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The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.
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COVID-19 , Modelos Biológicos , SARS-CoV-2 , COVID-19/genética , COVID-19/mortalidade , COVID-19/transmissão , Feminino , Humanos , Masculino , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Estados Unidos/epidemiologiaRESUMO
The emergence of the COVID-19 epidemic in the United States (U.S.) went largely undetected due to inadequate testing. New Orleans experienced one of the earliest and fastest accelerating outbreaks, coinciding with Mardi Gras. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large-scale events accelerate transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana had limited diversity compared to other U.S. states and that one introduction of SARS-CoV-2 led to almost all of the early transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras, and the festival dramatically accelerated transmission. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate epidemics.
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COVID-19/epidemiologia , Epidemias , SARS-CoV-2/fisiologia , COVID-19/transmissão , Bases de Dados como Assunto , Surtos de Doenças , Humanos , Louisiana/epidemiologia , Filogenia , Fatores de Risco , SARS-CoV-2/classificação , Texas , Viagem , Estados Unidos/epidemiologiaRESUMO
Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease.
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AMP Desaminase/metabolismo , Atrofias Olivopontocerebelares/metabolismo , Purinas/biossíntese , AMP Desaminase/química , AMP Desaminase/genética , Animais , Tronco Encefálico/patologia , Cerebelo/patologia , Criança , Feminino , Guanosina Trifosfato/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Mutação , Células-Tronco Neurais/metabolismo , Atrofias Olivopontocerebelares/genética , Atrofias Olivopontocerebelares/patologia , Biossíntese de Proteínas , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/metabolismoRESUMO
BACKGROUND: The uptake of nirmatrelvir plus ritonavir (NPR) in patients with coronavirus disease 2019 (COVID-19) has been limited by concerns around the rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of rebound in NPR-treated and untreated participants with acute COVID-19 infection. METHODS: We designed a prospective, observational study in which participants who tested positive for COVID-19 and were clinically eligible for NPR were recruited to be evaluated for either viral or symptom clearance and rebound. Participants were assigned to the treatment or control group based on their decision to take NPR. Following initial diagnosis, both groups were provided 12 rapid antigen tests and asked to test on a regular schedule for 16 days and answer symptom surveys. Viral rebound based on test results and COVID-19 symptom rebound based on patient-reported symptoms were evaluated. RESULTS: Viral rebound incidence was 14.2% in the NPR treatment group (n = 127) and 9.3% in the control group (n = 43). Symptom rebound incidence was higher in the treatment group (18.9%) compared to controls (7.0%). There were no notable differences in viral rebound by age, gender, preexisting conditions, or major symptom groups during the acute phase or at the 1-month interval. CONCLUSIONS: This preliminary report suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, notably we observed a similar rate of rebound in both the NPR treatment and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.
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COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiologia , Tratamento Farmacológico da COVID-19 , Estudos Prospectivos , Ritonavir/uso terapêutico , Antivirais/uso terapêuticoRESUMO
Protein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans-mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole-exome sequencing identified compound heterozygous variants in the TIM22 gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts of TIM22 were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore-forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange.
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Proteínas de Transporte/genética , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Miopatias Mitocondriais/genética , Criança , DNA Mitocondrial/genética , Feminino , Fibroblastos/metabolismo , Predisposição Genética para Doença , Humanos , Ácido Láctico/líquido cefalorraquidiano , Proteínas de Membrana Transportadoras/genética , Mitocôndrias/patologia , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Miopatias Mitocondriais/líquido cefalorraquidiano , Miopatias Mitocondriais/patologia , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Mutação , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Sequenciamento do ExomaRESUMO
Deficits in the ability to encode small differences in contrast between adjacent parts of an image (contrast sensitivity) are well documented in schizophrenic patients. In the present study, we sought to determine whether contrast sensitivity deficits reported in schizophrenic patients are also evident in those who exhibit high schizotypy scores in a typical (i.e., non-schizophrenic) population. Using the O-Life Questionnaire, we determined the effects of schizotypy on spatial (0.5, 2 and 8 c/deg) and spatiotemporal (0.5 and 8 c/deg at 0.5 and 8 Hz) contrast sensitivity in 73 young (18-26 years), majority female (n = 68) participants. We found differences in contrast sensitivity that were spatial, spatiotemporal and O-Life subscale specific. Spatial contrast sensitivity was significantly lower in high, compared to low schizotypes at low spatial frequencies (0.5 c/deg) in those who scored highly on the Unusual Experiences and Cognitive Disorganisation O-Life subscales. For moving stimuli, individuals with high scores on the Unusual Experiences subscale exhibited lower spatiotemporal contrast sensitivity for 0.5 and 8 c/deg patterns drifting at 8 Hz. Although the effects reported here were relatively small, this is the first report of reduced contrast sensitivity in schizotypy.
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Sensibilidades de Contraste/fisiologia , Percepção de Movimento/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Transtorno da Personalidade Esquizotípica/fisiopatologia , Percepção Espacial/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Atrial fibrillation (AF) is the most commonly encountered arrhythmia and is associated with an elevated risk of stroke. Improving the identification of patients with the highest risk for AF to enable appropriate surveillance and treatment, if necessary, is critical to reducing AF-associated morbidity and mortality. Multiple common single nucleotide polymorphisms (SNPs) are unequivocally associated with the lifetime risk of AF. In the current study we aimed to prospectively validate an AF genetic risk score (GRS) in previously undiagnosed patients at risk for AF. METHODS AND FINDINGS: Individuals 40 years of age or older with 1 clinical risk factor for AF, presenting with symptoms of AF, or with a first diagnosis of AF, were enrolled for genetic testing and ambulatory cardiac rhythm monitoring with an adhesive patch monitor or a long-term Holter monitor (mean wear time 10 days 21 hours and 13 days 18 hours, respectively). An AF event was the first diagnosis of AF by ECG, patch monitor, or long-term Holter monitor. The AF GRS was determined for each participant based on the weighted contribution of 12 genetic risk loci. Of 904 participants, 85 manifested AF. Their mean age was 66.2 (SD 11.8) years; 38% of participants were male. Participants in the highest quintile of AF GRS were more likely (odds ratio 3.11; 95% CI 1.27-7.58; p = 0.01) to have had an AF event than participants in the lowest quintile after adjusting for age, sex, smoking status, BMI, hypertension, diabetes mellitus, heart failure, and prior myocardial infarction. Study limitations included an ethnically homogenous population, a restricted rhythm monitoring period, and the evolving discovery of SNPs associated with AF. CONCLUSIONS: Prospective assessment of a GRS for AF identified participants with elevated risk of AF beyond established clinical criteria. Accordingly, a GRS for AF could be incorporated into overall risk assessment to better identify patients at the highest risk of developing AF, although further testing in larger populations is needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01970969.
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Fibrilação Atrial , Medição de Risco/métodos , Acidente Vascular Cerebral , Idoso , Aminopeptidases/genética , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/genética , Caveolina 1/genética , Estudos de Coortes , Eletrocardiografia Ambulatorial/métodos , Feminino , Testes Genéticos/métodos , Proteínas de Homeodomínio/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Fatores de Tempo , Fatores de Transcrição/genética , Proteína Homeobox PITX2RESUMO
This article critically appraises the ethical and legal duties to disclose findings to the family members of research participants. These family members stand to benefit in important ways from discoveries that can inform their own health and reproductive risks. However, careful appreciation of how medical research differs from clinical practice and of the uncertainties at stake in genomic research complicates any warning to relatives. Research laboratories should generally be immune from liability for failing to diagnose or disclose a genetic disorder in time to prevent adverse outcomes for a participant's family members or to return properly interpreted test results for even direct findings under investigation, let alone incidental ones. The only exception is where warning relatives of medical risks is very likely to prevent imminent harm and would not override known participant wishes. Genomic autopsy studies for sudden death satisfy these conditions of life-saving potential for relatives without disrespect to subjects. These are among the rare instances in which we conclude that offering results to family members is not just permissible but obligatory, not just as a moral matter but as a legal one.
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Revelação/legislação & jurisprudência , Relações Profissional-Família , Sujeitos da Pesquisa/legislação & jurisprudência , Família , Pesquisa em Genética/legislação & jurisprudência , Testes Genéticos , Humanos , Estados UnidosRESUMO
Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.
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Proteínas de Ciclo Celular/genética , Doenças Cerebelares/genética , Anormalidades do Olho/genética , Deleção de Genes , Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Retina/anormalidades , Anormalidades Múltiplas , Encéfalo/patologia , Proteínas de Ciclo Celular/metabolismo , Centrossomo/metabolismo , Cerebelo/anormalidades , Cílios/genética , Cílios/patologia , Estudos de Coortes , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Proteínas Associadas aos Microtúbulos/metabolismo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
PURPOSE: Nail-Patella syndrome is a dominantly inherited genetic disorder characterized by abnormalities of the nails, knees, elbows, and pelvis. Nail abnormalities are the most constant feature of Nail-Patella syndrome. Pathogenic mutations in a single gene, LMX1B, a mesenchymal determinant of dorsal-ventral patterning, explain approximately 95% of Nail-Patella syndrome cases. However, 5% of cases remain unexplained. METHODS: Here, we present exome sequencing and analysis of four generations of a family with a dominantly inherited Nail-Patella-like disorder (nail dysplasia with some features of Nail-Patella syndrome) who tested negative for LMX1B mutation. RESULTS: We identify a loss-of-function mutation in WIF1 (NM_007191 p.W15*), which is involved in mesoderm segmentation, as the suspected cause of the Nail-Patella-like disorder observed in this family. CONCLUSIONS: Mutation of WIF1 is a potential novel cause of a Nail-Patella-like disorder. Testing of additional patients negative for LMX1B mutation is needed to confirm this finding and further clarify the phenotype.Genet Med advance online publication 06 April 2017.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Síndrome da Unha-Patela/genética , Proteínas Repressoras/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Idoso , Feminino , Humanos , Rim/metabolismo , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Masculino , Mutação , Síndrome da Unha-Patela/metabolismo , Patela , Linhagem , Fenótipo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The corpus callosum is the principal cerebral commissure connecting the right and left hemispheres. The development of the corpus callosum is under tight genetic control, as demonstrated by abnormalities in its development in more than 1,000 genetic syndromes. We recruited more than 25 families in which members affected with corpus callosum hypoplasia (CCH) lacked syndromic features and had consanguineous parents, suggesting recessive causes. Exome sequence analysis identified C12orf57 mutations at the initiator methionine codon in four different families. C12orf57 is ubiquitously expressed and encodes a poorly annotated 126 amino acid protein of unknown function. This protein is without significant paralogs but has been tightly conserved across evolution. Our data suggest that this conserved gene is required for development of the human corpus callosum.
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Agenesia do Corpo Caloso/genética , Corpo Caloso/metabolismo , Exoma , Mutação , Sequência de Aminoácidos , Córtex Cerebral/metabolismo , Códon/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Metionina/genética , Dados de Sequência Molecular , Análise de Sequência de DNA/métodosRESUMO
Microcephaly-capillary malformation syndrome (MIC-CAP syndrome) is a newly recognized autosomal recessive congenital neurocutaneous central nervous system disorder characterized by severe microcephaly, early-onset seizures, profound psychomotor disability, and multiple cutaneous capillary lesions. In addition, affected patients have variable dysmorphic facial features and hypoplastic distal phalanges. It is distinctively caused by mutations in a newly characterized gene, STAMBP, encoding the deubiquitinating (DUB) isopeptidase that has a key role in cell surface receptor-mediated endocytosis and sorting. Herein, we describe an Arab family of two siblings with classic features of MIC-CAP syndrome that harbor a novel predicted splice mutation in STAMBP, which additionally display previously unreported findings of congenital hypothyroidism and alopecia areata.
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Anormalidades Múltiplas/diagnóstico , Capilares/anormalidades , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Microcefalia/diagnóstico , Ubiquitina Tiolesterase/genética , Malformações Vasculares/diagnóstico , Anormalidades Múltiplas/genética , Árabes , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Masculino , Microcefalia/genética , Mutação Puntual , SíndromeAssuntos
DNA/genética , Triagem e Testes Direto ao Consumidor , Testes Genéticos/métodos , Adulto , Criança , Humanos , Marketing , PropriedadeRESUMO
Nurses and other emergency department (ED) staff often experience verbal and physical abuse as part of their everyday work. Body-worn cameras are one tool that ED staff can use to try to reduce workplace violence and abuse and have been shown to be effective in other healthcare environments, such as mental health units. This article describes a pilot service evaluation which used a survey to assess the effectiveness of using body-worn cameras for staff in the author's ED. Findings suggest that nurses believed the cameras provided support when they were confronted by abusive or aggressive patients or relatives and in some instances diffused potentially violent situations.
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Introduction Group B streptococcus (GBS) is the leading cause of bacterial sepsis and meningitis in neonates worldwide, but brain abscess secondary to GBS is extremely rare. While temporal brain abscesses have been described as a sequelae of otogenic infections in children and adults, such a presentation has not been described in neonates. Case Description An 8-day-old female infant presented with a fever and irritability along with bilateral purulent otorrhea. Maternal GBS screening was negative, but the delivery was complicated by chorioamnionitis. Workup revealed neutrophilic pleocytosis in the cerebrospinal fluid and culture of the ear drainage was positive for GBS. Magnetic resonance imaging showed a circular lesion with rim enhancement within the left temporal lobe concerning for an abscess. The infant was treated with 14 days of intravenous vancomycin, cefepime, and metronidazole followed by 10 weeks of intravenous ampicillin. The hospital course was complicated by seizures and obstructive hydrocephalus requiring multiple neurosurgical interventions. Conclusion Brain abscess can occur as a sequela of GBS meningitis in neonates, but they are rare. Otogenic infections require prompt evaluation and treatment as they can progress to serious central nervous infections in neonates.
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AIM: Sex-differences in heart failure with preserved ejection fraction (HFpEF) are important, but key mechanisms involved are incompletely understood. While animal models can inform about sex-dependent cellular and molecular changes, many previous preclinical HFpEF models have failed to recapitulate sex-dependent characteristics of human HFpEF. We tested for sex-differences in HFpEF using a two-hit mouse model (leptin receptor-deficient db/db mice plus aldosterone infusion for 4 weeks; db/db+Aldo). METHODS AND RESULTS: We performed echocardiography, electrophysiology, intracellular Ca2+ imaging, and protein analysis. Female HFpEF mice exhibited more severe diastolic dysfunction in line with increased titin N2B isoform expression and PEVK element phosphorylation, and reduced troponin-I phosphorylation. Female HFpEF mice had lower BNP levels than males despite similar comorbidity burden (obesity, diabetes) and cardiac hypertrophy in both sexes. Male HFpEF mice were more susceptible to cardiac alternans. Male HFpEF cardiomyocytes (versus female) exhibited higher diastolic [Ca2+], slower Ca2+ transient decay, reduced L-type Ca2+ current, more pronounced enhancement of the late Na+ current, and increased short-term variability of action potential duration (APD). However, male and female HFpEF myocytes showed similar downregulation of inward rectifier and transient outward K+ currents, APD prolongation, and frequency of delayed afterdepolarizations. Inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) reversed all pathological APD changes in HFpEF in both sexes, and empagliflozin pretreatment mimicked these effects of CaMKII inhibition. Vericiguat had only slight benefits, and these effects were larger in HFpEF females. CONCLUSION: We conclude that the db/db+Aldo preclinical HFpEF murine model recapitulates key sex-specific mechanisms in HFpEF and provides mechanistic insights into impaired excitation-contraction coupling and sex-dependent differential arrhythmia susceptibility in HFpEF with potential therapeutic implications. In male HFpEF myocytes, altered Ca2+ handling and electrophysiology aligned with diastolic dysfunction and arrhythmias, while worse diastolic dysfunction in females may depend more on altered myofilaments properties.
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OBJECTIVES: Provision of personalised care planning is a national priority for people with dementia. Research suggests a lack of quality and consistency of care plans and reviews. The PriDem model of care was developed to deliver feasible and acceptable primary care-based postdiagnostic dementia care. We aimed to increase the adoption of personalised care planning for people with dementia, exploring implementation facilitators and barriers. DESIGN: Mixed-method feasibility and implementation study. SETTING: Seven general practices from four primary care networks (PCNs) in the Northeast and Southeast of England. PARTICIPANTS: A medical records audit collected data on 179 community-dwelling people with dementia preintervention, and 215 during the intervention year. The qualitative study recruited 26 health and social care professionals, 14 people with dementia and 16 carers linked to participating practices. INTERVENTION: Clinical dementia leads (CDL) delivered a 12-month, systems-level intervention in participating PCNs, to develop care systems, build staff capacity and capability, and deliver tailored care and support to people with dementia and their carers. PRIMARY AND SECONDARY OUTCOME MEASURES: Adoption of personalised care planning was assessed through a preintervention and postintervention audit of medical records. Implementation barriers and facilitators were explored through semistructured qualitative interviews and non-participant observation, analysed using codebook thematic analysis informed by Normalisation Process Theory. RESULTS: The proportion of personalised care plans increased from 37.4% (95% CI 30.3% to 44.5%) preintervention to 64.7% (95% CI 58.3% to 71.0%) in the intervention year. Qualitative findings suggest that the flexible nature of the PriDem intervention enabled staff to overcome contextual barriers through harnessing the skills of the wider multidisciplinary team, delivering increasingly holistic care to patients. CONCLUSIONS: Meaningful personalised care planning can be achieved through a team-based approach. Although improved guidelines for care planning are required, commissioners should consider the benefits of a CDL-led approach. TRIAL REGISTRATION NUMBER: ISRCTN11677384.
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Demência , Estudos de Viabilidade , Planejamento de Assistência ao Paciente , Atenção Primária à Saúde , Pesquisa Qualitativa , Humanos , Demência/terapia , Atenção Primária à Saúde/organização & administração , Inglaterra , Masculino , Feminino , Planejamento de Assistência ao Paciente/organização & administração , Idoso , Cuidadores , Medicina de Precisão/métodos , Idoso de 80 Anos ou mais , Acessibilidade aos Serviços de Saúde/organização & administração , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: To evaluate the feasibility and acceptability of a primary care-based intervention for improving post-diagnostic dementia care and support (PriDem), and implementation study procedures. DESIGN: A non-randomised, mixed methods, feasibility study. SETTING: Seven general practices from four primary care networks (PCNs) in the Northeast and Southeast of England. PARTICIPANTS: We aimed to recruit 80 people with dementia (PWD) and 66 carers INTERVENTION: Clinical Dementia Leads delivered a 12-month intervention in participating PCNs, to develop care systems, build staff capacity and capability, and deliver tailored care and support to PWD and carers. OUTCOMES: Recruitment and retention rates were measured. A mixed methods process evaluation evaluated feasibility and acceptability of the intervention and study procedures. Using electronic care records, researchers extracted service use data and undertook a dementia care plan audit, preintervention and postintervention, assessing feasibility of measuring the primary implementation outcome: adoption of personalised care planning by participating general practices. Participants completed quality of life, and service use measures at baseline, 4 and 9 months. RESULTS: 60 PWD (75% of recruitment target) and 51 carers (77% of recruitment target) were recruited from seven general practices across four PCNs. Retention rate at 9 months was 70.0% of PWD and 76.5% of carers. The recruitment approach showed potential for including under-represented groups within dementia. Despite implementation challenges, the intervention was feasible and acceptable, and showed early signs of sustainability. Study procedures were feasible and accessible, although researcher capacity was crucial. Participants needed time and support to engage with the study. Care plan audit procedures were feasible and acceptable. CONCLUSIONS: The PriDem model is an acceptable and feasible intervention. A definitive study is warranted to fully inform dementia care policy and personalised dementia care planning guidance. Successful strategies to support inclusion of PWD and their carers in future research were developed. TRIAL REGISTRATION NUMBER: ISRCTN11677384.
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Cuidadores , Demência , Estudos de Viabilidade , Atenção Primária à Saúde , Humanos , Demência/diagnóstico , Demência/terapia , Feminino , Idoso , Masculino , Inglaterra , Idoso de 80 Anos ou mais , Qualidade de Vida , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Care is often inadequate and poorly integrated after a dementia diagnosis. Research and policy highlight the unaffordability and unsustainability of specialist-led support, and instead suggest a task-shared model, led by primary care. This study is part of the PriDem primary care led postdiagnostic dementia care research programme and will assess delivery of an evidence-informed, primary care based, person-centred intervention. The intervention involves Clinical Dementia Leads (CDLs) working in primary care to develop effective dementia care systems that build workforce capacity and support teams to deliver tailored support to people living with dementia and their carers. METHODS AND ANALYSIS: This is a 15-month mixed-methods feasibility and implementation study, situated in four National Health Service (NHS) primary care networks in England. The primary outcome is adoption of personalised care planning by participating general practices, assessed through a patient records audit. Feasibility outcomes include recruitment and retention; appropriateness and acceptability of outcome measures; acceptability, feasibility and fidelity of intervention components. People living with dementia (n=80) and carers (n=66) will be recruited through participating general practices and will complete standardised measures of health and well-being. Participant service use data will be extracted from electronic medical records. A process evaluation will explore implementation barriers and facilitators through methods including semistructured interviews with people living with dementia, carers and professionals; observation of CDL engagement with practice staff; and a practice fidelity log. Process evaluation data will be analysed qualitatively using codebook thematic analysis, and quantitatively using descriptive statistics. Economic analysis will determine intervention cost-effectiveness. ETHICS AND DISSEMINATION: The study has received favourable ethical opinion from Wales REC4. NHS Confidentiality Advisory Group support allows researchers preconsent access to patient data. Results will inform intervention adaptations and a future large-scale evaluation. Dissemination through peer-review journals, engagement with policy-makers and conferences will inform recommendations for dementia services commissioning. TRIAL REGISTRATION NUMBER: ISRCTN11677384.
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Demência , Medicina Estatal , Humanos , Estudos de Viabilidade , Aclimatação , Atenção Primária à Saúde , Demência/diagnóstico , Demência/terapiaRESUMO
Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor-deficient db/db mice with a 4-week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium-glucose cotransporter-2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B-type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short-term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone-treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.