetic syndrome within the spectrum of KCNC1‐related neurological disorders.

Background and Aims: Benign esophageal strictures often present with dysphagia and can significantly impair a patient’s quality of life, especially when refractory to standard endoscopic techniques. When repeat dilations fail to achieve an adequate luminal diameter or resolve dysphagia, further therapy with needle-knife or steroid injections is needed. However, patients can still clinically fail. To manage such strictures, we employed a novel combination of all three techniques. Methods: Single-center case series of adult patients with benign strictures that were refractory to conventional endoscopic therapy and removable self-expanding metal stenting. Primary clinical success was defined as complete resolution in dysphagia. Secondary outcomes included periodic dilation index (frequency of dilations over the follow-up time), esophageal diameter changes, technical success, and complications. Results: Four patients (median age 49.7 years old, interquartile range [IQR] 30–59) underwent endoscopic therapy for complex, benign strictures using our triple therapy technique. Etiologies of the strictures included peptic strictures (n = 3) and an anastomotic stricture (n = 1). There was 100% technical success rate with no associated adverse events. There was a 50% clinical success rate, with 1 additional patient having partial improvement in dysphagia. The median diameter of the esophagus before and after triple therapy was 3.2 mm (IQR 3.5–5.5) and 12.8 mm (IQR 11.7–14.2), respectively. The periodic dilation index was 6.3 before and 1.5 after triple therapy. The median length of follow-up was 362.5 days. Conclusion: Triple combination therapy may be useful in benign strictures that are refractory to standard techniques. Larger studies are needed to validate these findings.

**Objective**: To understand the usability of telehealth among physicians caring for older adults during the COVID-19 pandemic. **Methods**: We interviewed US-based physicians specializing in emergency medicine, geriatrics, and primary care who provided care during the COVID-19 pandemic. The interview guide was grounded in the unified theory of acceptance and use of technology (UTAUT). After conducting interviews probing their experiences delivering care using telehealth, we performed framework analysis to reveal major themes in telehealth usability. **Results**: Forty-eight physicians (15 emergency physicians, 18 geriatricians, 15 primary care physicians) participated in interviews from September 2, 2020 to November 20, 2020. Lack of prior use of telehealth, quick adoption of telehealth, technical deficiencies in platforms, and frequent visits with older adults made using telehealth more difficult. Physicians shared low self-efficacy when using telehealth for diagnosis in certain patient populations, like older patients, new patients, and patients with atypical presentations or non-specific symptoms. By contrast, they had high self-efficacy if they received training, had existing technical proficiency, or were meeting established patients. Key facilitating conditions include easy-to-use telehealth platforms, the inclusion of third parties---like patients' children or nurses---in virtual visits, and at-home medical devices like blood pressure cuffs or pulse oximeters. **Conclusions**: While physicians largely found that telehealth platforms were usable to deliver care to patients remotely, there were several technical and training-related barriers that impeded telehealth's usability at the onset of the pandemic. Simpler telehealth platforms with easy-to-use features, involvement of caregivers, telehealth training, and remote diagnostic devices increased the usability of telehealth.

Dravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is typically caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1, a 250-kDa voltage-gated sodium channel. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector–mediated delivery of a codon-modified SCN1A open reading frame into the brain improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus and/or the thalamus of DS mice increased survival, reduced the occurrence of epileptic spikes, provided protection from thermally induced seizures, corrected background electrocorticographic activity and behavioral deficits, and restored hippocampal inhibition. Together, our results provide a proof of concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.

Background Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined the relationship between overall survival (OS) and baseline QOL. Patients and Methods A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan [IFL] vs infusional 5-FU/leucovorin [LV]/oxaliplatin [FOLFOX] vs. irinotecan/oxaliplatin [IROX]) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0–100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0–50) vs not clinically deficient (nCD-QOL, score 51–100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy. Results Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2 months vs 18.4 months, P < .0001), and in each arm IFL 12.4 vs 15.1 months, FOLFOX 11.1 months vs 20.6 months, and IROX 8.9 months vs 18.1 months. Baseline QOL was associated with baseline performance status (PS) ( P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS ( P = .017). Conclusions Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.

Summary: Dravet syndrome (DS) is a severe neurodevelopmental disorder caused by loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1. We recently showed that neocortical vasoactive intestinal peptide interneurons (VIP-INs) express Nav1.1 and are hypoexcitable in DS (Scn1a+/−) mice. Here, we investigate VIP-IN function at the circuit and behavioral level by performing in vivo 2-photon calcium imaging in awake wild-type (WT) and Scn1a+/− mice. VIP-IN and pyramidal neuron activation during behavioral transition from quiet wakefulness to active running is diminished in Scn1a+/− mice, and optogenetic activation of VIP-INs restores pyramidal neuron activity to WT levels during locomotion. VIP-IN selective Scn1a deletion reproduces core autism-spectrum-disorder-related behaviors in addition to cellular- and circuit-level deficits in VIP-IN function, but without epilepsy, sudden death, or avoidance behaviors seen in the global model. Hence, VIP-INs are impaired in vivo, which may underlie non-seizure cognitive and behavioral comorbidities in DS.

BackgroundOlder adults who have difficulty moving around are commonly advised to adopt mobility-assistive devices to prevent injuries. However, limited evidence exists on the safety of these devices. Existing data sources such as the National Electronic Injury Surveillance System tend to focus on injury description rather than the underlying context, thus providing little to no actionable information regarding the safety of these devices. Although online reviews are often used by consumers to assess the safety of products, prior studies have not explored consumer-reported injuries and safety concerns within online reviews of mobility-assistive devices. ObjectiveThis study aimed to investigate injury types and contexts stemming from the use of mobility-assistive devices, as reported by older adults or their caregivers in online reviews. It not only identified injury severities and mobility-assistive device failure pathways but also shed light on the development of safety information and protocols for these products. MethodsReviews concerning assistive devices were extracted from the “assistive aid” categories, which are typically intended for older adult use, on Amazon’s US website. The extracted reviews were filtered so that only those pertaining to mobility-assistive devices (canes, gait or transfer belts, ramps, walkers or rollators, and wheelchairs or transport chairs) were retained. We conducted large-scale content analysis of these 48,886 retained reviews by coding them according to injury type (no injury, potential future injury, minor injury, and major injury) and injury pathway (device critical component breakage or decoupling; unintended movement; instability; poor, uneven surface handling; and trip hazards). Coding efforts were carried out across 2 separate phases in which the team manually verified all instances coded as minor injury, major injury, or potential future injury and established interrater reliability to validate coding efforts. ResultsThe content analysis provided a better understanding of the contexts and conditions leading to user injury, as well as the severity of injuries associated with these mobility-assistive devices. Injury pathways—device critical component failures; unintended device movement; poor, uneven surface handling; instability; and trip hazards—were identified for 5 product types (canes, gait and transfer belts, ramps, walkers and rollators, and wheelchairs and transport chairs). Outcomes were normalized per 10,000 posting counts (online reviews) mentioning minor injury, major injury, or potential future injury by product category. Overall, per 10,000 reviews, 240 (2.4%) described mobility-assistive equipment–related user injuries, whereas 2318 (23.18%) revealed potential future injuries. ConclusionsThis study highlights mobility-assistive device injury contexts and severities, suggesting that consumers who posted online reviews attribute most serious injuries to a defective item, rather than user misuse. It implies that many mobility-assistive device injuries may be preventable through patient and caregiver education on how to evaluate new and existing equipment for risk of potential future injury.

This study's objective was to determine how frontline physicians perceived telehealth for older adults with sensory impairments, cognitive impairments, mobility challenges, or those receiving end-of-life care. We conducted a multiple-methods study of US emergency, geriatric, and primary care physicians. Phase 1 involved semi-structured interviews with 48 physicians on their experiences using telehealth with older adults. In phase 2, we used those qualitative findings to generate a web-based survey administered to 74 physicians. In phase 3, we reintegrated qualitative data to enrich survey results. We identified 3 key findings: (1) 50% of emergency physicians, 33% of geriatricians, and 18% of primary care physicians considered telehealth to be a poor substitute for providing end-of-life care ( p = .68); (2) for hearing, vision, and cognitive impairments, 61%, 58%, and 54%, respectively, saw telehealth as a good or fair substitute for providing care ( p = .14); and (3) 98% indicated that telehealth was a good or fair substitute for in-person care for those with mobility impairment ( p

Background Inequitable access to high‐technology therapeutics may perpetuate inequities in care. We examined the characteristics of US hospitals that did and did not establish left atrial appendage occlusion (LAAO) programs, the patient populations those hospitals served, and the associations between zip code–level racial, ethnic, and socioeconomic composition and rates of LAAO among Medicare beneficiaries living within large metropolitan areas with LAAO programs. Methods and Results We conducted cross‐sectional analyses of Medicare fee‐for‐service claims for beneficiaries aged 66 years or older between 2016 and 2019. We identified hospitals establishing LAAO programs during the study period. We used generalized linear mixed models to measure the association between zip code–level racial, ethnic, and socioeconomic composition and age‐adjusted rates of LAAO in the most populous 25 metropolitan areas with LAAO sites. During the study period, 507 candidate hospitals started LAAO programs, and 745 candidate hospitals did not. Most new LAAO programs opened in metropolitan areas (97.4%). Compared with non‐LAAO centers, LAAO centers treated patients with higher median household incomes (difference of $913 [95% CI, $197–$1629], P=0.01). Zip code–level rates of LAAO procedures per 100 000 Medicare beneficiaries in large metropolitan areas were 0.34% (95% CI, 0.33%–0.35%) lower for each $1000 zip code–level decrease in median household income. After adjustment for socioeconomic markers, age, and clinical comorbidities, LAAO rates were lower in zip codes with higher proportions of Black or Hispanic patients. Conclusions Growth in LAAO programs in the United States had been concentrated in metropolitan areas. LAAO centers treated wealthier patient populations in hospitals without LAAO programs. Within major metropolitan areas with LAAO programs, zip codes with higher proportions of Black and Hispanic patients and more patients experiencing socioeconomic disadvantage had lower age‐adjusted rates of LAAO. Thus, geographic proximity alone may not ensure equitable access to LAAO. Unequal access to LAAO may reflect disparities in referral patterns, rates of diagnosis, and preferences for using novel therapies experienced by racial and ethnic minority groups and patients experiencing socioeconomic disadvantage.

Summary: Here, we present a protocol using optogenetics or chemogenetics to assess the neuronal circuits contributing to seizure initiation. Both approaches allow for targeted control of neuronal populations in vivo and can be combined with experimental manipulations to acutely induce seizures in rodent models. We describe how to (1) introduce and (2) activate optogenetic or chemogenetic actuators while (3) inducing seizures via hyperthermia in a mouse model of epilepsy. This protocol can be adapted for use in other induced seizure models.For complete details on the use and execution of this protocol, please refer to Mattis et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background Telehealth delivery expanded quickly during the COVID-19 pandemic after the reduction of payment and regulatory barriers, but older adults are the least likely to benefit from this expansion. Little is known about physician experiences initiating telehealth and factors that fostered or discouraged adoption during the COVID-19 pandemic with older adult patients. Therefore, our objective was to understand experiences of frontline physicians caring for older adults via telehealth during the COVID-19 pandemic. Methods We conducted semi-structured interviews from September 2020 to November 2020 with 48 physicians. We recruited a diverse sample of geriatricians (n = 18), primary care (n = 15), and emergency (n = 15) physicians from all United Stated (US) regions, rural-urban settings, and academic-community practices who cared for older adult patients during the pandemic using purposive sampling methods. We completed framework analysis of the transcribed interviews to identify emerging themes and used the Quadruple Aim to organize themes. Results Frontline physicians described telehealth as a more flexible, value-based, and patient-centered mode of health care delivery. Benefits of using telehealth to treat older adults included reducing deferred care and increasing timely care, improving efficiency for physicians, enhancing communication with caregivers and patients, reducing patient travel burdens, and facilitating health outreach and education. Challenges included unequal access for rural, older, or cognitively impaired patients. Physicians noted that payment parity with in-person visits, between video and telephone visits, and relaxation of restrictive regulations would enhance their ability to continue to offer telehealth. Conclusions Frontline physicians who treated older adults during the COVID-19 pandemic were largely in favor of continuing telehealth use beyond the pandemic; however, they noted that sustainability would depend on enacting policies that address access inequities and reimbursement concerns. Our data provide policy insights that if placed into action could facilitate the long-term success of telehealth and encourage a more flexible healthcare delivery system in the US.

[This corrects the article DOI: 10.1371/journal.pgph.0000193.].

Pancreatic cancer is the fourth leading cause of cancer mortality in the United States. Chemotherapy in resectable pancreatic cancer has improved survival by 10-20%. It only converted 10-30% of the borderline resectable and locally advanced pancreatic cancers to be surgically resectable. Radiation therapy has a documented role in managing localized pancreatic cancer, more so for borderline and locally advanced pancreatic cancer, where it can potentially improve the resectability rate of a given neoadjuvant treatment. The role of radiation therapy in resected pancreatic cancer is controversial, but it is used routinely to treat positive margins after pancreatic cancer surgery. Radiation therapy paradigms continue to evolve with advancements in treatment modalities, delivery techniques, and combination approaches. Despite the advances, there continues to be a controversy on the role of radiation therapy in managing this disease. In this review article, we discuss the recent updates, delivery techniques, and motion management in radiation therapy and dissect the applicability of this therapy in pancreatic cancer.

Abstract Lymph nodes (LNs) and distant metastases can arise from independent subclones of the primary tumor. Herein, we characterized the molecular landscape and the differences between LNs, distant metastases and primary colorectal cancers (CRCs). Samples were analyzed using next generation sequencing (NGS, MiSeq on 47 genes, NextSeq on 592 genes) and immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. In total, 11,871 samples were examined, comprising primaries (N = 5862), distant (N = 5605) and LNs metastases (N = 404). The most frequently mutated genes in LNs were TP53 (72%), APC (61%), KRAS (39%), ARID1A (20%), PIK3CA (12%). LNs showed a higher mean TMB (13 mut/MB) vs distant metastases (9 mut/MB, p

Vaccines against SARS-CoV-2 have alleviated infection rates, hospitalization and deaths associated with COVID-19. In order to monitor humoral immunity, several serology tests have been developed, but the recent emergence of variants of concern has revealed the need for assays that predict the neutralizing capacity of antibodies in a fast and adaptable manner. Sensitive and fast neutralization assays would allow a timely evaluation of immunity against emerging variants and support drug and vaccine discovery efforts. Here we describe a simple, fast, and cell-free multiplexed flow cytometry assay to interrogate the ability of antibodies to prevent the interaction of Angiotensin-converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of the original Wuhan-1 SARS-CoV-2 strain and emerging variants simultaneously, as a surrogate neutralization assay. Using this method, we demonstrate that serum antibodies collected from representative individuals at different time-points during the pandemic present variable neutralizing activity against emerging variants, such as Omicron BA.1 and South African B.1.351. Importantly, antibodies present in samples collected during 2021, before the third dose of the vaccine was administered, do not confer complete neutralization against Omicron BA.1, as opposed to samples collected in 2022 which show significant neutralizing activity. The proposed approach has a comparable performance to other established surrogate methods such as cell-based assays using pseudotyped lentiviral particles expressing the spike of SARS-CoV-2, as demonstrated by the assessment of the blocking activity of therapeutic antibodies (i.e. Imdevimab) and serum samples. This method offers a scalable, cost effective and adaptable platform for the dynamic evaluation of antibody protection in affected populations against variants of SARS-CoV-2.

Compassion fatigue is the result of repeated vicarious trauma from caring for those who have suffered. Although not well-researched in pediatric nephrology to date, there is reason to believe that it is a real and sustained threat to the pediatric nephrology workforce. Interventions aimed at individuals, the profession, and the organizations in which pediatric nephrologists work can create spaces to discuss and ameliorate compassion fatigue. This will result in better care for patients, more stable pediatric nephrology divisions and a stronger, more resilient pediatric nephrology workforce.

**Introduction:** While the COVID-19 pandemic increased telehealth uptake, concerns surrounding access to telehealth visits emerged for older adults, especially those that are under-resourced, rural, and non-English speaking. We aimed to identify strategies employed by physicians to improve access to medical care via telehealth for older adults during the pandemic. **Methods:** Using purposeful sampling, we recruited physicians for 30-minute semi-structured interviews. The interviews focused mainly on telehealth’s usability for older patients, and specific strategies physicians employed to facilitate access to care for older adults with varied needs and skills. Interviews were coded using NVivo software and analyzed using framework matrix analysis. **Results:** Of 48 physicians (geriatrician n = 18, primary care n=15, emergency n=15) interviewed, median age was 37 (interquartile range 34-45), and 27 (56%) were women. Our data suggests that older adults who were under-resourced, rural, or non-English speaking faced greater challenges in using telehealth. Physicians addressed these barriers with strategies tailored to individual patient needs and practice setting resources. Strategies included employing auditory augmentation and speech modifications to enhance understanding, using caregivers and home services to overcome inexperience with navigating technology, device distribution programs for those without equipment access, and real-time interpreter technologies. Physicians reported that telehealth was successful in reducing transportation barriers, whether due to distance or mobility impairments, especially among older adult populations and reducing “no-show” appointment rates. **Conclusions:** Adoption of strategies to overcome technological and systemic barriers may improve equitable access to age-friendly telehealth for older adult patients. Physicians reported optimism that telehealth could be used to expand access to medical care for older adults with the right technological infrastructure, payment models, and support. Although challenges remain, they may be overcome with additional technical training for clinicians and patients, investment in telehealth infrastructure and broadband internet, and policy changes to promote telehealth access for this diverse patient population.

Introduction Difficult working conditions could be associated with addictive behaviors. Objectives To examine the prospective associations between atypical working hours and substance use, including sugar and fat consumption. Methods In the CONSTANCES cohort, a total of 47,288 men and 53,324 women currently employed were included from 2012-2017 for tobacco and cannabis outcomes, and 35,647 and 39,767, respectively from 2012-2016 for alcohol and sugar and fat outcomes, and they were then followed up annually. Atypical working hours were self-reported at baseline and considered three different indicators: night shifts, weekend work and non-fixed working hours. Generalized linear models computed odds of substance use and sugar and fat consumption at follow-up according to baseline atypical working hours while adjusting for sociodemographic factors, baseline depression and baseline level of consumption. Results Night shifts increased significantly the odds of using tobacco in women (Odds ratios, ORs varying from 1.55 to 1.62) and cannabis in men (ORs varying from 1.80 to 1.95). Weekend work increased the odds of using tobacco (ORs varying from 1.51 to 1.67) and alcohol (OR of 1.16) in women. Non-fixed working hours increased the odds of using tobacco and alcohol in men and women (ORs varying from 1.15 to 1.19 and 1.12 to 1.14, respectively). Dose-dependent relationships were found for tobacco use in women (P for trends

Social media integration into research has increased, and 92% of American social media participants state they would share their data with researchers. Yet, the potential of these data to transform health outcomes has not been fully realized, and the way clinical research is performed has been held back. The use of these technologies in research is dependent on the investigators’ awareness of their potential and their ability to innovate within regulatory and institutional guidelines. The Brown-Lifespan Center for Digital Health has launched an initiative to address these challenges and provide a helpful framework to expand social media use in clinical research.

Clinical researchers are using mobile-based sensors to obtain detailed and objective measures of the activity and health of research participants, but many investigators lack expertise in integrating wearables and sensor technologies effectively into their studies. Here, we describe the steps taken to design a study using sensors for disease monitoring in older adults and explore the benefits and drawbacks of our approach. In this study, the Geriatric Acute and Post-acute Fall Prevention Intervention (GAPcare), we created an iOS app to collect data from the Apple Watch's gyroscope, accelerometer, and other sensors; results of cognitive and fitness tests; and participant-entered survey data. We created the study app using ResearchKit, an open-source framework developed by Apple for medical research that includes neuropsychological tests (e.g., of executive function and memory), gait speed, balance, and other health assessments. Data is transmitted via an Application Programming Interface (API) from the app to REDCap for researchers to monitor and analyze in real-time. Employing the lessons learned from GAPcare could help researchers create study-tailored research apps and access timely information about their research participants from wearables and smartphone devices for disease prevention, monitoring, and treatment.

Older adults are among the fastest-growing demographic groups in the United States, increasing by over a third this past decade. Consequently, the older adult consumer product market has quickly become a multi-billion-dollar industry in which millions of products are sold every year. However, the rapidly growing market raises the potential for an increasing number of product safety concerns and consumer product-related injuries among older adults. Recent manufacturer and consumer injury prevention efforts have begun to turn towards online reviews, as these provide valuable information from which actionable, timely intelligence can be derived and used to detect safety concerns and prevent injury. The presented dataset contains 1966 curated online product reviews from consumers, equally distributed between safety concerns and non-concerns, pertaining to product categories typically intended for older adults. Identified safety concerns were manually sub-coded across thirteen dimensions designed to capture relevant aspects of the consumer's experience with the purchased product, facilitate the safety concern identification and sub-classification process, and serve as a gold-standard, balanced dataset for text classifier learning.

Electronic documentation systems have been widely implemented in the healthcare field. These systems have become a critical part of the nursing profession. This research examines how nurses’ general computer skills, training, and self-efficacy affect their perceptions of using these systems. A sample of 248 nurses was surveyed to examine their general computer skills, self-efficacy, and training in electronic documentation systems in nursing programs. We propose a model to investigate the extent to which nurses’ computer skills, self-efficacy, and training in electronic documentation influence perceptions of using electronic documentation systems in hospitals. The data supports a mediated model in which general computer skills, self-efficacy, and training influence perceived usefulness through perceived ease of use. The significance of these findings was confirmed through structural equation modeling. As the electronic documentation systems are customized for every organization, our findings suggest value in nurses receiving training to learn these specific systems in the workplace or during their internships. Doing so may improve patient outcomes by ensuring that nurses use the systems consistently and effectively.

Plasmodium protein phosphatase PP1 is essential for the asexual proliferation of malaria parasites. Here the authors show that PP1 regulates egress of parasites from host red blood cells, integrating parasite intrinsic pathways with environmental signals for release into the bloodstream.

Dravet syndrome (DS) is a neurodevelopmental disorder due to pathogenic variants in SCN1A encoding the Nav1.1 sodium channel subunit, characterized by treatment-resistant epilepsy, temperature-sensitive seizures, developmental delay/intellectual disability with features of autism spectrum disorder, and increased risk of sudden death. Convergent data suggest hippocampal dentate gyrus (DG) pathology in DS (Scn1a+/-) mice. We performed two-photon calcium imaging in brain slice to uncover a profound dysfunction of filtering of perforant path input by DG in young adult Scn1a+/- mice. This was not due to dysfunction of DG parvalbumin inhibitory interneurons (PV-INs), which were only mildly impaired at this timepoint; however, we identified enhanced excitatory input to granule cells, suggesting that circuit dysfunction is due to excessive excitation rather than impaired inhibition. We confirmed that both optogenetic stimulation of entorhinal cortex and selective chemogenetic inhibition of DG PV-INs lowered seizure threshold in vivo in young adult Scn1a+/- mice. Optogenetic activation of PV-INs, on the other hand, normalized evoked responses in granule cells in vitro. These results establish the corticohippocampal circuit as a key locus of pathology in Scn1a+/- mice and suggest that PV-INs retain powerful inhibitory function and may be harnessed as a potential therapeutic approach toward seizure modulation.

Ensuring responsive healthcare which meets patient expectations and generates trust is important to increase rates of access and retention. This need is important for aging populations where non-communicable diseases (NCDs) are a growing cause of morbidity and mortality. We performed a cross-sectional household survey including socio-demographic; morbidities; and patient-reported health system utilization, responsiveness, and quality outcomes in individuals 40 and older in northwestern Burkina Faso. We describe results and use exploratory factor analysis to derive a contextually appropriate grouping of health system responsiveness (HSR) variables. We used linear or logistic regression to explore associations between socio-demographics, morbidities, and the grouped-variable, then between these variables and health system quality outcomes. Of 2,639 eligible respondents, 26.8% had least one NCD, 56.3% were frail or pre-frail and 23.9% had a recent healthcare visit, including only 1/3 of those with an NCD. Highest ratings of care experience (excellent/very good) included ease of following instructions (86.1%) and trust in provider skills (81.1%). The HSR grouping with the greatest factor loading included involvement in decision-making, clarity in communication, trust in the provider, and confidence in providers' skills, labelled Shared Understanding and Decision Making (SUDM). In multivariable analysis, higher quality of life (OR 1.02,95%CI 1.01-1.04), frailty (OR 1.47,95%CI 1.00-2.16), and SUDM (OR 1.06,95%CI 1.05-1.09) were associated with greater health system trust and confidence. SUDM was associated with overall positive assessment of the healthcare system (OR 1.02,95%CI 1.01-1.03) and met healthcare needs (OR 1.09,95%CI 1.08-1.11). Younger age and highest wealth quintile were also associated with higher met needs. Recent healthcare access was low for people with existing NCDs, and SUDM was the most consistent factor associated with higher health system quality outcomes. Results highlight the need to increase continuity of care for aging populations with NCDs and explore strengthening SUDM to achieve this goal.

Abstract Objectives Emergency medicine physicians have played a pivotal role throughout the coronavirus disease 19 (COVID‐19) pandemic through in‐person and remote management and treatment. Our primary objectives were to understand emergency medicine physicians’ experiences using telehealth throughout the pandemic, any facilitators/barriers to successful usage, lessons learned during implementation, and successful/abandoned strategies used to engage with older adults. Methods Using a semi‐structured interview guide, we conducted 30‐min interviews. We used purposeful sampling to recruit emergency medicine physicians from all United States regions, rural–urban settings, and academic and community practices, who reported caring for patients 65 years or older in‐person or virtually during the pandemic. Interviews were audio‐recorded, transcribed, double‐coded, and analyzed for emergent themes using framework analysis. Results A total of 15 in‐depth interviews were completed from September to November 2020. Physicians had a median age of 37 years, 7 were women, and 9 had experience with telehealth before the pandemic. We identified several themes: (1) there were various motivations for telehealth use; (2) telehealth was used primarily to supplement, not replace in‐person care; (3) most platforms were easy to use; (4) patients and caregivers had high acceptability of telemedicine; and (5) older adults with sensory and cognitive impairments often relied on caregivers. Emergency medicine physicians played a critical role during primary care office closures during the first wave—dispelling misinformation about COVID‐19, triaging patients to testing and treatment, and providing care that would otherwise have been deferred. Conclusions Our data show that telemedicine gained acceptability among emergency medicine physicians and provided options to patients who may have otherwise deferred care. These findings can inform future healthcare delivery for acute care needs or pandemic responses.

Introduction: Coinfection with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and another virus may influence the clinical trajectory of emergency department (ED) patients. However, little empirical data exists on the clinical outcomes of coinfection with SARS-CoV-2 Methods: In this retrospective cohort analysis, we included adults presenting to the ED with confirmed, symptomatic coronavirus 2019 who also underwent testing for additional viral pathogens within 24 hours. To investigate the association between coinfection status with each of the outcomes, we performed logistic regression. Results: Of 6,913 ED patients, 5.7% had coinfection. Coinfected individuals were less likely to experience index visit or 30-day hospitalization (odds ratio [OR] 0.57; 95% confidence interval [CI], 0.36–0.90 and OR 0.39; 95% CI, 0.25–0.62, respectively). Conclusion: Coinfection is relatively uncommon in symptomatic ED patients with SARS-CoV-2 and the clinical short- and long-term outcomes are more favorable in coinfected individuals.

Abstract Objective Pathogenic variants in SCN8A, encoding the voltage‐gated sodium (Na+) channel α subunit Nav1.6, is a known cause of epilepsy. Here, we describe clinical and genetic features of all patients with SCN8A epilepsy evaluated at a single‐tertiary care center, with biophysical data on identified Nav1.6 variants and pharmacological response to selected Na+ channel blockers. Methods SCN8A variants were identified via an exome‐based panel of epilepsy‐associated genes for next generation sequencing (NGS), or via exome sequencing. Biophysical characterization was performed using voltage‐clamp recordings of ionic currents in heterologous cells. Results We observed a range in age of onset and severity of epilepsy and associated developmental delay/intellectual disability. Na+ channel blockers were highly or partially effective in most patients. Nav1.6 variants exhibited one or more biophysical defects largely consistent with gain of channel function. We found that clinical severity was correlated with the presence of multiple observed biophysical defects and the extent to which pathological Na+ channel activity could be normalized pharmacologically. For variants not previously reported, functional studies enhanced the evidence of pathogenicity. Interpretation We present a comprehensive single‐center dataset for SCN8A epilepsy that includes clinical, genetic, electrophysiologic, and pharmacologic data. We confirm a spectrum of severity and a variety of biophysical defects of Nav1.6 variants consistent with gain of channel function. Na+ channel blockers in the treatment of SCN8A epilepsy may correlate with the effect of such agents on pathological Na+ current observed in heterologous systems.

Abstract Background Falls are the leading cause of fatal and non-fatal injuries among older adults. Older emergency department (ED) patients who present for evaluations after falls have a 30% higher risk of falling again in the subsequent 6 months than age-matched controls. Although EDs frequently evaluate older adults after their falls, the typical evaluation consists of an injury assessment alone. As such, an opportunity is lost to assess and address the potential causes of falls in this vulnerable population. In this manuscript, we present a multidisciplinary fall prevention protocol for a pilot study of older adult ED patients who recently sustained a fall (GAPcare: the Geriatric Acute and Post-acute Fall Prevention Intervention). Methods GAPcare is a randomized single-blinded pilot study. Participants in GAPcare are 120 older adults (≥ 65 years old) who present to 1 of 2 academic US EDs after a fall. We randomly assign participants 1:1 to an intervention or a usual care (control) arm. In the intervention arm, the patient’s ED physician, a pharmacist, and a physical therapist (PT) collaborate to identify and address any risk factors that may have contributed to the fall. Intervention arm participants and their caregivers return home with a medication-related action plan to taper or stop potentially inappropriate medications and to address polypharmacy and a PT assessment and plan. Participants in the usual care arm receive standard assessments and care in the ED and a home safety brochure. Participants in both study arms complete fall calendars for 6 months to document the number of falls and healthcare visits during follow-up. The primary outcome is feasibility of the GAPcare fall prevention intervention (number and proportion of screened participants who are eligible, recruited, and retained; impact on ED length of stay), while the secondary outcome is to estimate its initial efficacy. Discussion The GAPcare-ED fall prevention intervention has the potential to promote older adult-sensitive care for millions of Americans presenting to EDs after falls and establish a protocol for a future large-scale randomized controlled trial on this topic. Trial registration ClinicalTrials.gov, NCT03360305. Trial registration date: December 4, 2017. Protocol version: 1

ObjectivesAccurate and reliable criteria to rapidly estimate the probability of infection with the novel coronavirus-2 that causes the severe acute respiratory syndrome (SARS-CoV-2) and associated disease (COVID-19) remain an urgent unmet need, especially in emergency care. The objective was to derive and validate a clinical prediction score for SARS-CoV-2 infection that uses simple criteria widely available at the point of care.MethodsData came from the registry data from the national REgistry of suspected COVID-19 in EmeRgency care (RECOVER network) comprising 116 hospitals from 25 states in the US. Clinical variables and 30-day outcomes were abstracted from medical records of 19,850 emergency department (ED) patients tested for SARS-CoV-2. The criterion standard for diagnosis of SARS-CoV-2 required a positive molecular test from a swabbed sample or positive antibody testing within 30 days. The prediction score was derived from a 50% random sample (n = 9,925) using unadjusted analysis of 107 candidate variables as a screening step, followed by stepwise forward logistic regression on 72 variables.ResultsMultivariable regression yielded a 13-variable score, which was simplified to a 13-point score: +1 point each for age>50 years, measured temperature>37.5°C, oxygen saturation75% probability with +5 or more points).ConclusionCriteria that are available at the point of care can accurately predict the probability of SARS-CoV-2 infection. These criteria could assist with decisions about isolation and testing at high throughput checkpoints.

“General-purpose cohorts” in epidemiology and public health are designed to cover a broad scope of determinants and outcomes, in order to answer several research questions, including those not defined at study inception. In this context, the general objective of the CONSTANCES project is to set up a large population-based cohort that will contribute to the development of epidemiological research by hosting ancillary projects on a wide range of scientific domains, and to provide public health information. CONSTANCES was designed as a randomly selected sample of French adults aged 18–69 years at study inception; 202,045 subjects were included over an 8-year period. At inclusion, the selected participants are invited to attend one of the 24 participating Health Prevention Centers (HPCs) for a comprehensive health examination. The follow-up includes a yearly self-administered questionnaire, and a periodic visit to an HPC. Procedures have been developed to use the national healthcare databases to allow identification and validation of diseases over the follow-up. The biological collection (serum, lithium heparinized plasma, EDTA plasma, urine and buffy coat) began gradually in June 2018. At the end of the inclusions, specimens from 83,000 donors will have been collected. Specimens are collected according to a standardized protocol, identical in all recruitment centers. All operations relating to bio-banking have been entrusted by Inserm to the Integrated Biobank of Luxembourg (IBBL). A quality management system has been put in place. Particular attention has been paid to the traceability of all operations. The nature of the biological samples stored has been deliberately limited due to the economic and organizational constraints of the inclusion centers. Some research works may require specific collection conditions, and can be developed on request for a limited number of subjects and in specially trained centers. The biological specimens that are collected will allow for a large spectrum of biomarkers studies and genetic and epigenetic markers through candidate or agnostic approaches. By linking the extensive data on personal, lifestyle, environmental, occupational and social factors with the biomarker data, the CONSTANCES cohort offers the opportunity to study the interplays between these factors using an integrative approach and state-of-the-art methods.

Background: The role of alcohol, tobacco and cannabis use in social differences in terms of depression is poorly understood. Method: We have applied mediation and moderated-mediation models stratified by gender to a population-based sample (N = 37,192) of French men and women from the Constances cohort with baseline and follow-up measures of depressive states. We have examined whether socioeconomic status (SES, measured by education and income) differences in the prevalence of depressive states may be explained by both differences in prevalence of substance use according to SES (mediating effects) and differential effects of substance use on depressive state according to SES (moderating effects). Results: In the mediation models, substance use only explained 5.3% and 2.4% of the association between low education and depressive state in men and women respectively, and was not a significant mediator for income. Moderated mediation models showed robust moderation effects of education and income in both men and women. The association of tobacco use with depressive symptoms, which was the only substance for which a mediation effect remained and for which the moderation effect of SES was the strongest, was significantly higher in participants with low SES. Limitations: The partially cross-sectional nature of the data restricts the possibility of drawing causality with regards to associations between SES and substance use. Conclusion: Targeting substance use, particularly tobacco, can especially reduce depression risk in individuals of low SES.