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BACKGROUND: The origin of novel SARS-CoV-2 spike sequences found in wastewater, without corresponding detection in clinical specimens, remains unclear. We sought to determine the origin of one such cryptic wastewater lineage by tracking and characterising its persistence and genomic evolution over time. METHODS: We first detected a cryptic lineage, WI-CL-001, in municipal wastewater in Wisconsin, USA, in January, 2022. To determine the source of WI-CL-001, we systematically sampled wastewater from targeted sub-sewershed lines and maintenance holes using compositing autosamplers. Viral concentrations in wastewater samples over time were measured by RT digital PCR. In addition to using metagenomic 12s rRNA sequencing to determine the virus's host species, we also sequenced SARS-CoV-2 spike receptor binding domains, and, where possible, whole viral genomes to identify and characterise the evolution of this lineage. FINDINGS: We traced WI-CL-001 to its source at a single commercial building. There we detected the cryptic lineage at concentrations as high as 2·7 × 109 genome copies per L. The majority of 12s rRNA sequences detected in wastewater leaving the identified source building were human. Additionally, we generated over 100 viral receptor binding domain and whole-genome sequences from wastewater samples containing the cryptic lineage collected over the 13 consecutive months this virus was detectable (January, 2022, to January, 2023). These sequences contained a combination of fixed nucleotide substitutions characteristic of Pango lineage B.1.234, which circulated in humans in Wisconsin at low levels from October, 2020, to February, 2021. Despite this, mutations in the spike gene and elsewhere resembled those subsequently found in omicron variants. INTERPRETATION: We propose that prolonged detection of WI-CL-001 in wastewater indicates persistent shedding of SARS-CoV-2 from a single human initially infected by an ancestral B.1.234 virus. The accumulation of convergent omicron-like mutations in WI-CL-001's ancestral B.1.234 genome probably reflects persistent infection and extensive within-host evolution. People who shed cryptic lineages could be an important source of highly divergent viruses that sporadically emerge and spread. FUNDING: The Rockefeller Foundation, Wisconsin Department of Health Services, Centers for Disease Control and Prevention, National Institute on Drug Abuse, and the Center for Research on Influenza Pathogenesis and Transmission.
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COVID-19 , Águas Residuárias , Estados Unidos , Humanos , SARS-CoV-2/genética , COVID-19/epidemiologia , Centers for Disease Control and Prevention, U.S.RESUMO
BACKGROUND: Despite infection control guidance, sporadic nosocomial coronavirus disease 2019 (COVID-19) outbreaks occur. We describe a complex severe acute respiratory coronavirus virus 2 (SARS-CoV-2) cluster with interfacility spread during the SARS-CoV-2 δ (delta) pandemic surge in the Midwest. SETTING: This study was conducted in (1) a hematology-oncology ward in a regional academic medical center and (2) a geographically distant acute rehabilitation hospital. METHODS: We conducted contact tracing for each COVID-19 case to identify healthcare exposures within 14 days prior to diagnosis. Liberal testing was performed for asymptomatic carriage for patients and staff. Whole-genome sequencing was conducted for all available clinical isolates from patients and healthcare workers (HCWs) to identify transmission clusters. RESULTS: In the immunosuppressed ward, 19 cases (4 patients, 15 HCWs) shared a genetically related SARS-CoV-2 isolate. Of these 4 patients, 3 died in the hospital or within 1 week of discharge. The suspected index case was a patient with new dyspnea, diagnosed during preprocedure screening. In the rehabilitation hospital, 20 cases (5 patients and 15 HCWs) positive for COVID-19, of whom 2 patients and 3 HCWs had an isolate genetically related to the above cluster. The suspected index case was a patient from the immune suppressed ward whose positive status was not detected at admission to the rehabilitation facility. Our response to this cluster included the following interventions in both settings: restricting visitors, restricting learners, restricting overflow admissions, enforcing strict compliance with escalated PPE, access to on-site free and frequent testing for staff, and testing all patients prior to hospital discharge and transfer to other facilities. CONCLUSIONS: Stringent infection control measures can prevent nosocomial COVID-19 transmission in healthcare facilities with high-risk patients during pandemic surges. These interventions were successful in ending these outbreaks.
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COVID-19 , Infecção Hospitalar , Viroses , Humanos , COVID-19/prevenção & controle , SARS-CoV-2 , Controle de Infecções/métodos , Pessoal de SaúdeRESUMO
BACKGROUND: Concern about weight gain is a barrier to smoking-cessation, but determinants of postcessation weight-concern have not been comprehensively assessed in the context of community-based cessation programs. METHODS: This cross-sectional analysis used baseline data from a cessation trial of 392 adults randomized to physical activity (PA) or general wellness counseling as adjunctive treatment for smoking. Outcomes were 1) smoking behaviors to control weight and 2) anticipating relapse due to weight gain. Independent variables were PA and perceptions, sociodemographics, psychosocial measures, smoking behavior and perceptions, diet, and BMI. From bivariable models examining main and sex interaction effects, significant variables were entered into a linear (control) or logistic (relapse) regression model to identify key determinants. RESULTS: For both measures, weight-concern was greater (p < .05) for female smokers (standardized b = 0.52, SE = 0.10; OR = 0.29, 95 % CI = 0.17-0.49), White (b = 0.12, SE = 0.05; OR = 0.39, 95 % CI = 0.23-0.66), and less motivated to quit (b = -0.14, SE = 0.05; OR = 0.77, 95 % CI = 0.59-1.0). Higher scores for smoking to control weight were associated with less PA (b = -0.10, SE = 0.05) and higher BMI (b = 0.21, SE = 0.05). For men, higher BMI was associated with greater anticipation of relapse (OR = 2.54, 95 % CI = 1.42-4.56). CONCLUSIONS: Among adults attempting cessation, women, White smokers, and those less motivated to quit were more likely to smoke for weight control and to relapse due to weight gain. Higher BMI was associated with greater anticipation of relapse for men, but not women. Weight-concerns, for both measures, were not related to smoking history, psychosocial functioning, PA engagement or attitudes, or dietary variables. Results suggest potential cessation intervention targets for weight-concerned smokers.
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Fumantes , Aumento de Peso , Adulto , Masculino , Humanos , Feminino , Estudos Transversais , Fumar/epidemiologia , RecidivaRESUMO
Objective: The efficacy of individualized, community-based physical activity as an adjunctive smoking cessation treatment to enhance long-term smoking cessation rates was evaluated for the Lifestyle Enhancement Program (LEAP). Methods: The study was a two-arm, parallel-group, randomized controlled trial. All participants (n = 392) received cessation counseling and a nicotine patch and were randomized to physical activity (n = 199; YMCA membership and personalized exercise programming from a health coach) or an equal contact frequency wellness curriculum (n = 193). Physical activity treatment was individualized and flexible (with each participant selecting types of activities and intensity levels and being encouraged to exercise at the YMCA and at home, as well as to use "lifestyle" activity). The primary outcome (biochemically verified prolonged abstinence at 7-weeks (end of treatment) and 6- and 12-months postcessation) and secondary outcomes (7-day point prevalent tobacco abstinence (PPA), total minutes per week of leisure time physical activity and strength training) were assessed at baseline, 7 weeks, 6 months, and 12 months. Results: Prolonged abstinence in the physical activity and wellness groups was 19.6% and 25.4%, respectively, at 7-weeks, 15.1% and 16.6% at 6-months, and 14.1% and 17.1% at 12 months (all between-group P values >0.18). Similarly, PPA rates did not differ significantly between groups at any follow-up. Change from baseline leisure-time activity plus strength training increased significantly in the physical activity group at 7 weeks (P = 0.04). Across treatment groups, an increase in the number of minutes per week in strength training from baseline to 7 weeks predicted prolonged abstinence at 12 months (P ≤ 0.001). Further analyses revealed that social support, fewer years smoked, and less temptation to smoke were associated with prolonged abstinence over 12 months in both groups. Conclusions: Community-based physical activity programming, delivered as adjunctive treatment with behavioral/pharmacological cessation treatment, did not improve long-term quit rates compared to adjunctive wellness counseling plus behavioral/pharmacological cessation treatment. This trial is registered with https://beta.clinicaltrials.gov/study/NCT00403312, registration no. NCT00403312.
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Diagnosis by rapid antigen tests (RATs) is useful for early initiation of antiviral treatment. Because RATs are easy to use, they can be adapted for self-testing. Several kinds of RATs approved for such use by the Japanese regulatory authority are available from drug stores and websites. Most RATs for COVID-19 are based on antibody detection of the SARS-CoV-2 N protein. Since Omicron and its subvariants have accumulated several amino acid substitutions in the N protein, such amino acid changes might affect the sensitivity of RATs. Here, we investigated the sensitivity of seven RATs available in Japan, six of which are approved for public use and one of which is approved for clinical use, for the detection of BA.5, BA.2.75, BF.7, XBB.1, and BQ.1.1, as well as the delta variant (B.1.627.2). All tested RATs detected the delta variant with a detection level between 7500 and 75 000 pfu per test, and all tested RATs showed similar sensitivity to the Omicron variant and its subvariants (BA.5, BA.2.75, BF.7, XBB.1, and BQ.1.1). Human saliva did not reduce the sensitivity of the RATs tested. Espline SARS-CoV-2 N showed the highest sensitivity followed by Inspecter KOWA SARS-CoV-2 and V Trust SARS-CoV-2 Ag. Since the RATs failed to detect low levels of infectious virus, individuals whose specimens contained less infectious virus than the detection limit would be considered negative. Therefore, it is important to note that RATs may miss individuals shedding low levels of infectious virus.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , Substituição de Aminoácidos , AntiviraisAssuntos
Anticorpos Antivirais , Antivirais , COVID-19 , SARS-CoV-2 , Eficácia de Vacinas , Humanos , Anticorpos Antivirais/imunologia , Antivirais/imunologia , Antivirais/farmacologia , Técnicas In Vitro , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , COVID-19/genética , COVID-19/imunologia , COVID-19/virologiaRESUMO
APRIL (A proliferation inducing ligand) and BLyS (B Lymphocyte Stimulator) are two critical survival factors for B lymphocytes and plasma cells, the main source of alloantibody. We sought to characterize the specific effects of these cytokines in a kidney transplant model of antibody mediated rejection (AMR). We engineered APRIL-/- and BLyS-/- Lewis rats using CRISPR/Cas9. APRIL-/- and BLyS-/- rats were sensitized with Brown Norway (BN) blood (complete MHC mismatch). Twenty-one days following sensitization, animals were harvested and collected tissues were analyzed using flow cytometry, ELISPOT, and immunohistochemistry. Flow cross match and a 3 day mixed lymphocyte reaction (MLR) was performed to assess donor specific antibody (DSA) production and T-cell proliferation, respectively. Sensitized dual knock out Lewis rats (APRIL-/-/BLyS-/-) underwent kidney transplantation and were sacrificed on day 7 post-transplant. Sensitized BLyS-/- had significant decreases in DSA and cell proliferation compared to WT and APRIL-/- (p<0.02). Additionally, BLyS-/- rats had a significant reduction in IgG secreting cells in splenic marginal zone B lymphocytes, and in cell proliferation when challenged with alloantigen compared to WT and APRIL-/-. Transplanted APRIL-/-/BLyS-/- rodents had significantly less DSA and antibody secreting cells compared to WT (p<0.05); however, this did not translate into a significant difference in AMR seen between groups. In summary, our studies suggest that APRIL and BLyS play a greater role in DSA generation rather than AMR, highlighting the role of cellular pathways that regulate AMR.
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Transplante de Rim , Animais , Fator Ativador de Células B , Proliferação de Células , Rejeição de Enxerto , Imunoglobulina G , Isoanticorpos , Isoantígenos , Ratos , Ratos Endogâmicos Lew , Roedores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose TumoralRESUMO
The SARS-CoV-2 Delta Variant of Concern is highly transmissible and contains mutations that confer partial immune escape. The emergence of Delta in North America caused the first surge in COVID-19 cases after SARS-CoV-2 vaccines became widely available. To determine whether individuals infected despite vaccination might be capable of transmitting SARS-CoV-2, we compared RT-PCR cycle threshold (Ct) data from 20,431 test-positive anterior nasal swab specimens from fully vaccinated (n = 9,347) or unvaccinated (n = 11,084) individuals tested at a single commercial laboratory during the interval 28 June- 1 December 2021 when Delta variants were predominant. We observed no significant effect of vaccine status alone on Ct value, nor when controlling for vaccine product or sex. Testing a subset of low-Ct (<25) samples, we detected infectious virus at similar rates, and at similar titers, in specimens from vaccinated and unvaccinated individuals. These data indicate that vaccinated individuals infected with Delta variants are capable of shedding infectious SARS-CoV-2 and could play a role in spreading COVID-19.
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COVID-19 , Vacinas Virais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , SARS-CoV-2 , VacinaçãoRESUMO
Examining the neutralizing capacity of monoclonal antibodies (MAbs) used to treat COVID-19, as well as antibodies recovered from unvaccinated, previously vaccinated, and infected individuals, against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) remains critical to study. Here, we report on a SARS-CoV-2 nosocomial outbreak caused by the SARS-CoV-2 R.1 variant harboring the E484K mutation in a 281-bed psychiatric facility in New Jersey among unvaccinated inpatients and health care professionals (HCPs). A total of 81 inpatients and HCPs tested positive for SARS-Cov-2 by reverse transcription (RT)-PCR from 29 October 9 to 30 November 2020. The R.1 variant exhibits partial or complete resistance to two MAbs in clinical use, as well as 2 receptor binding domain MAbs and 4 N-terminal domain (NTD) MAbs. NTD MAbs against pseudovirus harboring single characteristic R.1 mutations highlight the role of S255F in loss of activity. Additionally, we note dampened neutralization capacity by plasma from individuals with previous SARS-CoV-2 infection or sera from vaccinated individuals. The relative resistance of the R.1 variant is likely lower than that of B.1.351 and closer to that of P.1 and B.1.526. The R.1 lineage has been reported in 47 states in the United States and 40 countries. Although high proportions exhibited symptoms (26% and 61% among patients and HCPs, respectively) and relative antibody resistance, we detected only 10 R.1 variants from over 2,900 samples (~0.34%) collected from January to October 2021. Among 3 vaccinated individuals previously infected with R.1, we observed robust neutralizing antibody responses against SARS-CoV-2 wild type and VOCs. IMPORTANCE The neutralizing capacities of monoclonal antibodies used to treat COVID-19 and of those recovered from previously infected and vaccinated individuals against SARS-CoV-2 variants of concern (VOCs) remain important questions. We report on a nosocomial outbreak caused by a SARS-CoV-2 R.1 variant harboring an E484K mutation among 81 unvaccinated inpatients and health care professionals. We note high attack rates with symptoms in nearly 50% of infected individuals, in sharp contrast to an unrelated institutional outbreak caused by the R.1 variant among a vaccinated population. We found little evidence of significant community spillover. This variant exhibits partial or complete resistance to two monoclonal antibodies in clinical use and dampened the neutralization capacity of convalescent-phase plasma from individuals with previous infection or sera from vaccinated individuals. Among three vaccinated individuals previously infected with R.1, we observed robust neutralizing antibody responses against SARS-CoV-2 wild type and VOCs. These findings underscore the importance of vaccination for prevention of symptomatic COVID-19 disease.
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COVID-19 , Infecção Hospitalar , Humanos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , COVID-19/epidemiologia , Testes de Neutralização , Anticorpos Antivirais , New Jersey/epidemiologia , Anticorpos Neutralizantes , Surtos de Doenças , Anticorpos Monoclonais , GenômicaRESUMO
Allograft kidney transplantation, which triggers host cellular- and antibody-mediated rejection of the kidney, is a major contributor to kidney damage during transplant. Here, we asked whether PrC-210 would suppress damage seen in allograft kidney transplant. Brown Norway (BN) rat kidneys were perfused in situ (UW Solution) with or without added 30 mM PrC-210, and then immediately transplanted into Lewis (LEW) rats. 20 h later, the transplanted BN kidneys and LEW rat plasma were analyzed. Kidney histology, and kidney/serum levels of several inflammation-associated cytokines, were measured to assess mismatch-related kidney pathology, and PrC-210 protective efficacy. Twenty hours after the allograft transplants: (i) significant histologic kidney tubule damage and mononuclear inflammatory cell infiltration were seen in allograft kidneys; (ii) kidney function metrics (creatinine and BUN) were significantly elevated; (iii) significant changes in key cytokines, i.e., TIMP-1, TNF-alpha and MIP-3A/CCL20, and kidney activated caspase levels were seen. In PrC-210-treated kidneys and recipient rats, (i) kidney histologic damage (Banff Scores) and mononuclear infiltration were reduced to untreated background levels; (ii) creatinine and BUN were significantly reduced; and (iii) activated caspase and cytokine changes were significantly reduced, some to background. In conclusion, the results suggest that PrC-210 could provide broadly applicable organ protection for many allograft transplantation conditions; it could protect transplanted kidneys during and after all stages of the transplantation process-from organ donation, through transportation, re-implantation and the post-operative inflammation-to minimize acute and chronic rejection.
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Diaminas/farmacologia , Inflamação/tratamento farmacológico , Transplante de Rim/efeitos adversos , Rim/efeitos dos fármacos , Compostos de Sulfidrila/farmacologia , Adenosina , Aloenxertos , Alopurinol , Animais , Caspases/metabolismo , Creatinina/sangue , Citocinas/metabolismo , Diaminas/administração & dosagem , Sequestradores de Radicais Livres/farmacologia , Glutationa , Inflamação/patologia , Insulina , Rim/patologia , Transplante de Rim/métodos , Masculino , Mitocôndrias/efeitos dos fármacos , Soluções para Preservação de Órgãos , Rafinose , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Compostos de Sulfidrila/administração & dosagemRESUMO
BACKGROUND: Transplant glomerulopathy (TG) is a pathological feature of chronic active antibody-mediated rejection (cAMR) and is associated with renal allograft failure. The specific role of B cells in the pathogenesis of TG is unclear. METHODS: We used a minor mismatched rat kidney transplant model with B cell-deficient recipients, generated by clustered regularly interspaced short palindromic repeats/Cas9 technology, to investigate the impact of B-cell depletion on the pathogenesis of TG. We hypothesized that B-cell deficiency would prevent TG in the rat kidney transplant model of cAMR. Treatment groups included syngeneic, allogeneic, sensitized allogeneic, and B cell-deficient allogeneic transplant recipients. RESULTS: B cell-deficient recipients demonstrated reduced TG lesions, decreased microvascular inflammation, reduced allograft infiltrating macrophages, and reduced interferon gamma transcripts within the allograft. Allograft transcript levels of interferon gamma, monocyte chemoattractant protein-1, and interleukin-1ß correlated with numbers of intragraft macrophages. B cell-deficient recipients lacked circulating donor-specific antibodies and had an increased splenic regulatory T-cell population. CONCLUSIONS: In this model of cAMR, B-cell depletion attenuated the development of TG with effects on T cell and innate immunity.
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Linfócitos B/imunologia , Glomerulonefrite/prevenção & controle , Rejeição de Enxerto/prevenção & controle , Isoanticorpos/sangue , Rim/imunologia , Animais , Linfócitos B/metabolismo , Proliferação de Células , Células Cultivadas , Doença Crônica , Técnicas de Cocultura , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Glomerulonefrite/genética , Glomerulonefrite/imunologia , Glomerulonefrite/metabolismo , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Imunidade Celular , Imunidade Inata , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Ativação Linfocitária , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Ratos Transgênicos , Baço/imunologia , Baço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Ischemia-reperfusion injury, including injury from warm- and cold-ischemia (CI) organ storage, remains a significant problem for all solid organ transplants. Suppressing CI damage would reduce delayed graft function and increase the donor organ pool size. PrC-210 has demonstrated superior prevention of damage in several preclinical studies as an immediate-acting free-radical scavenger. Here, we describe its profound efficacy in suppressing CI injury in a rat kidney model. METHODS: Kidneys in 300 gm Sprague-Dawley rats were perfused in situ with UW solution with or without added PrC-210 and then stored at 4°C in the same solution for 0 to 48 hours. When procured, kidney-activated caspase-3 level (a marker of cell death) was measured, and direct histological analysis of kidneys was performed to assess PrC-210 protective efficacy. In vitro analyses of PrC-210-conferred protection to isolated rat kidneys or naked DNA were also performed. RESULTS: A single 15 seconds in situ perfusion of kidneys with 20 mmol/L PrC-210 in UW solution resulted in significant reductions in (1) 30-hour CI-induced kidney-activated caspase level (P < 0.0001); activated caspase was reduced to levels not significantly different than control activated caspase levels seen in unperturbed kidneys, (2) 30-hour CI-induced renal Tubular Injury Scores (P = 0.0004) where brush border and tubular necrosis were markedly reduced, (3) PrC-210 conferred 100% protection against ·OH damage to naked DNA and isolated kidney mitochondria while current UW solution antioxidants were without protective effect. CONCLUSIONS: A single PrC-210-UW solution perfusion of rat kidneys upon removal from the rat profoundly reduced caspase and renal tubular injury in kidneys exposed to 30 hours of CI organ storage. These findings support further development of the PrC-210 molecule to suppress or to prevent ischemia-reperfusion injury in organ transplant and other ischemia-reperfusion injury settings.
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BACKGROUND/OBJECTIVES: Although several approaches have been developed to provide comprehensive care for persons living with dementia (PWD) and their family or friend caregivers, the relative effectiveness and cost effectiveness of community-based dementia care (CBDC) versus health system-based dementia care (CBDC) and the effectiveness of both approaches compared with usual care (UC) are unknown. DESIGN: Pragmatic randomized three-arm superiority trial. The unit of randomization is the PWD/caregiver dyad. SETTING: Four clinical trial sites (CTSs) based in academic and clinical health systems. PARTICIPANTS: A total of 2,150 English- or Spanish-speaking PWD who are not receiving hospice or residing in a nursing home and their caregivers. INTERVENTIONS: Eighteen months of (1) HSDC provided by a nurse practitioner or physician's assistant dementia care specialist who works within the health system, or (2) CBDC provided by a social worker or nurse care consultant who works at a community-based organization, or (3) UC with as needed referral to the Alzheimer's Association Helpline. MEASUREMENTS: Primary outcomes: PWD behavioral symptoms and caregiver distress as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q) Severity and Modified Caregiver Strain Index scales. SECONDARY OUTCOMES: NPI-Q Distress, caregiver unmet needs and confidence, and caregiver depressive symptoms. Tertiary outcomes: PWD long-term nursing home placement rates, caregiver-reported PWD functional status, cognition, goal attainment, "time spent at home," Dementia Burden Scale-Caregiver, a composite measure of clinical benefit, Quality of Life of persons with dementia, Positive Aspects of Caregiving, and cost effectiveness using intervention costs and Medicare claims. RESULTS: The results will be reported in the spring of 2024. CONCLUSION: D-CARE will address whether emphasis on clinical support and tighter integration with other medical services has greater benefit than emphasis on social support that is tied more closely to community resources. It will also assess the effectiveness of both interventions compared with UC and will evaluate the cost effectiveness of each intervention.
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Doença de Alzheimer/terapia , Sobrecarga do Cuidador/psicologia , Serviços de Saúde Comunitária/organização & administração , Assistência Integral à Saúde/métodos , Idoso , Análise Custo-Benefício , Feminino , Humanos , Masculino , Estudos Multicêntricos como Assunto , Ensaios Clínicos Pragmáticos como Assunto , Melhoria de Qualidade , Qualidade de VidaRESUMO
Importance: Older adults who are homebound and have low income have limited access to psychosocial treatments because of their homebound state and geriatric mental health workforce shortages. Objective: To evaluate clinical effectiveness of a brief, aging service-integrated, videoconferenced behavioral activation (tele-BA) treatment delivered by lay counselors compared with videoconferenced problem-solving therapy (tele-PST) delivered by licensed clinicians and attention control (AC; telephone support calls). Design, Setting, and Participants: This 3-group randomized clinical trial using a randomization prior to consent approach included individuals aged 50 years or older who were homebound and had 24-item Hamilton Depression Rating Scale (HAMD) scores of 15 or greater between February 15, 2016, and April 15, 2019. Tele-BA and tele-PST participants received 5 weekly treatment sessions. Assessments were performed at baseline and 12, 24, and 36 weeks after baseline. Intention-to-treat statistical analyses were performed from January 1, 2020, to February 15, 2020. Interventions: Tele-BA participants were taught 5 steps for reinforcing healthy behaviors to improve mood, physical functioning, and social engagement. Tele-PST participants were taught a 7-step approach for problem solving coping skills. Main Outcomes and Measures: The primary outcome was the 24-item HAMD scores. Response (ie, ≥50% reduction in HAMD) and remission (ie, HAMD <10) rates and effect sizes for clinically meaningful differences were examined. Secondary outcomes were disability, social engagement and activity frequency, and satisfaction with participation in social roles. Results: A total of 277 participants were enrolled, including 193 (69.7%) women, 83 (30.0%) who were Black, 81 (29.2%) who were Hispanic, and 255 (92.1%) with income of $35â¯000 or less. The mean (SD) age was 67.5 (8.9) years. Among these, 90 participants were randomized to tele-BA, 93 participants were randomized to tele-PST, and 94 participants were randomized to the AC. Compared with participants in the AC group, participants in the tele-BA and tele-PST groups had significantly higher response and remission rates and medium to large effect sizes (tele-BA: raw growth modeling analysis d = 0.62 [95% CI, 0.35 to 0.89]; P < .001; tele-PST: raw growth modeling analysis d = 1.00 [95% CI, 0.73 to 1.26]; P < .001) for HAMD scores. While tele-PST was significantly more effective than tele-BA for reducing HAMD scores (t258 = -2.79; P = .006), there was no difference between tele-BA and tele-PST on secondary outcomes. Conclusions and Relevance: In this randomized clinical trial, participants who received tele-BA by lay counselors achieved statistically and clinically meaningful changes in depressive symptoms. Given shortages of licensed mental health clinicians, tele- and lay counselor-delivered services may help improve access to evidence-based depression treatment for large numbers of underserved older adults. Trial Registration: ClinicalTrials.gov Identifier: NCT02600754.
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Depressão/terapia , Pacientes Domiciliares/psicologia , Psicoterapia/métodos , Telemedicina/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pobreza , Resultado do TratamentoRESUMO
Glomerular endothelial cells (GEnC) are a specialized microvascular subset of endothelial cells that, when injured, result in many types of diseases within the kidney. Thus, techniques to study GEnC in a cell culture system are important to investigate mechanisms of GEnC injury. Studies of endothelial cell function in culture have predominately relied on using macrovascular endothelial cells from vascular areas other than the glomerulus. Over the last 15 years, glomerular endothelial cells lines have been created but were isolated by targeting cells expressing CD31. Some studies identified endothelial cells isolated from the microvasculature do not express CD31 and some suggest that CD31+ cells are phenotypically different than endothelial cells found in capillaries. Here we detail our method of isolation, purification, and conditional immortalization of mouse glomerular endothelial cells targeting endothelial cells that do not express CD31.â¢This method allows for isolation, purification, and conditional immortalization of glomerular endothelial cells for continued passage of GEnCs beyond that of primary cell culture.â¢This method can be used in genetically modified mice to investigate how a modification of a specific gene or protein affects the glomerular endothelium at the cellular level.
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BACKGROUND: Regional variation in pharmacy-dispensed naloxone rates could create access disparities that undermine the effectiveness of this approach. We explored individual and public health unit (PHU)-level determinants of regional variation in naloxone distribution through the Ontario Naloxone Program for Pharmacies. METHODS: We conducted a population-based study between April 1, 2017 and March 31, 2018. We calculated age- and sex-standardized pharmacy-dispensed naloxone rates for the 35 Ontario PHUs, and identified determinants of these rates using generalized estimating equations negative binomial regression. RESULTS: The age- and sex-standardized pharmacy-dispensed naloxone rate in Ontario was 5.5 (range 1.8-11.6) kits per 1000 population. Variables associated with higher naloxone dispensing rates included opioid use disorder history [rate ratio (RR) 2.27; 95% confidence interval (CI) 1.75-2.96], opioid agonist therapy (RR 11.17; 95% CI 7.15-17.44), and PHU opioid overdose rate (RR 1.09 per 10 deaths; 95% CI 1.06-1.13). Pharmacy-dispensed naloxone rates were lower in rural areas (RR 0.83; 95% CI 0.73-0.94) and among individuals dispensed one (RR 0.72; 95% CI 0.65-0.79), two to five (RR 0.67; 95% CI 0.54-0.84) or 6-10 (RR 0.92; 95% CI 0.74-1.14) opioids in the prior year relative to those receiving no opioids. CONCLUSION: Pharmacy-dispensed naloxone programs are important components of a public health response to the opioid overdose crisis. We found considerable variation in pharmacy-dispensed naloxone rates that could limit program effectiveness, particularly in rural settings with limited access to health and harm reduction services..
Assuntos
Overdose de Drogas/tratamento farmacológico , Naloxona/uso terapêutico , Adulto , Analgésicos Opioides/uso terapêutico , Overdose de Drogas/epidemiologia , Feminino , Redução do Dano , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Entorpecentes/uso terapêutico , Ontário , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Assistência Farmacêutica , Farmácias , Análise de Pequenas ÁreasRESUMO
OBJECTIVES: Capacity for safe and independent living (SAIL) refers to an individual's ability to solve problems associated with everyday life and perform activities necessary for living independently. Little guidance exists on the assessment of capacity for SAIL among nursing home residents. As a result, capacity for SAIL is not fully considered in the development of discharge plans to ensure safety and independence in the community. We reasoned that this problem could be addressed with the Making and Executing Decisions for Safe and Independent Living (MEDSAIL) tool, developed to screen for capacity for SAIL among community-dwelling older adults. In this report, we describe findings on the validity of the MEDSAIL when used with nursing home residents. DESIGN: Prospective cross-sectional pilot study. SETTING AND PARTICIPANTS: Twenty-four residents of a Veterans Health Affairs Community Living Center (CLC; nursing home); exclusion criteria were cognitive impairment too severe to complete the protocol, diagnosis of serious mental illness or developmental disability, inability to hear, or inability to communicate verbally. METHODS: Participants completed 2 assessments: the MEDSAIL interview administered by a research assistant and the criterion standard capacity interview administered by a geriatric psychiatrist. We examined internal consistency, divergent validity, and criterion-based validity. RESULTS: Five of 7 MEDSAIL scenarios approximated acceptable levels of internal consistency (α >0.70). MEDSAIL scores were highly positively correlated with criterion standard capacity determination (0.88, P = .001), and the Wilcoxon rank-sum test statistic for the 2 assessments was also statistically significant (P = .001). CONCLUSIONS AND IMPLICATIONS: MEDSAIL has promise as a user-friendly brief screening tool for use by nursing home staff to understand resident capacity for SAIL. This information can be used in the development of discharge plans to keep the resident safe and independent in the community. In addition, tailoring the MEDSAIL scenarios specifically to the nursing home setting may further enhance the tool's validity and utility in this new application.