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INTRODUCTION: Chronic kidney disease (CKD) has an increasing global prevalence and has previously been associated with increased complications and morbidity after spine surgery. Understanding the isolated effect of CKD on short-term patient outcomes is critical for optimizing perioperative risk management and healthcare utilization. OBJECTIVE: The aim of this study is to utilize coarsened exact matching (CEM) to analyze the isolated effect of CKD on short-term patient outcomes in single-level posterior lumbar fusion surgery. METHODS: A retrospective analysis of 4680 consecutive patients undergoing single-level, posterior-only lumbar fusion was performed. Univariate logistic regression comparing the odds of outcomes in patients with CKD (n=40) to patients without medical comorbidities (n=2329) was performed. CEM was then employed to match patients with CKD to those without any comorbidities 1:1 on ten patient characteristics known to affect neurosurgical outcomes. Primary outcomes included intraoperative complications, length of stay, discharge disposition, and 30-day Emergency Department (ED) visits, readmissions, reoperations, and mortality. RESULTS: In a univariate logistic regression, CKD was associated with increased risk of 30-day ED visits (OR=3.53, p=0.003) but not complication, discharge disposition, or 30-day readmissions or reoperations. Between otherwise exactly matched patients (n=72), CKD similarly remained associated with an increased risk of 30-day ED visits (OR=7.00, p=0.034) and not with other outcomes. CONCLUSION: Between otherwise exactly matched patients undergoing single-level posterior lumbar fusion, CKD was related to increased risk of 30-day ED utilization but not other markers indicative of inferior surgical outcomes. Further study must investigate the reasons for increased ED visitation and implement risk-mitigation strategies for these patients.
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Vértebras Lombares , Insuficiência Renal Crônica , Fusão Vertebral , Humanos , Fusão Vertebral/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Vértebras Lombares/cirurgia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/complicações , Idoso , Estudos Retrospectivos , Resultado do Tratamento , Complicações Pós-Operatórias/epidemiologia , Adulto , Tempo de Internação , Readmissão do Paciente/estatística & dados numéricos , Complicações Intraoperatórias/epidemiologiaRESUMO
Previous studies on crosslinguistic influence (CLI) on third language (L3) morphosyntactic acquisition have provided support for competing theories about the source(s) of CLI. The present study aimed to test if both L1 and L2 can be the source of CLI, and whether they influence L3 learning in similar or different ways. In particular, we aimed to add to our knowledge of the neural correlates of CLI by conducting an exploratory EEG study to investigate how L1 and L2 CLI affect L3 neural processing. Predictions based on the D/P model, which posited different memory systems sustaining L1 and L2, were tested. The findings confirmed both L1-sourced and L2-sourced facilitation on L3 morphosyntactic acquisition. Specifically, we suggest that L1-similarity showed a consolidating effect on L3 implicit knowledge and neurocognitive internalization, whereas L2-similarity contributed to enhanced L3 metalinguistic knowledge. This preliminary study is the first to investigate the neurocognitive mechanisms underlying CLI in L3 learning by natural language learners.
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Eletroencefalografia , Memória , Multilinguismo , Humanos , Feminino , Masculino , Memória/fisiologia , Adulto Jovem , Adulto , Aprendizagem/fisiologia , IdiomaRESUMO
OBJECTIVE: Preoperative stereotactic radiosurgery (SRS) is emerging as a viable alternative to standard postoperative SRS. Studies have suggested that preoperative SRS provides comparable tumor control and overall survival (OS) and may reduce the incidence of leptomeningeal disease (LMD) and adverse radiation effects (AREs). It is unknown, however, if preoperative SRS remains effective in cohorts including large brain metastases (> 14 cm3) or if preoperative SRS affects steroid taper/immunotherapy. Here, the authors report the results of a phase 2 single-arm trial assessing a prospectively acquired series of 26 patients who underwent preoperative SRS, without a volumetric cutoff, compared with a propensity score-matched concurrent cohort of 30 patients who underwent postoperative SRS to address these salient questions. METHODS: Demographics, oncological history, surgical details, and outcomes were collected from the medical records. Coprimary endpoints were local tumor control (LTC) and a composite outcome of LTC, ARE, and LMD. Additional outcomes were OS, steroid taper details, and immunotherapy resumption. For survival analyses, cohorts were propensity score matched. RESULTS: Preoperative and postoperative SRS patients were comparable in terms of age, sex, Karnofsky Performance Status score, oncological history, and operative details. Gross tumor volume (GTV) was significantly higher in the preoperative group (median 12.2 vs 5.3 cm3, p < 0.001). One-year LTC (preoperative SRS: 77.2% vs postoperative SRS: 82.5%, p = 0.61) and composite outcome (68.3% vs 72.7%, p = 0.38) were not significantly different between the groups. In multivariable analysis, preoperative SRS did not have a significant effect on LTC (HR 1.57 [95% CI 0.38-6.49], p = 0.536) or the composite outcome (HR 1.18 [95% CI 0.38-3.72], p = 0.771), although the confidence intervals were large. The median OS (preoperative SRS: 17.0 vs postoperative SRS: 14.0 months, p = 0.61) was not significantly different. Rates of LMD were nonsignificantly lower in the preoperative SRS group (3.8% vs 16.7%, p = 0.200). Greater GTV volume was associated with prolonged (> 10 days) steroid taper (OR 1.24 [95% CI 1.04-1.55], p = 0.032). However, in multivariable analysis, preoperative SRS markedly reduced the steroid taper length (OR 0.13 [95% CI 0.02-0.61], p = 0.016). Time to immunotherapy was shorter in the preoperative SRS group (36 [IQR 26, 76] vs OR 228 [IQR 129, 436] days, p = 0.02). CONCLUSIONS: Compared with postoperative SRS, preoperative SRS is a safe and effective strategy in the management of cerebral metastases of all sizes and provides comparable tumor control without increased adverse effects. Notably, preoperative SRS enabled rapid steroid taper, even in larger tumors. Future studies should specifically examine the interaction of preoperative SRS with steroid usage and resumption of systemic therapies and the subsequent effects on systemic progression and OS.
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Person-centered care for people living with dementia has been associated with improved functional ability and quality of life, yet little is known about person-centered care in the home settings. Our objective was to explore home care worker perspectives on providing person-centered care for their clients living with dementia. Using secondary qualitative analysis of 22 semi-structured interviews with home care workers, we identified themes related to the Dementia Initiative's person-centered dementia care framework (Initiative, 2013). We found that home care workers acknowledged their client's personhood while also advocating for their needs. However, home care workers encountered barriers to providing person-centered care, including role limitations and challenging dynamics with other home care workers and family caregivers. This analysis can inform further approaches to better integrate home care workers in person-centered healthcare teams and improve how the needs of people living with dementia are identified and met in the home.
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BACKGROUND AND OBJECTIVES: Nonhuman primates (NHPs) are important preclinical models for evaluating therapeutics because of their anatomophysiological similarities to humans, and can be especially useful for testing new delivery targets. With the growing promise of cell and gene therapies for the treatment of neurological diseases, it is important to ensure the accurate and safe delivery of these agents to target structures in the brain. However, a standard guideline or method has not been developed for stereotactic targeting in NHPs. In this article, we describe the safe use of a magnetic resonance imaging-guided frameless stereotactic system to target bilateral cerebellar dentate nuclei for accurate, real-time delivery of viral vector in NHPs. METHODS: Seventeen rhesus macaques (Macaca mulatta) underwent stereotactic surgery under real-time MRI guidance using the ClearPoint® system. Bilateral cerebellar dentate nuclei were targeted through a single parietal entry point with a transtentorial approach. Fifty microliters of contrast-impregnated infusate was delivered to each dentate nucleus, and adjustments were made as necessary according to real-time MRI monitoring of delivery. Perioperative clinical outcomes and postoperative volumes of distribution were recorded. RESULTS: All macaques underwent bilateral surgery successfully. Superficial pin site infection occurred in 4/17 (23.5%) subjects, which resolved with antibiotics. Two episodes of transient neurological deficit (anisocoria and unilateral weakness) were recorded, which did not require additional postoperative treatment and resolved over time. Volume of distribution of infusate achieved satisfactory coverage of target dentate nuclei, and only 1 incidence (2.9%) of cerebrospinal fluid penetration was recorded. Mean volume of distribution was 161.22 ± 39.61 mm3 (left, 173.65 ± 48.29; right, 148.80 ± 23.98). CONCLUSION: MRI-guided frameless stereotactic injection of bilateral cerebellar dentate nuclei in NHPs is safe and feasible. The use of this technique enables real-time modification of the surgical plan to achieve adequate target coverage and can be readily translated to clinical use.
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Stargardt disease and age-related macular degeneration are the leading causes of blindness in the juvenile and geriatric populations, respectively. The formation of atrophic regions of the macula is a hallmark of the end-stages of both diseases. The progression of these diseases is tracked using various imaging modalities, two of the most common being fundus autofluorescence (FAF) imaging and spectral-domain optical coherence tomography (SD-OCT). This study seeks to investigate the use of longitudinal FAF and SD-OCT imaging (month 0, month 6, month 12, and month 18) data for the predictive modelling of future atrophy in Stargardt and geographic atrophy. To achieve such an objective, we develop a set of novel deep convolutional neural networks enhanced with recurrent network units for longitudinal prediction and concurrent learning of ensemble network units (termed ReConNet) which take advantage of improved retinal layer features beyond the mean intensity features. Using FAF images, the neural network presented in this paper achieved mean (± standard deviation, SD) and median Dice coefficients of 0.895 (± 0.086) and 0.922 for Stargardt atrophy, and 0.864 (± 0.113) and 0.893 for geographic atrophy. Using SD-OCT images for Stargardt atrophy, the neural network achieved mean and median Dice coefficients of 0.882 (± 0.101) and 0.906, respectively. When predicting only the interval growth of the atrophic lesions with FAF images, mean (± SD) and median Dice coefficients of 0.557 (± 0.094) and 0.559 were achieved for Stargardt atrophy, and 0.612 (± 0.089) and 0.601 for geographic atrophy. The prediction performance in OCT images is comparably good to that using FAF which opens a new, more efficient, and practical door in the assessment of atrophy progression for clinical trials and retina clinics, beyond widely used FAF. These results are highly encouraging for a high-performance interval growth prediction when more frequent or longer-term longitudinal data are available in our clinics. This is a pressing task for our next step in ongoing research.
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BACKGROUND: Critical bleeding events in adults and children with ITP are medical emergencies; however, evidence-based treatment protocols are lacking. Due to the severe thrombocytopenia, (typically platelet count less than 20 × 109/L), a critical bleed portends a high risk of death or disability. We plan to perform a systematic review and meta-analysis of treatments for critical bleeding in patients with ITP that will inform evidence-based recommendations. METHODS: Literature searches will be conducted in four electronic databases: Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed. Eligible studies will be randomized controlled trials or observational studies that enrolled patients with ITP describing one or more interventions for the management of critical bleeding. Title and abstract screening, full-text screening, data extraction, and risk of bias evaluation will be conducted independently and in duplicate using Covidence and Excel. Outcomes will be pooled for meta-analysis where appropriate or summarized descriptively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology will be used to evaluate the certainty of the evidence. Primary outcomes of interest will include frequency of critical bleeds, mortality and bleeding-related mortality, bleeding resolution, platelet count, and disability. DISCUSSION: Evidence-based treatments for critical bleeding in patients with ITP are needed to improve patient outcomes and standardize care in the emergency setting. SYSTEMATIC REVIEW REGISTRATION: CRD42020161206.
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Hemorragia , Púrpura Trombocitopênica Idiopática , Adulto , Criança , Humanos , Hemorragia/terapia , Metanálise como Assunto , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/terapia , Revisões Sistemáticas como Assunto , Trombocitopenia/complicações , Trombocitopenia/terapiaRESUMO
Introduction: On October 12, 2021, the FDA issued its first marketing granted orders for Vuse, the e-cigarette product by R.J. Reynolds Vapor Company. The public perceptions and reactions to the FDA's Vuse authorization are prevalent on social media platforms such as Twitter/X. We aim to understand public perceptions of the FDA's Vuse authorization in the US using Twitter/X data. Methods: Through the Twitter/X streaming API (Application Programming Interface), 3,852 tweets between October 12, 2021, and October 23, 2021, were downloaded using the keyword of Vuse. With the elimination of retweets, irrelevant tweets, and tweets from other countries, the final dataset consisted of 523 relevant tweets from the US. Based on their attitudes toward the FDA authorization on Vuse, these tweets were coded into three major categories: positive, negative, and neutral. These tweets were further manually classified into different categories based on their contents. Results: There was a large peak on Twitter/X mentioning FDA's Vuse authorization on October 13, 2021, just after the authorization was announced. Of the 523 US tweets related to FDA's Vuse authorization, 6.12% (n=32) were positive, 26.77% (n=140) were negative, and 67.11% (n=351) were neutral. In positive tweets, the dominant subcategory was Cessation Claims (n=18, 56.25%). In negative tweets, the topics Health Risk (n=43, 30.71%), Criticize Authorization (n=42, 30.00%), and Big Tobacco (n=40, 38.57%) were the major topics. News (n=271, 77.21%) was the most prevalent topic among neutral tweets. In addition, tweets with a positive attitude tend to have more likes. Discussion: Public perceptions and discussions on Twitter/X regarding the FDA's Vuse authorization in the US showed that Twitter/X users were more likely to show a negative than a positive attitude with a major concern about health risks.
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Sistemas Eletrônicos de Liberação de Nicotina , Mídias Sociais , Humanos , Marketing , Opinião PúblicaRESUMO
Introduction: While premium cigars have similar addictive, toxic, and carcinogenic constituents as other cigars and cigarettes, about 1% of the US adults reported premium cigar use from 2010 to 2019. This study aimed to understand public perceptions and discussions of premium cigars on Reddit, one of the most popular social media platforms. Methods: Using keywords such as "premium cigar", we extracted 2,238 Reddit posts from Reddit Archive between July 2019 and June 2021. Among them, 1,626 posts were related to premium cigars. By employing the inductive approach, we manually coded each Reddit post on premium cigars to understand public perceptions and discussions of premium cigars by summarizing them into different topics and subtopics. Results: Longitudinal analysis showed that the number of Reddit posts on premium cigars increased since June 2020. Content analysis showed that among Reddit posts related to premium cigars, the most popular topic is "Information sharing" (75.72%), in which Reddit users shared their perceptions about premium cigars, asked for advice, and provided some recommendations about premium cigars. Over one-quarter of posts (27.17%) are sharing user experiences of premium cigars (such as taste). Nearly one-fifth (18.99%) of posts are discussing the affordability of premium cigars. In addition, 7.87% of posts are discussing legal/policy issues related to premium cigars, and 6.82% of posts are related to the health risks of premium cigars compared to cigarettes. Conclusions: Public perceptions including misperceptions, user experiences, and affordability related to premium cigars have been actively discussed on Reddit.
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PURPOSE: The incidence of metabolic bone diseases in pediatric neurosurgical patients is rare. We examined our institutional experience of metabolic bone diseases along with a review of the literature in an effort to understand management for this rare entity. METHODS: Retrospective review of the electronic medical record database was performed to identify patients with primary metabolic bone disorders who underwent craniosynostosis surgery between 2011 and 2022 at a quaternary referral pediatric hospital. Literature review was conducted for primary metabolic bone disorders associated with craniosynostosis. RESULTS: Ten patients were identified, 6 of whom were male. The most common bone disorders were hypophosphatemic rickets (n = 2) and pseudohypoparathyroidism (n = 2). The median age at diagnosis of metabolic bone disorder was 2.02 years (IQR: 0.11-4.26), 2.52 years (IQR: 1.24-3.14) at craniosynostosis diagnosis, and 2.65 years (IQR: 0.91-3.58) at the time of surgery. Sagittal suture was most commonly fused (n = 4), followed by multi-suture craniosynostosis (n = 3). Other imaging findings included Chiari (n = 1), hydrocephalus (n = 1), and concurrent Chiari and hydrocephalus (n = 1). All patients underwent surgery for craniosynostosis, with the most common operation being bifronto-orbital advancement (n = 4). A total of 5 patients underwent reoperation, 3 of which were planned second-stage surgeries and 2 of whom had craniosynostosis recurrence. CONCLUSIONS: We advocate screening for suture abnormalities in children with primary metabolic bone disorders. While cranial vault remodeling is not associated with a high rate of postoperative complications in this patient cohort, craniosynostosis recurrences may occur, and parental counseling is recommended.
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Doenças Ósseas Metabólicas , Craniossinostoses , Raquitismo Hipofosfatêmico Familiar , Hidrocefalia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/epidemiologia , Craniossinostoses/complicações , Craniossinostoses/cirurgia , Raquitismo Hipofosfatêmico Familiar/complicações , Hidrocefalia/complicações , Estudos Retrospectivos , Crânio/diagnóstico por imagem , Crânio/cirurgiaRESUMO
Cone-rod dystrophy 6 (CORD6) is caused by gain-of-function mutations in the GUCY2D gene, which encodes retinal guanylate cyclase-1 (RetGC1). There are currently no treatments available for this autosomal dominant disease, which is characterized by severe, early-onset visual impairment. The purpose of our study was to develop an adeno-associated virus (AAV)-CRISPR-Cas9-based approach referred to as "ablate and replace" and evaluate its therapeutic potential in mouse models of CORD6. This two-vector system delivers (1) CRISPR-Cas9 targeted to the early coding sequence of the wild-type and mutant GUCY2D alleles and (2) a CRISPR-Cas9-resistant cDNA copy of GUCY2D ("hardened" GUCY2D). Together, these vectors knock out ("ablate") expression of endogenous RetGC1 in photoreceptors and supplement ("replace") a healthy copy of exogenous GUCY2D. First, we confirmed that ablation of mutant R838S GUCY2D was therapeutic in a transgenic mouse model of CORD6. Next, we established a proof of concept for "ablate and replace" and optimized vector doses in Gucy2e+/-:Gucy2f-/- and Gucy2f-/- mice, respectively. Finally, we confirmed that the "ablate and replace" approach stably preserved retinal structure and function in a novel knockin mouse model of CORD6, the RetGC1 (hR838S, hWT) mouse. Taken together, our results support further development of the "ablate and replace" approach for treatment of CORD6.
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PURPOSE: Carbonated calcium phosphate (CCP) cement is an alloplastic material which has been increasingly utilized for cranioplasty reconstruction; however, there is a paucity of data investigating its use in patients with syndromic craniosynostosis. The purpose of this study was to characterize our institutional experience with CCP cement for secondary contouring cranioplasty in these patients to establish safety and aesthetic efficacy. METHODS: Patients with syndromic craniosynostosis undergoing cranioplasty with CCP cement from 2009 to 2022 were retrospectively reviewed for prior medical and surgical history, cranioplasty size, cement usage, and postoperative complications. Aesthetic ratings of the forehead region were quantified using the Whitaker scoring system at three timepoints: preoperative (T1), < 6 months postoperative (T2), and > 1 year postoperative (T3). RESULTS: Twenty-one patients were included. Age at surgery was 16.2 ± 2.8 years, forehead cranioplasty area was 135 ± 112 cm2, and mass of cement was 17.2 ± 7.8 g. Patients were followed for 3.0 ± 3.1 years. Whitaker scores decreased from 1.9 ± 0.4 at T1 to 1.4 ± 0.5 at T2 (p = 0.005). Whitaker scores at T2 and T3 were not significantly different (p = 0.720). Two infectious complications (9.5%) were noted, one at 4.5 months postoperatively and the other at 23 months, both requiring operative removal of CCP cement. CONCLUSION: Our results suggest that aesthetic forehead ratings improve after CCP contouring cranioplasty and that the improvement is sustained in medium-term follow-up. Complications were uncommon, suggesting that CCP is relatively safe though longer-term follow-up is needed before reaching definitive conclusions.
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Craniossinostoses , Procedimentos de Cirurgia Plástica , Humanos , Adolescente , Adulto Jovem , Adulto , Estudos Retrospectivos , Crânio/cirurgia , Craniossinostoses/cirurgia , Craniossinostoses/complicações , Cimentos Ósseos/uso terapêutico , Complicações Pós-Operatórias/etiologia , Fosfatos de Cálcio/uso terapêuticoRESUMO
Training in a segregated health care system means that health professions students and trainees learn bias and experience helplessness and burnout if they wish to-but cannot-rectify segregated care. When racial segregation is built into training environments, many students and trainees quickly internalize which patients are de facto deemed more worthy of care. Students and trainees who recognize this feature of their professional training as dysfunctional and as an ethical and equity problem need support when reporting inequities and advocating for desegregated health systems. By supporting such efforts, faculty and organizations can help desegregate health care, minimize iatrogenic harm from bias, motivate health equity, and promote equitable access to quality health service delivery.
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Aprendizagem , Estudantes , Humanos , Emoções , Atenção à SaúdeRESUMO
Home care workers played critical roles in meeting the complex medical and social needs of homebound adults during COVID-19, yet their contributions remain underappreciated. This study characterizes home care workers' roles during COVID-19 and examines how home care disruptions impacted homebound individuals and caregivers. Using a qualitative analysis of electronic medical records among a randomly sampled subset of homebound patients in a home-based primary care practice, we found that home care workers were essential in meeting existing and new needs of homebound individuals. Insufficient home care worker services, including unstable schedules and inadequate hours of paid care, became particularly disruptive, leading to risks for patients and their caregivers. Given their integral role on care teams, home care workers must be a policy focus to prepare for emergent situations and ensure that homebound individuals have access to high quality, stable home care.
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COVID-19 , Serviços de Assistência Domiciliar , Feminino , Humanos , Idoso , COVID-19/epidemiologia , Pandemias , Estudos Retrospectivos , CuidadoresRESUMO
Background: Research on deaths during COVID-19 has largely focused on hospitals and nursing homes. Less is known about medically complex patients receiving care in the community. We examined care disruptions and end-of-life experiences of homebound patients receiving home-based primary care (HBPC) in New York City during the initial 2020 COVID-19 surge. Methods: We conducted a retrospective chart review of patients enrolled in Mount Sinai Visiting Doctors who died between March 1-June 30, 2020. We collected patient sociodemographic and clinical data and analyzed care disruptions and end-of-life experiences using clinical notes, informed by thematic and narrative analysis. Results: Among 1300 homebound patients, 112 (9%) died during the study period. Patients who died were more likely to be older, non-Hispanic white, and have dementia than those who survived. Thirty percent of decedents had confirmed or probable COVID-19. Fifty-eight (52%) were referred to hospice and 50 enrolled. Seventy-three percent died at home. We identified multiple intersecting disruptions in family caregiving, paid caregiving, medical supplies and services, and hospice care, as well as hospital avoidance, complicating EOL experiences. The HBPC team responded by providing clinical, logistical and emotional support to patients and families. Conclusion: Despite substantial care disruptions, the majority of patients in our study died at home with support from their HBPC team as the practice worked to manage care disruptions. Our findings suggest HBPC's multi-disciplinary, team-based model may be uniquely suited to meet the needs of the most medically and socially vulnerable older adults at end of life during public health emergencies.
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COVID-19 , Serviços de Assistência Domiciliar , Cuidados Paliativos na Terminalidade da Vida , Humanos , Idoso , Cidade de Nova Iorque/epidemiologia , Estudos Retrospectivos , Pandemias , Morte , Atenção Primária à SaúdeRESUMO
Background: There is limited evidence regarding the challenges of providing hospice care to those dying at home during the COVID-19 pandemic. Objective: To describe the challenges of home hospice care and the specific types of disruptions in care processes experienced by patients and families. Design: Qualitative study of the electronic medical record notes of a large New York City (NYC) home-based primary care program. Setting/Subjects: Subjects were 58 patients referred to hospice who died during the initial NYC COVID-19 surge from March to June 2020. Results: We identified six domains of disruptions in home hospice care: delayed hospice enrollment, inability to conduct home visits, lack of needed supplies, communication failures, strained caregivers, and limitations of telehealth. Conclusions: This study provides a critical first analysis of disruptions in home hospice care that can feasibly be addressed and must be prioritized by hospices throughout the ongoing pandemic and in advance of future emergencies.
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COVID-19 , Serviços de Assistência Domiciliar , Cuidados Paliativos na Terminalidade da Vida , Hospitais para Doentes Terminais , Humanos , PandemiasRESUMO
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. We sought to correct the multiple organ dysfunction of the F508del CF-causing mutation using systemic delivery of peptide nucleic acid gene editing technology mediated by biocompatible polymeric nanoparticles. We confirmed phenotypic and genotypic modification in vitro in primary nasal epithelial cells from F508del mice grown at air-liquid interface and in vivo in F508del mice following intravenous delivery. In vivo treatment resulted in a partial gain of CFTR function in epithelia as measured by in situ potential differences and Ussing chamber assays and correction of CFTR in both airway and GI tissues with no off-target effects above background. Our studies demonstrate that systemic gene editing is possible, and more specifically that intravenous delivery of PNA NPs designed to correct CF-causing mutations is a viable option to ameliorate CF in multiple affected organs.
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The unequal partitioning of molecules and organelles during cell division results in daughter cells with different fates. An extreme example is female meiosis, in which consecutive asymmetric cell divisions give rise to 1 large oocyte and 2 small polar bodies with DNA and minimal cytoplasm. Here, we test the hypothesis that during an asymmetric cell division during spermatogenesis of the nematode Auanema rhodensis, the late segregating X chromatids orient the asymmetric partitioning of cytoplasmic components. In previous studies, the secondary spermatocytes of wild-type XO males were found to divide asymmetrically to generate functional spermatids that inherit components necessary for sperm viability and DNA-containing residual bodies that inherit components to be discarded. Here we extend that analysis to 2 novel contexts. First, the isolation and analysis of a strain of mutant XX pseudomales revealed that such animals have highly variable patterns of X-chromatid segregation. The pattern of late segregating X chromatids nevertheless predicted the orientation of organelle partitioning. Second, while wild-type XX hermaphrodites were known to produce both 1X and 2X sperm, here, we show that spermatocytes within specific spermatogonial clusters exhibit 2 different patterns of X-chromatid segregation that correlate with distinct patterns of organelle partitioning. Together this analysis suggests that A. rhodensis has coopted lagging X chromosomes during anaphase II as a mechanism for determining the orientation of organelle partitioning.
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Cromátides , Espermatócitos , Animais , Masculino , Feminino , Cromátides/genética , Sêmen , Meiose , OrganelasRESUMO
INTRODUCTION: Seriously ill people with dementia living at home may be particularly vulnerable to disruptions in their care during times of crisis. The study sought to describe care experiences of those receiving home-based primary care in New York City during the COVID-19 pandemic and compare the experiences of people with and without dementia. METHODS: We conducted a retrospective review of all electronic medical record notes between March 1, 2020 and December 30, 2020 among a sample of home-based primary care recipients (n = 228), including all deaths that occurred in the spring of 2020. Drawing from administrative records and using an abstraction tool that included both structured (e.g., documented COVID-19 exposure) and unstructured (e.g., text passage describing caregiver burden) data, we identified salient COVID-19 related care experiences and identified and categorized major disruptions in care. RESULTS: Both people with and without dementia experienced significant disruptions of paid caregiving, family caregiving, and home-based services during the COVID-19 pandemic. While the paid caregivers of people with dementia reported more burden to the home-based primary care team as compared to people without dementia, we found little evidence of differences in quantity or type of COVID-19 related disruptions relative to dementia status. DISCUSSION: While those with dementia have distinct care needs, our findings emphasize the way that dementia may be one piece of a larger clinical picture of serious illness. In order to support all patients with high care needs in crisis, we need to understand the interdependence of clinical care, long-term care, and family caregiving support for older adults and view dementia within the larger context of serious illness and care need.