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Among critically ill patients, acutely depressed level of consciousness is associated with mortality, but its relationship to long-term outcomes such as disability and physical function is unknown. We investigated the relationship of level of consciousness during hospitalization with long-term disability and physical function in ICU survivors.Multi-center observational cohort study.Medical or surgical ICUs at five U.S. centers.Adult survivors of respiratory failure or shock.None.Depressed level of consciousness during hospitalization was defined using the Richmond Agitation Sedation Scale (RASS) score (including all negative scores) by calculating the area under the curve using linear interpolation. Sedative-associated level of consciousness was similarly defined for all hospital days that sedation was received. We measured disability in basic activities of daily living (BADLs), instrumental activities of daily living (IADLs), discharge destination, and self-reported physical function. In separate models, we evaluated associations between these measures of level of consciousness and outcomes using multivariable regression, adjusted for age, sex, race, body mass index, education level, comorbidities, baseline frailty, baseline IADLs and BADLs, hospital type (civilian vs veteran), modified mean daily Sequential Organ Failure Assessment score, duration of severe sepsis, duration of mechanical ventilation, and hospital length of stay. Of the 1,040 patients enrolled in the ICU, 781 survived to hospital discharge. We assessed outcomes in 624 patients at 3 months and 527 patients at 12 months. After adjusting for covariates, there was no association between depressed level of consciousness (total or sedation-associated) with BADLs or IADLs at either 3- or 12-month follow-up. There was also no association with self-reported physical function at 3 or 12 months or with discharge destination.Depressed level of consciousness, as defined by the RASS, was not associated with disability or self-reported physical function. Future studies should investigate additional modifiable in-hospital risk factors for disability and poor physical function following critical illness.

Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications.A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine.None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

During fall 2020 in rural Pierce County, Washington, school districts and the county health department offered weekly rapid antigen screening to students and staff. Asymptomatic screening identified 42.5% of confirmed cases from the population. Parents reported it was a positive experience for their children. The program supported decisions to return to in-person learning, but screening ended because of resource and technical limitations. When planning in-school screening, stakeholder engagement and resource sustainability are important factors to consider. (Am J Public Health. 2022;112(8):1134–1137. https://doi.org/10.2105/AJPH.2022.306875 )

Age-related distance esotropia (ARDET) is characterized by an esodeviation greater at distance than near in older aged patients and generally managed with prism spectacles or surgery. The purpose of this study is to describe the prevalence, clinical characteristics, and natural history of age-related distance esotropia in a defined population. The medical records of all adult (≥19 years of age) residents of Olmsted County, Minnesota, diagnosed with an esodeviation at least 2 prism diopters (PD) greater at distance than near, from 1 January 1985, through 31 December 2004, were retrospectively reviewed. Seventy-three (9.7%) of 751 new cases of adult-onset strabismus were diagnosed with age-related distance esotropia during the 20-year period. The mean age of onset was 70 years (range, 19 to 93 years) and 48 (65.8%) were female (

To investigate concordance in symptom onset, area of dark autofluorescence (DAF), and growth rate (GR) between Stargardt disease siblings at an age-matched time point.In this retrospective longitudinal study of sibling pairs with identical biallelic ABCA4 variants, age at symptom onset, best-corrected visual acuity, atrophy area, and effective radius of DAF on ultra-widefield fundus autofluorescence were recorded. Absolute intersibling differences for both eyes were compared with absolute interocular differences using the Mann-Whitney test.Overall 39 patients from 19 families were recruited. In 16 families, age-matched best-corrected visual acuity and DAF were compared between siblings. In 8 families, DAF GR was compared. The median (range) absolute difference in age at symptom onset between siblings was 3 (0-35) years. Absolute intersibling differences in age-matched best-corrected visual acuity were greater than interocular differences ( P = 0.01). Similarly, absolute intersibling differences in DAF area and radius were greater than interocular differences ( P = 0.04 for area and P = 0.001 for radius). Differences between absolute interocular and intersibling GR were not statistically significant ( P = 0.44 for area GR and P = 0.61 for radius GR).There was significant discordance in age-matched best-corrected visual acuity and DAF beyond the expected limits of interocular asymmetry. Lack of significant intersibling differences in GR warrants further investigation.

Adaptive communication is an essential requirement to deliver quality patient-centred care. Determining patients' informational needs and acting on the needs are skills radiation therapists (RTs) employ daily with patients. Learning health literacy (HL) strategies to assist with the informational delivery provides RTs with options to improve patients' understanding of vital radiotherapy treatment information or tasks. This research investigates the lived experiences of RTs from the Illawarra and Shoalhaven Cancer Care Centres in Australia using HL strategies during patient interactions after undertaking HL training workshops.An interpretative phenomenological analysis (IPA) approach was used. Audio-recorded semi-structured interviews were conducted with six RTs. Two reviewers analysed each interview script separately before discussing and constructing substantive and sub-themes.Four substantive themes were constructed: RT personal attitudes and responses to HL, HL strategies used by RTs, patient associated HL needs and barriers when addressing patient HL needs. RTs were either person- or process-focussed during patient interactions. It was identified that information is provided to patients according to how RTs themselves like to learn new information.This research has allowed an opportunity to inquire into the lived experiences of RTs implementing HL strategies when providing information to patients. While RTs may be person or process-focussed, the patient's needs are always prioritised when providing information, which ultimately results in patient understanding and increased engagement.

Background Cluster randomised trials (CRTs) are often designed with a small number of clusters, but it is not clear which analysis methods are optimal when the outcome is binary. This simulation study aimed to determine (i) whether cluster-level analysis (CL), generalised linear mixed models (GLMM), and generalised estimating equations with sandwich variance (GEE) approaches maintain acceptable type-one error including the impact of non-normality of cluster effects and low prevalence, and if so (ii) which methods have the greatest power. We simulated CRTs with 8–30 clusters, altering the cluster-size, outcome prevalence, intracluster correlation coefficient, and cluster effect distribution. We analysed each dataset with weighted and unweighted CL; GLMM with adaptive quadrature and restricted pseudolikelihood; GEE with Kauermann-and-Carroll and Fay-and-Graubard sandwich variance using independent and exchangeable working correlation matrices. P-values were from a t-distribution with degrees of freedom (DoF) as clusters minus cluster-level parameters; GLMM pseudolikelihood also used Satterthwaite and Kenward-Roger DoF. Results Unweighted CL, GLMM pseudolikelihood, and Fay-and-Graubard GEE with independent or exchangeable working correlation matrix controlled type-one error in > 97% scenarios with clusters minus parameters DoF. Cluster-effect distribution and prevalence of outcome did not usually affect analysis method performance. GEE had the least power. With 20–30 clusters, GLMM had greater power than CL with varying cluster-size but similar power otherwise; with fewer clusters, GLMM had lower power with common cluster-size, similar power with medium variation, and greater power with large variation in cluster-size. Conclusion We recommend that CRTs with ≤ 30 clusters and a binary outcome use an unweighted CL or restricted pseudolikelihood GLMM both with DoF clusters minus cluster-level parameters.

OBJECTIVE Health disparities are evident for Black Americans with HIV disease, who are disproportionally affected by the epidemic in the United States. The current study investigated whether the higher rates of neurocognitive impairment in Black Americans with HIV disease may be at least partly attributable to health literacy, which is a potentially modifiable factor. Method: Participants were 61 White and 25 Black participants (ages 27-70) with HIV disease who were enrolled in studies at an urban academic center in Southern California. Neurocognitive function was assessed by an age-adjusted global score from the Cogstate battery. Health literacy was measured by a composite score derived from the Rapid Estimate of Adult Literacy in Medicine, Newest Vital Sign, and 3-Brief. Results: Bootstrap confidence interval mediation analyses showed that health literacy was a significant mediator of the relationship between race and neurocognition; that is, there were no direct ethnoracial differences in neurocognition after accounting for health literacy. A follow-up model to confirm the directionality of this association demonstrated that neurocognition was not a significant mediator of the relationship between race and health literacy. Conclusions: Low health literacy may contribute to the higher rates of neurocognitive impairment for Black Americans with HIV disease. Future studies might examine the possible mechanism of this mediating relationship (e.g., access to health information, health behaviors, socioeconomics) and determine whether culturally tailored interventions that improve health literacy also confer broader brain health benefits for Black Americans with HIV disease.

BACKGROUND AND AIMS: Risk factors for poor outcomes after critical illness are incompletely understood. While nutritional risk is associated with mortality in critically ill patients, its association with disability, cognitive, and health-related quality of life is unclear in survivors of critical illness. This study’s objective was to determine whether greater nutritional risk at ICU admission is associated with greater disability, worse cognition, and worse HRQOL at 3 and 12-month follow-up. METHODS: We enrolled adults (≥ 18 years of age) with respiratory failure or shock treated in medical and surgical intensive care units from two U.S. centers. We measured nutritional risk using the modified Nutrition Risk in Critically Ill (mNUTRIC) score (range 0 to 9 [highest risk]) at intensive care unit admission. We measured associations between mNUTRIC scores and discharge destination, disability in basic activities of daily living (ADLs) using the Katz ADL, instrumental ADLs using the Functional Activities Questionnaire (FAQ), global cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), executive function using the Trail Making Test Part B (Trails B), and health-related quality of life using the SF-36, adjusting for sex, education, BMI, baseline frailty, disability, and cognition, severity of illness, days of delirium, coma, and mechanical ventilation. RESULTS: Of the 821 patients enrolled in the ICU, 636 patients survived to hospital discharge. We assessed outcomes in 448 of 535 survivors (84%) at 3 months and 382 of 476 survivors (80%) at 12 months. Higher mNUTRIC scores predicted greater odds of discharge to an institution (OR 2.0, 95% CI: 1.6 to 2.6; P

Objective To examine the factor structure and sociodemographic correlates of a battery of clinical neuropsychological tests administered in-home and via telephone. Method Participants included 280 healthy adults who completed a 35–40 min battery consisting of seven auditory-verbal neuropsychological tests (i.e., 10 variables) that included digit span, list learning and memory, prospective memory, verbal fluency, and oral trail making. Results After removing oral trail making part A, a three-factor model comprised of executive functions, memory and attention demonstrated the best fit to the data. Nevertheless, the shared variance between the nine remaining neuropsychological variables was also adequately explained by a single-factor model and a two-factor model comprised of executive functions and memory. Factor scores were variably associated with education, race/ethnicity, and IQ, but not with sex or age. Conclusions Findings provide preliminary support for the feasibility and factor structure and sociodemographic correlates of a brief telephone-based screening neuropsychological battery comprised mostly of commonly administered clinical measures. Future studies are needed to determine the test–retest reliability, sensitivity, and ecological relevance of this battery, as well as equivalency to in-person assessment.

Women are becoming more prevalent in clinical neuropsychology, but gender bias and disparities persist across multiple professional domains. This study examined potential gender disparities in hist...

Statins are the pillar of secondary prevention in reducing cardiovascular disease in high-risk adults. However, statin discontinuation is the standard recommendation in pregnant and lactating patients. This review evaluates whether we can justify the early treatment of reproductive aged women with statin therapy.Statins have several potential benefits including its antioxidant, anti-inflammatory, and anti-thrombogenic properties that may prevent the worsening of atherosclerosis in high-risk women. Nevertheless, most studies on statins and teratogenicity have a limited sample size and the effects of long-term statin use on fetal and neonatal health remain unknown. Not all statins may be safe and pravastatin's cholesterol-lowering properties may be too limited to provide much maternal benefit in pregnancy. While emerging evidence supports the use of pravastatin in pregnancy, we need to better assess the risk of early cardiovascular disease and acute progression of atherosclerosis before and during pregnancy to better understand the risks and benefits of statin use.

To examine the usefulness of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS) as a cognitive screening tool for the detection of behavioral variant frontotemporal dementia (bvFTD). A secondary aim was to determine whether people with FTD combined with ALS (ALS-FTD) exhibit a similar ECAS profile to that of people with bvFTD alone. Methods: Patients with ALS-FTD and bvFTD and healthy controls were recruited. Participants were administered the ECAS, which comprises tests of language, verbal fluency, executive functions, memory, and visual-spatial functions. They also carried out analogous, full-length cognitive tests that examine naming, spelling, sentence completion, and social cognition skills. Results: The study cohort comprised 20 ALS-FTD patients, 23 with bvFTD, and 30 controls. Highly significant group differences were elicited for all cognitive domains, reflecting poorer performance in patients compared to controls. No significant differences in overall test scores were found between ALS-FTD and bvFTD patients, although ALS-FTD patients showed a higher frequency of impairment on verbal fluency. Correlative analyses revealed inter-relationships in patients (but not controls) between scores in different domains, most marked in bvFTD. There were strong correlations between performance on ECAS subtests and analogous cognitive tasks. Conclusion: The ECAS is a sensitive and valuable tool for the assessment of FTD. Executive, language and behavioral breakdown may, however, compromise performance in other cognitive domains, reducing the specificity of the ‘frontotemporal’ cognitive profile. Subtle differences observed between ALS-FTD and bvFTD raise questions regarding the precise relationship between bvFTD with and without ALS.

Objective Object location learning and memory may be important for older adults to successfully complete some everyday activities. Method This cross-sectional, correlational study investigated the ecological relevance of the Location Learning Test-Revised (LLT-R) in 195 community-dwelling, older adults in Western Australia. The LLT-R assesses object location learning and memory for everyday objects over five learning trials and after a 30-min delay. Knowledgeable informants provided structured ratings of participants’ activities of daily living and memory symptoms. Results A greater number of errors on LLT-R total learning trials were associated with mild problems in activities of daily living (particularly in travel and household domains), but not with memory symptoms. The LLT-R’s association with activities of daily living was accompanied by a small-to-medium effect size and was not better explained by demographics, global cognitive functioning, mood, or chronic medical conditions. Conclusions Findings provide some support for the ecological relevance of the LLT-R among older community-dwelling adults and suggest that object location learning may play a role in some everyday functioning problems that accompany typical aging.

Objectives Little is known about frailty that develops following critical illness. We sought to describe the prevalence of newly acquired frailty, its clinical course, and the co-occurrence of frailty with disability and cognitive impairment in survivors of critical illness. Design Longitudinal prospective cohort study. Setting Medical and surgical ICUs at five U.S. centers. Patients Adult patients treated for respiratory failure and/or shock. Measurements and main results We measured frailty with the Clinical Frailty Scale at baseline (i.e., study enrollment) and at 3 and 12 months postdischarge. We constructed alluvial diagrams to describe the course of frailty and Venn diagrams to describe the overlap of frailty with disability in activities of daily living and cognitive impairment. We included 567 participants a median (interquartile range) of 61 years old (51-70 yr old) with a high severity of illness (Acute Physiology and Chronic Health Evaluation II of 23). Frailty (Clinical Frailty Scale scores ≥ 5) was present in 135 of 567 (24%) at baseline, 239 of 530 (45%) at 3 months, and 163 of 445 (37%) at 12 months. Of those with frailty at 3- or 12-month follow-up, 61% were not frail at baseline. Transition to a worse frailty state occurred in 242 of 530 of patients (46%) between baseline and 3 months and in 179 of 445 of patients (40%) between baseline and 12 months. There were 376 patients with frailty, disability, or cognitive impairment at 3-month follow-up. Of these, 53 (14%) had frailty alone. At 12 months, 276 patients had frailty, disability, or cognitive impairment, 37 (13%) of whom had frailty alone. Conclusions Frailty is common among survivors of critical illness. In the majority, frailty is newly acquired. Roughly one in seven had frailty without co-occurring disability or cognitive impairment. Studies to understand outcomes of frailty that develops as the result of a critical illness and to identify modifiable risk factors for this potentially reversible syndrome are needed.

OBJECTIVES: Delirium, a heterogenous syndrome, is associated with worse long-term cognition after critical illness. We sought to determine if duration of motoric subtypes of delirium are associated with worse cognition. DESIGN: Secondary analysis of prospective multicenter cohort study. SETTING: Academic, community, and Veteran Affairs hospitals. Patients: Five-hundred eighty-two survivors of respiratory failure or shock. PATIENTS: Five-hundred eighty-two survivors of respiratory failure or shock. INTERVENTIONS: We assessed delirium and level of consciousness using the Confusion Assessment Method-ICU and Richmond Agitation Sedation Scale daily during hospitalization. We defined a day with hypoactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score less than or equal to 0 and a day with hyperactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score greater than 0. At 3 and 12 months, we assessed global cognition with the Repeatable Battery for the Assessment of Neurologic Status and executive function with the Trail Making Test Part B. We used multivariable regression to examine the associations between days of hypoactive and hyperactive delirium with cognition outcomes. We allowed for interaction between days of hypoactive and hyperactive delirium and adjusted for baseline and in-hospital covariates. MEASUREMENTS AND RESULTS: Hypoactive delirium was more common and persistent than hyperactive delirium (71% vs 17%; median 3 vs 1 d). Longer duration of hypoactive delirium was associated with worse global cognition at 3 (−5.13 [−8.75 to −1.51]; p = 0.03) but not 12 (−5.76 [−9.99 to −1.53]; p = 0.08) months and with worse executive functioning at 3 (−3.61 [−7.48 to 0.26]; p = 0.03) and 12 (−6.22 [−10.12 to −2.33]; p = 0.004) months; these associations were not modified by hyperactive delirium. Hyperactive delirium was not associated with global cognition or executive function in this cohort. CONCLUSIONS: Longer duration of hypoactive delirium was independently associated with worse long-term cognition. Assessing motoric subtypes of delirium in the ICU might aid in prognosis and intervention allocation. Future studies should consider delineating motoric subtypes of delirium. (Crit Care Med 2020; 48:e480–e488)

The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10TC; 5603AT] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13-50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction.

Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed biallelic ABCA4 mutations from five genotype groups: c.6079C>T, c.[2588G>C;5603A>T], c.3113C>T, c.5882G>A and c.5603A>T. Fundus autofluorescence (AF) 30° × 30° images were manually segmented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean ± SD age 45 ± 19 years; range 21–86) were recruited. Patients with c.3113C>T or c.6079C>T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; p < 0.001 and 0.14 to 0.21; p < 0.001) respectively, as compared to those patients harbouring c.5882G>A at 0.06 mm/year (95% CI 0.03–0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset.

The COVID-19 pandemic has been an extraordinary moment of uncertainty and rapid transformation. The effects lockdowns had on youths' mental and physical health, as well as the challenges they posed for young peoples' learning, were of great concern. It quickly became clear that government responses to COVID-19, in particular regarding the social determinants of health, were not equally experienced across all social groups. This paper adopts an interdisciplinary lens at the intersection of health and education and uses Max Weber's lifestyle theory to analyze the inequitable experience of the COVID-19 pandemic. We examine most directly social inequities in education during the first wave of COVID-19 and explore long-term effects on youths' educational opportunities, health, and well-being.We use focus group materials collected from our Spring 2020 study. This study explored how youth were differentially experiencing the pandemic. Participants included 18 youth between the ages of 13 and 18 (11 girls, 7 boys). Participants were stratified by private and public secondary schools and we ran focus groups in which experiences of the pandemic were discussed.Our results show (1) clear differences in early access to education for youth who attended public and private institutions in Quebec during the COVID-19 pandemic; (2) access to the internet and computers offset learning opportunities for students across Quebec throughout the COVID-19 pandemic; and (3) few of the differences experienced during the pandemic were based on youth's behaviours, or life choices, but rather stemmed from differences in material and structural opportunities, based largely, but not solely, on what type of school the youth attended (public or private).The way in which the COVID-19 pandemic was handled by the Quebec education system deepened existing social inequities in education between private and public school attendees. Given the importance of education as one of the main determinants of health, particularly during transition periods such as adolescence, we must ensure that future policies do not repeat past mistakes.RéSUMé: OBJECTIFS: La pandémie de la COVID-19 a été un moment d’incertitude et de transformation rapide hors du commun, soulevant des questions inédites sur les effets du confinement sur la santé mentale et physique des jeunes ainsi que sur les défis engendrés en termes d’apprentissage chez les jeunes. Il s’est rapidement avéré que les réponses du gouvernement à la COVID-19, en particulier en ce qui concerne les déterminants sociaux de la santé, n’étaient pas vécues de la même manière dans tous les groupes sociaux. Cet article adopte une optique interdisciplinaire à l’intersection de la santé et de l’éducation et utilise la théorie du mode de vie de Max Weber pour analyser l’expérience inéquitable de la pandémie de COVID-19. Nous examinons plus directement les inégalités sociales dans l’éducation pendant la première vague de COVID-19 et explorons les effets à long terme sur la santé et le bien-être des jeunes. MéTHODES: Nous utilisons les données recueillies lors de notre étude du printemps 2020 qui a exploré comment les jeunes vivaient différemment la pandémie. Les participants sont 18 jeunes âgés de 13 à 18 ans (11 filles, 7 garçons). Les participants ont été stratifiés par écoles secondaires privées et publiques et nous avons organisé des groupes de discussion dans lesquels les expériences de la pandémie ont été discutées. RéSULTATS: Nos résultats montrent 1) de nouvelles et profondes inégalités sociales dans le système d’éducation qui ont été créées par les mesures de confinement gouvernementales au Québec et 2) un accès inéquitable aux ressources mobilisées pour s’adapter aux mesures gouvernementales. CONCLUSION: L’étude du cas des inégalités sociales en contexte d’éducation pendant la pandémie offre d’importants apprentissages sur les inégalités sociales en général. Nous concluons cette étude en réfléchissant à l’espace intersectoriel important entre l’éducation et la santé pour les jeunes.

Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized PRPF31 and CNOT3 expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C&gt, T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy MSR1 repeat in the PRPF31 promoter, while 3/5 NPCs carried a 4-copy MSR1 repeat. The CNOT3 rs4806718 genotype did not correlate with disease penetrance. PRFP31 expression declined with age in adult cadaveric retina. PRPF31 and CNOT3 expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy MSR1 repeat, but not with CNOT3 polymorphisms.

OBJECTIVES The Infectious Diseases Society of America (IDSA) guidelines regarding group A streptococcal (GAS) pharyngitis advise against routine testing for patients younger than 3 years, patients without pharyngitis, and patients with symptoms suggesting a viral infection. Group A streptococcal testing may be overused in some clinical settings; thus, we conducted this study to evaluate compliance with the IDSA guidelines in a pediatric emergency department (ED) setting. METHODS This retrospective cohort study describes patients younger than 18 years presenting to 2 urban pediatric EDs in 2016 who underwent rapid antigen detection testing for GAS pharyngitis. Testing was classified as noncompliant with the IDSA guidelines if the chief complaint was not indicative of GAS infection and/or the patient age was younger than 3 years. Appropriate nonparametric tests compared groups by IDSA testing compliance status. RESULTS A total of 13,585 patient encounters met inclusion criteria; 5255 (39%) were noncompliant with the IDSA testing guidelines, the majority due to a chief complaint inconsistent with GAS pharyngitis (67%) and secondarily due to the age of younger than 3 years (48%). Among the patients with noncompliant testing, 51% were prescribed an antibiotic, and return encounters were more likely to occur (13% vs 10%, P < 0.001). Return encounters more commonly resulted in respiratory diagnoses in those with noncompliant GAS testing (60% vs 45%, P < 0.001). CONCLUSIONS Nearly 40% of all pediatric ED encounters with GAS testing were noncompliant with the IDSA guidelines and were associated with greater return encounter rates. Potential negative outcomes from noncompliant GAS testing include misdiagnosis, inappropriate use of antibiotics, allergic reactions, and loss of school days. Informed interventions to reduce unnecessary GAS testing are warranted.

Overstating the impact of interventions through incomplete or inaccurate reporting can lead to inappropriate scale-up of interventions with low impact. Accurate reporting of the impact of interventions is of great importance in global health research to protect scarce resources. In global health, the cluster randomised trial design is commonly used to evaluate complex, multicomponent interventions, and outcomes are often binary. Complete reporting of impact for binary outcomes means reporting both relative and absolute measures. We did a systematic review to assess reporting practices and potential to overstate impact in contemporary cluster randomised trials with binary primary outcome. We included all reports registered in the Cochrane Central Register of Controlled Trials of two-arm parallel cluster randomised trials with at least one binary primary outcome that were published in 2017. Of 73 cluster randomised trials, most (60 [82%]) showed incomplete reporting. Of 64 cluster randomised trials for which it was possible to evaluate, most (40 [63%]) reported results in such a way that impact could be overstated. Care is needed to report complete evidence of impact for the many interventions evaluated using the cluster randomised trial design worldwide.

Background. Healthcare-associated infections (HAIs) are a persistent clinical challenge caused primarily by bacteria on the skin. Proper utilization of optimized antiseptic skin preparation solutions helps reduce the prevalence and impact of HAIs by decreasing patient skin microorganisms preoperatively. The purpose of this study was to evaluate the efficacy of two antimicrobial solutions containing iodine and isopropyl alcohol (IPA): Povidone iodine (PVP-I) with IPA (i.e., PVP-I+IPA, PurPrep™) and Iodine Povacrylex+IPA (DuraPrep™). Methods. The antimicrobial activity of the test solutions was evaluated in vitro by determinations of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) against 1105 diverse microbial isolates and a time-kill assay to evaluate efficacy against 120 strains of Gram-positive and Gram-negative bacteria and yeasts. Peel tests were performed between skin samples treated with test solutions and representative drape/dressing materials to determine effects of test solutions on the biomechanical adhesion properties. Finally, an Institutional Review Board (IRB)-approved, randomized, controlled, single-center, partially blinded in vivo study was performed to assess the immediate and persistent antimicrobial activity of the test solutions on the abdomen and groin. Results. Both PVP-I+IPA and Iodine Povacrylex+IPA solutions demonstrated broad-spectrum antimicrobial activity with MIC and MBC at less than 1% of the full-strength concentration of each product against a wide variety of microorganisms. In the time-kill tests, both solutions were able to successfully reduce all microbial populations by 99.99% (i.e., 4log10) at the contact times of 30 seconds, 2 minutes and 10 minutes. The two solutions showed relatively similar adhesion results when tested with three representative operating room materials. Both PVP-I+IPA and Iodine Povacrylex+IPA met the expected Food and Drug Administration (FDA) efficacy requirements at 10 minutes and 6 hours post-treatment for both anatomical sites (i.e., groin and abdomen) in the clinical study, with no safety issues or adverse events. Conclusions. Analysis of the in vitro antimicrobial activity, biomechanical adhesive strength, and in vivo efficacy of PVP-I+IPA demonstrated similar results compared to Iodine Povacrylex+IPA. Both products were efficacious at reducing or eliminating a wide range of clinically-relevant microorganisms in lab-based and clinical settings, supporting their use as antiseptic skin preparation solutions to reduce bacteria on the skin that can cause infection.

To understand the design and implementation models of US produce prescription programs.In a mixed-methods study, program providers completed an online survey and an individual phone interview regarding their 2019 programming.Twenty-three programs completed surveys; 20 completed interviews. Program locations included the mid-Atlantic (26%), Northeast (9%), Midwest (30%), Southwest (17%), and Western regions (17%). Although program models varied, programs generally included a health care visit, usually at a safety-net clinic, and nutrition education, typically counseling, advice, or classes. Prescriptions tended to be farmers market vouchers worth a median of $15 a week (interquartile range, $7.81-$20.00). Transportation was a problem for nearly half of the programs.Current produce prescription program characteristics and operations can serve as a blueprint for new and existing programs. Future research should determine program best practices and the opportunity cost between program standardization and local flexibilities.

Older age and HIV disease are independent risk factors for problems in many aspects of everyday functioning. However, less is known about how these risk factors may combine to influence everyday functioning over time. The current study examined the possible combined effects of age and HIV serostatus on change in everyday functioning over a 1-year period and its specific associations with changes in neurocognition. A repeated measures factorial design was employed. Participants included 77 older persons with HIV (PWH), 35 younger PWH, 44 older HIV-, and 27 younger HIV-adults who each completed baseline and follow-up visits approximately 14 months apart. Everyday functioning was assessed using a standardized self-report measure of activities of daily living (ADLs) at each visit. A comprehensive clinical battery assessed six domains of neurocognition. Raw scores on each neurocognitive measure were converted to sample-based z-scores, from which a global neurocognitive z-score was derived. Older PWH reported the poorest everyday functioning at baseline and follow-up visits at medium-to-large effect sizes. However, these ADL disruptions among older PWH were relatively stable over time, differing significantly from younger PWH who evidenced mild ADL improvements from baseline to follow-up. Within the entire sample, everyday functioning at baseline predicted neurocognitive performance at follow-up, but the reciprocal relationship was not significant. Older adults with HIV have high rates of ADL problems, which appear stable over 1 year, the trajectory of which differed from younger adults with HIV for whom mild improvements were observed. Importantly, the results also suggest that problems with ADLs may sometimes precede neurocognitive declines. Further examination of longitudinal data is needed to elucidate the long-term trajectory of neurocognitive and functional changes in older PWH to support early detection and proper management of clinical care.

Mutations in ABCA4 gene are causative for autosomal recessive Stargardt disease (STGD1), the most common inherited retinal dystrophy. Here, we report the generation of an induced pluripotent stem cell (iPSC) line from a STGD1 patient carrying biallelic c.[5461-10T>C;5603A>T];[6077T>C] mutations in the ABCA4 gene. Episomes carrying OCT4, SOX2, KLF4, L-MYC, LIN28 and mp53DD were employed for the reprogramming of patient-derived fibroblasts. This iPSC line expressed comparable pluripotency markers as in a commercially available human iPSC line, displayed normal karyotype and potential for trilineage differentiation, and were negative for both reprogramming episomes and mycoplasma test.

Stargardt disease (STGD1) is the most common inherited retinal dystrophy and ABCA4 c.546-–10 T>C is the most commonly reported splice mutation. Here, we generated and characterized two induced pluripotent stem cell (iPSC) lines from a STGD1 patient with compound heterozygous mutations in ABCA4 (c.[5461-10 T > C;5603A > T];[4163 T > C;455G > A]). Episomal vectors containing OCT4, SOX2, KLF4, L-MYC, LIN28 and mp53DD were employed to conduct the reprogramming of patient-derived fibroblasts. Both lines had a normal karyotype, displayed iPSC morphology, expressed pluripotency markers and showed trilineage differentiation potential. These lines can provide a powerful platform for further investigating the pathophysiological consequences of mutations in ABCA4.

To examine Fruit and Vegetable Prescription (FVRx) Program participants' and nonparticipants' experiences and perceptions of farm direct (FD) settings.Multiple-case study of adults with low income from 3 study groups: (1) FVRx intervention (produce prescription, nutrition education [NE], financial literacy education, health screening), (2) NE only, and (3) control (standard health care). Participant interviews with each group at baseline and 6 months.Supplemental Nutrition Assistance Program-Education (SNAP-Ed) eligible adults from 3 Georgia counties.A total of 46 adults with ≥ 1 diet-related condition.Fruit and Vegetable Prescription Program participant and nonparticipant experiences and perceptions of FD settings.Constant comparative methods and thematic analysis of qualitative interview data across groups.Two main themes emerged: (1) baseline FD setting experiences and perceptions and (2) divergent experiences and perceptions with FD settings postintervention. Participants across each group employed price-conscious food purchasing practices because of limited food budgets, limiting local food access. Combining produce prescription, NE, and farmers' market access enhanced FVRx participant associations with FD settings to reinforce motivation for accessing and purchasing fruits and vegetables beyond program participation.Fruit and Vegetable Prescription Programs reduce multiple barriers to participating in FD settings compared with NE or standard health care alone.

Introduction: The rapid development of coronavirus disease 2019 (COVID-19) into a pandemic required people to quickly acquire, evaluate, and apply novel complex health-related information about the virus and transmission risks. This study examined the potentially unique and synergistic roles of individual differences in neurocognition and health literacy in the early uptake and use of COVID-19 public health information.Method: Data were collected between April 23 and 21 May 2020, a period during which 42 out of 50 states were under a stay-at-home order. Participants were 217 healthy adults who completed a telephone-based battery that included standard tests of neurocognition, health literacy, verbal IQ, personality, and anxiety. Participants also completed measures of COVID-19 information-seeking skills, knowledge, prevention intentions, and prevention behaviors.Results: A series of hierarchical multiple regressions with data-driven covariates showed that neurocognition (viz, episodic verbal memory and executive functions) was independently related to COVID-19 knowledge (e.g. symptoms, risks) at a medium effect size, but not to information-seeking skills, prevention intentions, or prevention behaviors. Health literacy was independently related to all measured aspects of COVID-19 health information and did not interact with neurocognition in any COVID-19 health domain.Conclusions: Individual differences in neurocognition and health literacy played independent and meaningful roles in the initial acquisition of knowledge related to COVID-19, which is a novel human health condition. Future studies might examine whether neurocognitive supports (e.g. spaced retrieval practice, elaboration) can improve COVID-19-related knowledge and health behaviors in vulnerable populations.

PURPOSE To establish a mutation-specific age-dependent ultra-widefield fundus autofluorescence (UWF-FAF) trajectory in a large Stargardt disease (STGD1) cohort using total lesion size (TLS) and to develop a clinical method for variant classification. METHODS A retrospective study of patients with biallelic ABCA4 mutations that were evaluated with UWF-FAF. Boundaries of TLS, defined by stippled hyper/hypoautofluorescence, were outlined manually. Pathogenicity was assessed according to ACMG/AMP criteria, and mutation severities were classified based on the current literature. Age-dependent trajectories in TLS were examined in patients with nullizygous, mild, and intermediate mutations. Mutations of uncertain severities were classified using a clinical criterion based on age of symptom onset and TLS. RESULTS Eighty-one patients with STGD1 (mean age = 42 ± 20 years and mean visual acuity = 20/200) were recruited from 65 unrelated families. Patients with biallelic null/severe variants (n = 6) demonstrated an increase in TLS during their second decade reaching a mean ± SD of 796 ± 29 mm2 by age 40. Those harboring mild mutations c.5882G>A or c.5603A>T had lesions confined to the posterior pole with a mean ± SD TLS of 30 ± 39 mm2. Intermediate mutations c.6079C>T or c.[2588G>C;5603A>T] in trans with a null/severe mutation had a mean ± SD TLS of 397 ± 29 mm2. Thirty-two mutations were predicted to cause severe (n = 22), intermediate (n = 6), and mild (n = 5) impairment of ABCA4 function based on age of symptom onset and TLS. CONCLUSION Age-dependent TLS showed unique ABCA4 mutation-specific trajectories. Our novel clinical criterion using age of symptom onset and TLS to segregate ABCA4 mutations into three severity groups requires further molecular studies to confirm its validity.

PRPF31-associated retinopathy (RP11) is a common form of autosomal dominant retinitis pigmentosa (adRP) that exhibits wide variation in phenotype ranging from non-penetrance to early-onset RP. Herein, we report inter-familial and intra-familial variation in the natural history of RP11 using multimodal imaging and microperimetry. Patients were recruited prospectively. The age of symptom onset, best-corrected visual acuity, microperimetry mean sensitivity (MS), residual ellipsoid zone span and hyperautofluorescent ring area were recorded. Genotyping was performed using targeted next-generation and Sanger sequencing and copy number variant analysis. PRPF31 mutations were found in 14 individuals from seven unrelated families. Four disease patterns were observed: (A) childhood onset with rapid progression (N = 4), (B) adult-onset with rapid progression (N = 4), (C) adult-onset with slow progression (N = 4) and (D) non-penetrance (N = 2). Four different patterns were observed in a family harbouring c.267del, patterns B, C and D were observed in a family with c.772_773delins16 and patterns A, B and C were observed in 3 unrelated individuals with large deletions. Our findings suggest that the RP11 phenotype may be related to the wild-type PRPF31 allele rather than the type of mutation. Further studies that correlate in vitro wild-type PRPF31 allele expression level with the disease patterns are required to investigate this association.

Host membrane remodeling is indispensable for viruses, bacteria, and parasites, to subvert the membrane barrier and obtain entry into cells. The malaria parasite Plasmodium spp. induces biophysical and molecular changes to the erythrocyte membrane through the ordered secretion of its apical organelles. To understand this process and address the debate regarding how the parasitophorous vacuole membrane (PVM) is formed, we developed an approach using lattice light-sheet microscopy, which enables the parasite interaction with the host cell membrane to be tracked and characterized during invasion. Our results show that the PVM is predominantly formed from the erythrocyte membrane, which undergoes biophysical changes as it is remodeled across all stages of invasion, from pre-invasion through to PVM sealing. This approach enables a functional interrogation of parasite-derived lipids and proteins in PVM biogenesis and echinocytosis during Plasmodium falciparum invasion and promises to yield mechanistic insights regarding how this is more generally orchestrated by other intracellular pathogens., Here, Geoghegan, Evelyn et al. provide a lattice light-sheet microscopy based 4D imaging pipeline to quantitatively investigate Plasmodium spp. invasion and show that the nascent parasitophorous vacuole is predominantly formed from host’s erythrocyte membrane and undergoes continuous remodeling throughout invasion.

The Brixton Spatial Anticipation Test is a well-established test of executive function that evaluates the capacity to abstract, follow, and switch rules. There has been remarkably little systematic analysis of Brixton test performance in the prototypical neurodegenerative disorder of the frontal lobes: behavioural variant frontotemporal dementia (bvFTD) or evaluation of the test’s ability to distinguish frontal from temporal lobe degenerative disease. We carried out a quantitative and qualitative analysis of Brixton performance in 76 patients with bvFTD and 34 with semantic dementia (SD) associated with temporal lobe degeneration. The groups were matched for demographic variables and illness duration. The bvFTD group performed significantly more poorly (U = 348, p

Background In longitudinal critical care studies, researchers may be interested in summarizing an exposure over time and evaluating its association with a long-term outcome. For example, the number of days a patient has delirium (i.e., brain dysfunction) during their critical care stay is associated with the presence and severity of long-term cognitive problems. In large pragmatic trials and multicenter observational studies, particularly when electronic medical record data is used, the information on daily exposure status may be available at some time points and not at others. Model-based multiple imputation is a well-established, widely adopted method to deal with missing data. But the uncertainty around multiple imputation for summary exposure variables is whether the imputation is to be performed at the summary level or at the daily assessment level. Methods We compare the following approaches to imputing and summarizing partially missing longitudinal data: 1) active imputation, where we impute the summary; 2) passive imputation, where we impute the daily missing data, and then compute the summary; 3) ad hoc methods where we assume all missing time points have the a) most or the b) least extreme value; and 4) complete case analysis where only participants with complete data are analyzed. These methods were applied under different missingness mechanisms, varying proportions of missingness, and association of missingness with an auxiliary variable using simulations that closely mirrors real-life critical care data to be relevant to real-world clinical practice. The performance of the approaches were compared using bias of the estimated coefficients, standard error of the estimate and coverage. We also apply these imputation strategies to two datasets in critical care. Results Simulations show that all methods performed comparably when the proportion of missingness was small, indicating that in such instances, the gain over using any imputation model is minimal. But as the proportion of missingness increases, the passive imputation approach provides efficient and less biased estimates under the missingness at random and missingness completely at random mechanism. Conclusions For longitudinal data where a summary exposure is of interest, we recommend practitioners adopting the passive imputation strategy.

Two human iPSC lines were generated from dermal fibroblasts derived from a patient with retinitis pigmentosa caused by CRB1 mutation using episomal plasmids containing OCT4, SOX2, LIN28, KLF4, L-MYC and mp53DD. These clonal iPSC lines carry compound heterozygous mutations in CRB1 (c.2555 T > C and c.3014A > T). Both lines expressed pluripotency markers, displayed a normal karyotype and demonstrated the ability to differentiate into the three primary germ layers, as well as retinal organoids.

Objective: To describe the co-design process in a project that “evaluated how the key worker role can best support people living with dementia in the community setting.”. Methods: People with dementia, care-partners, aged-care service experts, policymakers and academics utilised a co-design process to undertake a systematic literature review and a qualitative evaluation study. Results: The development of a successful co-design process that includes people living with dementia and their care-partners (“consumers”) at all stages of the research process and addresses their individual needs. Conclusions: The co-design approach utilised in this project provided support, for consumers living in the community to be fully involved in the research design, conduct and plans for dissemination and implementation of the findings. Consequently, the research outcomes are based on solid evidence and consumer need. Additionally, a successful model for supporting consumers to facilitate their involvement in all aspects of the research process, was developed. Refereed/Peer-reviewed

Background: Delirium in the extremes of the age spectrum may show similarities in presentations, and these similarities may provide information to develop tools for the diagnosis of delirium superimposed on dementia (DSD). We sought to investigate the symptom profile and subtypes of delirium in patients with dementia, and in infants and preschool children. Methods: This was an exploratory analysis of previous prospective cohort studies that evaluated delirium with the DSM-IV criteria in patients with dementia, and in critically ill infants (< 2 years of age) and preschool children (2–5 years of age), respectively. Delirium subtypes were defined based on the Richmond Agitation-Sedation Scale. Results: We included 147 patients, 35 adult patients with delirium DSD, 80 infants, and 32 preschool children with delirium. Hypokinesia and apathy were common among both DSD (72%), infants (74%) and preschool children (75%) with delirium, whereas hallucinations and anxiety were less common in both adults with DSD (26%) and infants (10%) and preschool children (14%). Hypoactive delirium was most common delirium subtype among infants (68%) and preschoolers (76%), whereas RASS = 0 (alert) delirium was the most common among adult patients with DSD (55%). Conclusions: The study reports similarities in the symptoms profile of delirium in a cohort of patients with dementia and delirium, and in infants and preschool-aged children with delirium. These preliminary findings might be informative to design future studies adapting delirium assessments used in in infants and preschool-aged children to patients with dementia, especially in the moderate to severe stages.

Listeriosis is a rare foodborne condition that can cause serious health consequences in neonates and pregnant women.To summarize the clinical and relevant evidence available regarding listeriosis in pregnancy and educate providers on common clinical symptoms, sequelae, and appropriate treatment guidelines.A PubMed review was conducted using search terms "pregnancy" OR "Listeria" OR "Maternal Listeriosis," and "Neonatal Listeriosis." The search included review articles, original research articles, and guidelines on diagnosis and management of listeriosis in pregnancy. The search was limited to the English language and publications between 1988 and July 2018.Listeriosis in pregnancy can result in severe adverse maternal, fetal, and neonatal outcomes including miscarriage, preterm labor, fetal death, and neonatal meningitis and sepsis. Early treatment has been shown to improve fetal and neonatal outcomes; therefore, prevention with education and early diagnosis prompting treatment will improve overall outcomes.The incidence of listeriosis is expected to rise in the coming years due to changes in the US population, with increasing numbers of older Americans and Hispanic individuals, both of whom are at higher risk. Pregnant women contract listeriosis at a rate that is 16- to 18-fold greater than the general population. Given the expected increased rise in incidence and increased susceptibility of pregnant women, understanding the common clinical symptoms, maternal and fetal sequelae, and appropriate treatment guidelines is essential.

A defining characteristic of pulmonary hypertension (PH) is the extensive remodeling of pulmonary arteries (PAs), which results in progressive increases in vascular resistance and stiffness and eventual failure of the right ventricle. There is no cure for PH and identification of novel molecular mechanisms that underlie increased proliferation, reduced apoptosis, and excessive extracellular matrix production in pulmonary artery smooth muscle cells (PASMCs) is a vital objective. Galectin-3 (Gal-3) is a chimeric lectin and potent driver of many aspects of fibrosis, but its role in regulating PASMC behavior in PH remains poorly understood. Herein, we evaluated the importance of increased Gal-3 expression and signaling on PA vascular remodeling and cardiopulmonary function in experimental models of PH. Gal-3 expression was quantified by qRT-PCR, immunoblotting, and immunofluorescence imaging, and its functional role was assessed by specific Gal-3 inhibitors and CRISPR/Cas9-mediated knockout of Gal-3 in the rat. In rat models of PH, we observed increased Gal-3 expression in PASMCs, which stimulated migration and resistance to apoptosis, whereas silencing or genetic deletion reduced cellular migration and PA fibrosis and increased apoptosis. Gal-3 inhibitors attenuated and reversed PA remodeling and fibrosis, as well as hemodynamic indices in monocrotaline (MCT)-treated rats in vivo. These results were supported by genetic deletion of Gal-3 in both MCT and Sugen Hypoxia rat models. In conclusion, our results suggest that elevated Gal-3 levels contribute to inappropriate PA remodeling in PH by enhancing multiple profibrotic mechanisms. Therapeutic strategies targeting Gal-3 may be of benefit in the treatment of PH.

Background: Activity-based therapies aim to improve neuromuscular capacity after spinal cord injury (SCI). Objective: The purpose of this prospective study was to report the impact of Activity-based Locomotor Training (AB-LT) on neuromuscular capacity in pediatric patients with SCI. Methods: Participants were enrolled for their first episode of AB-LT for a minimum of 60 daily, 1.5-hour sessions. The Segmental Assessment of Trunk Control (SATCo) and the Pediatric Neuromuscular Recovery Scale (Pediatric NRS) were assessed initially, every 20 sessions, and post 60 sessions. Results: Twenty-six consecutive patients, mean age 5 years (SD = 3), completed a mean 55 sessions (SD = 4) within 63 weekdays (SD = 9). The Pediatric NRS total score improved significantly, adjusted mean 11.4, from initial to post-60 sessions (p < .05) with an average adjusted evaluation-to-evaluation 3.7 change. SATCo scores improved significantly across 60 sessions, mean change 5.2, an estimated 1.7 change between evaluations (p < .05). Age at enrollment and chronicity had no effect; however, initial neuromuscular capacity scores were negatively correlated with change scores (p < .05). Conclusion: Sixty AB-LT sessions significantly improved trunk and neuromuscular capacity in children with SCI, regardless of age or chronicity at enrollment. Patients with lower initial scores made greater improvements than patients with higher initial neuromuscular capacity. Anecdotal parent reports of their child's functional change in the home and community highlight the synergy between quantitative change in neuromuscular capacity and meaningful, improved quality of life and the need for formal investigation of this relationship.

Our aim was to determine whether postoperative telephone follow-up was noninferior to in-person clinic visits based on patient satisfaction. Secondary outcomes were safety and clinical outcomes. Women scheduled for pelvic surgery were recruited from a single academic institution and randomized to clinic or telephone follow-up. The clinic group returned for visits 2, 6, and 12 weeks postoperatively and the telephone group received a call from a nurse at the same time intervals. Women completed the Consumer Assessment of Healthcare Providers and Systems Surgical Care Survey (S-CAHPS) questionnaire, Pelvic Floor Distress Inventory (PFDI)-20, and pain scales prior to and 3 months postoperatively. Randomized patients who completed the S-CAHPS at 3 months were included for analysis. Sample size calculations, based on a 15% noninferiority limit in the S-CAHPS global assessment surgeon rating, required 100 participants, with power = 80% and alpha = 0.025. From October 2016 to November 2017, 100 participants were consented, underwent surgery, were randomized, and included in the final analysis (clinic group n = 50, telephone group n = 50). Mean age was 58.5 ± 12.2 years. Demographic data and surgery type, dichotomized into outpatient and inpatient, did not differ between groups. The S-CAHPS global assessment surgeon rating from patients in the telephone group was noninferior to the clinic group (92 vs 88%, respectively, rated their surgeons 9 and10, with a noninferiority limit of 36.1; p = 0.006). Adverse events did not differ between groups (n = 26; 57% fclinic vs 43% telephone; p = 0.36). Patients in the telephone group did not require additional emergency room or primary care visits. Clinical outcome measures improved in both groups, with no differences (all p > 0.05). Telephone follow-up after pelvic floor surgery results in noninferior patient satisfaction, without differences in clinical outcomes or adverse events. Telephone follow-up may improve healthcare quality and decrease patient and provider burden for postoperative care. ClinicalTrials.gov , www.clinicaltrials.gov , NCT02891187.

OBJECTIVE: Decades-old, common ICU practices including deep sedation, immobilization, and limited family access are being challenged. We endeavoured to evaluate the relationship between ABCDEF bundle performance and patient-centered outcomes in critical care. DESIGN: Prospective, multicenter, cohort study from a national quality improvement collaborative. SETTING: 68 academic, community, and federal ICUs collected data during a 20-month period. PATIENTS: 15,226 adults with at least one ICU day. INTERVENTIONS: We defined ABCDEF bundle performance (our main exposure) in two ways: 1) complete performance (patient received every eligible bundle element on any given day) and 2) proportional performance (percentage of eligible bundle elements performed on any given day). We explored the association between complete and proportional ABCDEF bundle performance and three sets of outcomes: patient-related (mortality, ICU hospital discharge), symptom-related (mechanical ventilation, coma, delirium, pain, restraint use), and system-related (ICU readmission, discharge destination). All models were adjusted for a minimum of 18 a priori determined potential confounders. MEASUREMENTS AND RESULTS: Complete ABCDEF bundle performance was associated with lower likelihood of seven outcomes: hospital death within 7 days (adjusted hazard ratio, 0.32; CI, 0.17–0.62), next-day mechanical ventilation (adjusted odds ratio [AOR], 0.28; CI, 0.22–0.36), coma (AOR, 0.35; CI, 0.22–0.56), delirium (AOR, 0.60; CI, 0.49–0.72), physical restraint use (AOR, 0.37; CI, 0.30–0.46), ICU readmission (AOR, 0.54; CI, 0.37–0.79), and discharge to a facility other than home (AOR, 0.64; CI, 0.51–0.80). There was a consistent dose-response relationship between higher proportional bundle performance and improvements in each of the above-mentioned clinical outcomes (all p < 0.002). Significant pain was more frequently reported as bundle performance proportionally increased (p = 0.0001). CONCLUSIONS: ABCDEF bundle performance showed significant and clinically meaningful improvements in outcomes including survival, mechanical ventilation use, coma and delirium, restraint-free care, ICU readmissions, and post-ICU discharge disposition.

The human induced pluripotent stem cell (iPSC) lines LEIi015-A and LEIi015-B were derived from a patient with inherited retinal disease caused by compound heterozygous mutations in the SNRNP200 gene (c.[1792C>T];[3341T>C]). Dermal fibroblasts were transfected with episomal plasmids carrying transgenes encoding OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for P53. The clonal iPSC lines LEIi015-A and LEIi015-B expressed iPSC markers, were free from genomic alterations and demonstrated trilineage differentiation potential.

1. Jennifer L. Thompson, MD* 2. Thomas B. Russell, MD† 3. George C. Koberlein, MD‡ 4. Leslie M. Cristiano, MD* 1. *Department of Pulmonology, Critical Care, Allergy, and Immunologic Diseases, 2. †Department of Pediatric Hematology and Oncology, 3. ‡Department of Radiology, Wake Forest Baptist Hospital, Winston-Salem, NC A 7-month-old boy presents to the allergy, asthma, and immunology clinic with a medical history significant for slow weight gain in the newborn period, recurrent thrush, and a brief hospitalization for a viral respiratory illness at 3 months of age. He was referred from his primary care provider due to concerns of a rash that has not improved despite a variety of treatments. The rash first appeared at approximately 2 months of age, and although it has waxed and waned over the previous 5 months, it never completely resolves. While hospitalized for his respiratory illness at 3 months of age, a scabies prep of the rash was performed, but the result was inconclusive. The rash has been treated with permethrin on 2 separate occasions due to concern for scabies, along with topical corticosteroids for eczema and oral antifungals and antibiotics due to concern for fungal and bacterial infections. Despite these treatments there has been no significant improvement in the rash, and it has continued to spread throughout his inguinal area, trunk, face, and scalp. On physical examination he is a pleasant infant, but throughout the encounter he scratches at the various lesions on his body. His scalp has thick greasy yellow plaques with significant inflammation (Fig 1), and he has reddish-brown lesions on his trunk with severely erythematous areas of denuded skin in his inguinal folds and neck. He has a thick white exudate occluding visualization of his left tympanic membrane. There is an irregularly shaped hard mass measuring approximately 1.5 cm behind his lower 2 front teeth (Fig 2), and white plaques on his gums. …

Purpose Biallelic crumbs cell polarity complex component 1 (CRB1) mutations can present as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), or cystic maculopathy. This study reports a novel phenotype of asymptomatic fenestrated slit maculopathy (AFSM) and examines macular volume profile and microperimetry as clinical trial end points in CRB1-associated retinopathies. Methods Twelve patients from nine families with CRB1 mutation were recruited. Ultra-widefield (UWF) color fundus photography and autofluorescence (AF), spectral-domain optical coherence tomography (SD-OCT), microperimetry, and adaptive optics (AO) imaging were performed. Macular volume profiles were compared with age-matched healthy controls. Genotyping was performed using APEX genotyping microarrays, targeted next-generation sequencing, and Sanger sequencing. Results We identified one patient with LCA, five patients with RP, and four patients with macular dystrophy (MD) with biallelic CRB1 mutations. Two siblings with compound heterozygote genotype (c.[2843G>A]; [498_506del]) had AFSM characterized by localized outer retinal disruption on SD-OCT and parafoveal cone loss on AO imaging despite normal fundus appearance, visual acuity, and foveal sensitivity. UWF AF demonstrated preserved para-arteriolar retinal pigment epithelium (PPRPE) in all patients with RP. Microperimetry documented preserved central retinal function in six patients. The ratio of perifoveal-to-foveal retinal volume was greater than controls in 89% (8/9) of patients with RP or MD, whereas central subfield and total macular volume were outside normal limits in 67% (6/9). Conclusions AO imaging was helpful in detecting parafoveal cone loss in asymptomatic patients. Macular volume profile and microperimetry parameters may have utility as CRB1 trials end points. Translational relevance Macular volume and sensitivity can be used as structural and functional end points for trials on CRB1-associated RP and MD.

The fraction of cases reported, known as ‘reporting’, is a key performance indicator in an outbreak response, and an essential factor to consider when modelling epidemics and assessing their impact on populations. Unfortunately, its estimation is inherently difficult, as it relates to the part of an epidemic which is, by definition, not observed. We introduce a simple statistical method for estimating reporting, initially developed for the response to Ebola in Eastern Democratic Republic of the Congo (DRC), 2018–2020. This approach uses transmission chain data typically gathered through case investigation and contact tracing, and uses the proportion of investigated cases with a known, reported infector as a proxy for reporting. Using simulated epidemics, we study how this method performs for different outbreak sizes and reporting levels. Results suggest that our method has low bias, reasonable precision, and despite sub-optimal coverage, usually provides estimates within close range (5–10%) of the true value. Being fast and simple, this method could be useful for estimating reporting in real-time in settings where person-to-person transmission is the main driver of the epidemic, and where case investigation is routinely performed as part of surveillance and contact tracing activities.

Background Mutations in CLN3 cause Batten disease, however non‐syndromic CLN3 disease, characterized by retinal‐specific degeneration, has been also described. Here, we characterized an induced pluripotent stem cell (iPSC)‐derived disease model derived from a patient with non‐syndromic CLN3‐associated retinopathy. Methods Patient‐iPSC, carrying the 1 kb‐deletion and c.175G>A variants in CLN3, coisogenic iPSC, in which the c.175G>A variant was corrected, and control iPSC were differentiated into neural retinal organoids (NRO) and cardiomyocytes. CLN3 transcripts were analyzed by Sanger sequencing. Gene expression was characterized by qPCR and western blotting. NRO were characterized by immunostaining and electron microscopy. Results Novel CLN3 transcripts were detected in adult human retina and control‐NRO. The major transcript detected in patient‐NRO displayed skipping of exons 2 and 4–9. Accumulation of subunit‐C of mitochondrial ATPase (SCMAS) protein was demonstrated in patient‐derived cells. Photoreceptor progenitor cells in patient‐NRO displayed accumulation of peroxisomes and vacuolization of inner segments. Correction of the c.175G>A variant restored CLN3 mRNA and protein expression and prevented SCMAS and inner segment vacuolization. Conclusion Our results demonstrate the expression of novel CLN3 transcripts in human retinal tissues. The c.175G>A variant alters splicing of the CLN3 pre‐mRNA, leading to features consistent with CLN3 deficiency, which were prevented by gene correction., In this paper, we examined the phenotype of retinal organoids derived from a patient with non‐syndromic CLN3 disease. We showed that accumulation of subunit C of mitochondrial ATPase occurs in patient retinal cells and cardiomyocytes, and could be prevented by gene correction. Additionally, we demonstrated that novel CLN3 transcripts are expressed in the human retina.

ObjectiveThe precise relationship between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is incompletely understood. The association has been described as a continuum, yet data suggest that this may be an oversimplification. Direct comparisons between patients who have behavioural variant FTD (bvFTD) with and without ALS are rare. This prospective comparative study aimed to determine whether there are phenotypic differences in cognition and behaviour between patients with FTD-ALS and bvFTD alone.MethodsPatients with bvFTD or FTD-ALS and healthy controls underwent neuropsychological testing, focusing on language, executive functions and social cognition. Behavioural change was measured through caregiver interview. Blood samples were screened for known FTD genes.Results23 bvFTD, 20 FTD-ALS and 30 controls participated. On cognitive tests, highly significant differences were elicited between patients and controls, confirming the tests’ sensitivities to FTD. bvFTD and FTD-ALS groups performed similarly, although with slightly greater difficulty in patients with ALS-FTD on category fluency and a sentence-ordering task that assesses grammar production. Patients with bvFTD demonstrated more widespread behavioural change, with more frequent disinhibition, impulsivity, loss of empathy and repetitive behaviours. Behaviour in FTD-ALS was dominated by apathy. The C9ORF72 repeat expansion was associated with poorer performance on language-related tasks.ConclusionsDifferences were elicited in cognition and behaviour between bvFTD and FTD-ALS, and patients carrying the C9ORF72 repeat expansion. The findings, which raise the possibility of phenotypic variation between bvFTD and FTD-ALS, have clinical implications for early detection of FTD-ALS and theoretical implications for the nature of the relationship between FTD and ALS.