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Influenza Vaccination Among Children with Asthma: Challenges and Future Directions
No full textNo abstract availableNo embarg
Worm Perturb-Seq: massively parallel whole-animal RNAi and RNA-seq
Get PDFTranscriptomes provide highly informative molecular phenotypes that, combined with gene perturbation, can connect genotype to phenotype. An ultimate goal is to perturb every gene and measure transcriptome changes, however, this is challenging, especially in whole animals. Here, we present 'Worm Perturb-Seq (WPS)', a method that provides high-resolution RNA-sequencing profiles for hundreds of replicate perturbations at a time in living animals. WPS introduces multiple experimental advances combining strengths of Caenhorhabditis elegans genetics and multiplexed RNA-sequencing with a novel analytical framework, EmpirDE. EmpirDE leverages the unique power of large transcriptomic datasets and improves statistical rigor by using gene-specific empirical null distributions to identify DEGs. We apply WPS to 103 nuclear hormone receptors (NHRs) and find a striking 'pairwise modularity' in which pairs of NHRs regulate shared target genes. We envision the advances of WPS to be useful not only for C. elegans, but broadly for other models, including human cells.No embarg
A systemically deliverable lipid-conjugated siRNA targeting DUX4 as an facioscapulohumeral muscular dystrophy therapeutic
Get PDFFacioscapulohumeral muscular dystrophy (FSHD) is the third most diagnosed muscular dystrophy. The disease is caused by genetic and epigenetic disruptions that result in misexpression of the germline transcription factor DUX4 in skeletal muscle, leading to muscle toxicity and turnover. As a gene misexpressed exclusively in muscle, is a suitable for muscle-targeted small interfering RNA (siRNA) knockdown therapy. Here we identify a DUX4-targeting siRNA, DU01, that potently knocks down the expression of DUX4 target genes in FSHD patient-derived myotubes . Further, DU01 conjugated with the lipid docosanoic acid (DCA) is systemically deliverable to mice by subcutaneous injection to achieve greater than 50% knockdown of DUX4 target genes in FSHD patient muscle xenografts. These findings identify the DCA-conjugated DUX4 siRNA, DCA-siRNA, as a disease-targeting therapeutic for clinical development.No embarg
A multicenter, propensity score-matched analysis of functional outcomes and recanalization success with or without Trevo for Medium and distal vessel occlusion
No full textBackgroundEndovascular therapy (EVT) for stroke due to distal or medium vessel occlusion (DMVO) is safe. Due to the distinct anatomical characteristics of DMVOs, further evaluation of EVT is crucial to determine which devices may yield better outcomes.MethodsA retrospective analysis of adults with DMVO treated in 37 centers (11 countries) was queried. The primary outcome of favorable shift in 90-day modified Rankin Scale (mRS) was compared between patients treated with Trevo versus other devices on first pass using 1:1 propensity score matching (PSM) with multivariable adjustment. Secondary outcomes included the number of pass attempts, final thrombolysis in cerebral infarction (TICI) score 2b-3, symptomatic intracranial hemorrhage (sICH), improvement in National Institutes of Health Stroke Scale (NIHSS) at 24h, and 90-day mortality.ResultsOf the 1115 included patients, 264 (24%) were treated with Trevo (PSM cohort of 261 per group). Trevo use was not associated with a favorable 90-day mRS shift (proportional odds ratio [OR] 1.10, 95% confidence interval [CI] 0.80-1.51). Trevo was associated with fewer passes (adjusted β=-0.25, 95% CI -0.48 - -0.03), higher odds of TICI 2b-3 (adjusted OR 1.97, 95% CI 1.11-3.49), and a greater 24h NIHSS improvement (adjusted β= -1.74, 95% CI -3.11 - -0.36), with no difference in sICH or mortality (p>0.05). Results were similar in sensitivity analyses.ConclusionsWe observed no safety concerns with Trevo as compared to other EVT devices for DMVO recanalization. There was a signal of better technical efficacy and early clinical improvement.No embarg
Systematic identification of rare disease patients in electronic health records enables evaluation of clinical outcomes [preprint]
Get PDFThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Background: Identifying rare disease (RD) patients in electronic health records (EHR) is challenging, as more than 10,000 rare diseases are not typically captured by clinical coding systems. This limits the assessment of clinical outcomes for RD patients. This study introduces a semiautomated approach to map RDs to appropriate codes, that is applicable across various EHR systems. By improving RD patient identification, this method facilitates the analysis of clinical outcomes and disease severity in the RD population. We exemplify this by utilizing large EHR datasets such as those in the National COVID Cohort Collaborative (N3C) with over 21 million patients.
Methods: We developed a semiautomated workflow to enumerate RD-specific SNOMED-CT and ICD-10 codes, starting with 12,003 GARD IDs mapped to ORPHANET. This process linked RDs to SNOMED-CT and ICD-10 codes, applying exclusion criteria based on group of disorders. We created an extensive list of SNOMED-CT codes with descendants from the OHDSI atlas and performed phenotype filtering, removing irrelevant codes. The final list included 12,081 SNOMED-CT codes and 357 ICD-10 codes for further analysis, enabling the identification and mapping of rare diseases in EHR.
Results: Our semiautomated workflow identified 357 RD-specific ICD-10 codes and 12,081 SNOMED-CT codes representing 6,342 RDs which are categorized into 30 Orphanet linearization classes. We exemplify the utility of these codes by performing a preliminary univariate analysis of COVID-19 outcomes in a large cohort of 4,835,718 COVID-19 positive individuals in N3C, of which 404,735 (8.37%) were identified as having preexisting RD. The mortality and hospitalization risk ratios for rare RD classes ranged from 0.23 - 5.28 and 0.93 - 3.13, respectively (p-values <0.001).
Conclusions: Our systematic and automated workflow enables rapid identification of rare disease patients across diverse EHR systems. We demonstrate its utility by evaluating COVID-19 severity outcomes by rare disease classes in the N3C cohort. These findings support the need for targeted preventive healthcare interventions and highlight the potential for future research on long COVID, COVID-19 reinfection, and other outcomes in the rare disease population.The UMass Center for Clinical and Translational Science (UMCCTS), UL1TR001453, helped fund this study.No embarg
Clinician and patient readiness to engage with community health workers at epilepsy care centers
Get PDFIntroduction: For patients with epilepsy, medical and social support care gaps may potentially be addressed by clinic-based community health workers (CHWs), particularly for patients most susceptible to health disparities. However, little is known of health professionals' readiness to integrate CHWs into epilepsy health care delivery.
Methods: An online digital survey was developed and distributed to physicians, nurses and social workers working in 12 comprehensive epilepsy centers in the New England region. Questions in the survey pertained to respondents' perceptions of working with and addressing clinic needs via a CHW at an epilepsy center. Demographic data were also collected.
Results: Survey results across physicians, nurses and social workers (n = 65) revealed low knowledge and experience with CHWs. Epilepsy clinicians are unaware of the scientific evidence showing positive effects of CHW health outcomes. Knowledge of CHW recruitment, training and supervision is low. Despite this, the data collected demonstrate that social determinants of health care gaps exist for epilepsy patients receiving care at epilepsy centers. These gaps could potentially be addressed by a nontraditional healthcare professional, such as a CHW, instead of a social worker or nurse, thus alleviating burden from advanced practice provider members to address other clinically based patient needs.
Conclusion: Despite limited understanding of CHW roles or firsthand experience with CHWs, clinician and patient readiness for integration of CHW was high, with a strong indication that clinicians would refer patients to a CHW and that patients felt the potential for health benefit if provided with assistance from a CHW.No embarg
Experiences With Cancer Screenings Among Arabic-Speaking Refugee Women
No full textObjective: To explore breast, colorectal, and cervical cancer screening experiences among Arabic-speaking refugee women in Massachusetts.
Design: Qualitative descriptive.
Setting: The research was conducted in central Massachusetts, an area with a large refugee population from the Middle East. Despite cancer being the leading cause of death among Middle Eastern women aged 40 to 79 years, refugees experience significant disparities in cancer screenings. These refugees often pass through intermediary countries before permanently resettling, leading to preventive care becoming a lower priority as other life stressors take precedence.
Participants: Eleven women participated. Participants had an average age of 47 years; had come from Iraq, Syria, and Egypt; and had been in the United States an average of 7 years.
Methods: In 2022, semistructured individual interviews were conducted in person or via Zoom. An interview guide, constructed based on components of the Health Equity Implementation Science Framework and an expert panel of partners, refugee women, and medical providers, was used. Conventional content analysis was used to analyze the data.
Results: Three themes emerged: Facilitators of Cancer Screening, Barriers to Cancer Screening, and Interpreter-Related Factors. Women positively described providers' efforts to provide knowledge regarding screenings; however, language barriers, the invasive nature of some screenings, and scheduling appointments for screening posed significant obstacles.
Conclusion: This study highlights the unique health challenges faced by Arabic-speaking refugee women, focusing on their beliefs, experiences in clinical encounters, and communication regarding cancer screenings. Nurses can address these challenges by providing culturally sensitive care and building relationships with community resources.No embarg
Smartphone App-Based Survey Deployment Patterns and Longitudinal Response Rate: Randomized Controlled Trial
No full textBackground: Survey fatigue is a common challenge in longitudinal studies, particularly when using smartphone apps to collect survey data. Evidence-based strategies are needed to maintain longitudinal response rates.
Objective: This study aims to evaluate the effect of a more frequent smartphone-administered survey deployment strategy with smaller survey batches on participant response rates over an extended period.
Methods: We conducted a randomized controlled trial (NCT04752657) embedded in the electronic Framingham Heart Study cohorts between June 2021 and December 2023. Participants were randomly allocated to receive a full set of surveys every 4 weeks (control group) or half of the survey set biweekly, such that the full set is completed every 4 weeks (experimental group). Randomization was stratified by age (≤75 y vs >75 y) and phone type (Android vs iPhone). Married couples were assigned to the same group using a blocked randomization approach. The primary outcome was the proportion of surveys returned per participant assessed longitudinally across four periods (baseline to wk 8, wk 8-16, wk 16-24, and wk 24-32), with 19, 17, 16, and 15 unique surveys deployed, respectively. We used mixed-effects regression models with random intercepts to compare the repeated outcome between groups. Stratified analyses by age and sex were performed.
Results: Among 492 participants (mean age 74, SD 6.3 y; 58%, n=284 women, 84%, n=413 non-Hispanic White), there was evidence that the experimental group had higher response rates over time compared to the control group (P=.003 for interaction between deployment pattern and time). Both groups showed similar proportions of surveys returned during the first period (75% vs 76%). The experimental group had higher response rates than the control group in subsequent periods (70% vs 67% in wk 8-16, 64% vs 59% in wk 16-24, and 58% vs 50% in wk 24-32). The proportion of participants not returning any surveys increased from 3% to 38% in the control group compared to 1% to 28% in the experimental group across the four time periods. Stratified analyses revealed that among younger participants (≤75 y), the experimental group showed 12% higher survey response rates compared to the control group in the final period, while the difference was minimal among older participants (>75 years). The effect of the deployment pattern was similar for men and women. Three-way interaction analyses revealed no significant differences in the deployment pattern effect over time by age group (P=.95) or sex (P=.65).
Conclusions: Administering half of the surveys every 2 weeks, as compared to all surveys every 4 weeks, was associated with higher maintained longitudinal survey response rates. This strategy may help mitigate survey fatigue and improve data quality in digital health studies.
Trial registration: ClinicalTrials.gov NCT04752657; https://clinicaltrials.gov/study/NCT04752657.No embarg
A glial circadian gene expression atlas reveals cell-type and disease-specific reprogramming in response to amyloid pathology or aging
Get PDFWhile circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer's disease risk genes, displayed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function. Thus, circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer's disease and aging.No embarg
Impact of a Lifestyle Intervention Among Latina Women on Infant Birth and Anthropometric Measures: Pooled Analyses of 2 Randomized Controlled Trials
No full textBackground: To assess the impact of a pregnancy and postpartum culturally modified, motivationally targeted, individually tailored intervention on infant outcomes among Latinas.
Methods: We conducted a pooled analysis of 2 randomized controlled trials in Western Massachusetts: Estudio Parto (collected 2013-2017, analyzed 2018-2020, n = 203) and Proyecto Mamá (data collected 2014-2020, analyzed 2021-2022, n = 141) focused on pregnant Latinas (predominantly Puerto Rican) with abnormal glucose tolerance and prepregnancy body mass index in the overweight/obese range, respectively. Women were randomized in pregnancy to a Lifestyle Intervention (n = 167) focusing on healthy exercise and diet or to a comparison Health and Wellness Intervention (n = 177) with no mention of exercise or diet. The primary outcomes in both studies were birth weight, gestational age, birth weight-for-gestational-age z score, low birth weight, preterm birth, small-for-gestational-age, large for gestational age, macrosomia). Proyecto Mamá also assessed infant anthropometrics (ie, weight, length, sum and ratio of skin fold thickness, ponderal index) at 6 weeks of age. We used linear regression for continuous outcomes and logistic regression for dichotomous outcomes.
Results: In modified intent-to-treat analyses, we observed no statistically significant impact of the Lifestyle Intervention on infant outcomes or anthropometric measures. For example, there was no difference in odds of small-for-gestational-age between intervention arms (odds ratio = 1.29; 95% confidence interval, 0.60-2.76).
Conclusions: In these randomized trials among pregnant Latina women, we found that a culturally modified, individually tailored Lifestyle Intervention did not lead to a significant difference in infant birth weight outcomes or anthropometric measures when compared to the Health and Wellness control arm.No embarg