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2.
JAMA Intern Med ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515737

RESUMO

Importance: Guidelines recommend early specialty palliative care for all patients with advanced cancer, but most patients lack access to such services. Objective: To assess the effect of CONNECT (Care Management by Oncology Nurses to Address Supportive Care Needs), a primary palliative care intervention delivered by oncology nurses, on patient outcomes. Design, Setting, and Participants: This cluster randomized clinical trial of the CONNECT intervention vs standard care was conducted from July 25, 2016, to October 6, 2020. Participants were adult patients with metastatic solid tumors who were undergoing oncological care and for whom an oncologist would agree with the statement "would not be surprised if the patient died in the next year." The trial was conducted at 17 community oncology practices in western Pennsylvania. Data analyses adhered to the intention-to-treat principle. Interventions: The CONNECT intervention included 3 monthly visits with an existing infusion room nurse who was trained to address symptoms, provide emotional support, engage in advance care planning, and coordinate care. Main Outcomes and Measures: The primary outcome was quality of life. At baseline and 3 months, participants completed assessments of quality of life (Functional Assessment of Chronic Illness Therapy-Palliative care: score range, 0-184, with higher scores indicating better quality of life), symptom burden (Edmonton Symptom Assessment Scale: score range, 0-90, with higher scores indicating greater symptom burden), and mood symptoms (Hospital Anxiety and Depression Scale [HADS]: score range, 0-21, with higher scores indicating substantial anxiety and depression). Linear mixed-effects models were used to estimate adjusted mean differences in 3-month outcomes. Preplanned, intensity-adjusted analyses were conducted. Results: A total of 672 patients were enrolled (mean [SD] age, 69.3 [10.2] years; 360 women [53.6%]). The mean (SD) number of CONNECT visits completed was 2.2 (1.0). At 3 months, no difference in mean (SD) quality-of-life score was found between the CONNECT and standard care groups (130.7 [28.2] vs 134.1 [28.1]; adjusted mean difference, 1.20; 95% CI, -2.75 to 5.15; P = .55). Similarly, there was no difference between groups in 3-month mean (SD) symptom burden (23.2 [16.6] vs 24.0 [16.1]; adjusted mean difference, -2.64; 95% CI, -5.85 to 0.58; P = .11) or mood symptoms (HADS depression subscale score: 5.1 [3.4] vs 4.8 [3.7], adjusted mean difference, -0.08 [95% CI, -0.71 to 0.57], P = .82; HADS anxiety subscale score: 5.7 [3.9] vs 5.4 [4.2], adjusted mean difference, -0.31 [95% CI, -0.96 to 0.33], P = .34). Intensity-adjusted analyses revealed a larger estimated treatment effect for patients who received a full dose (3 visits) of the CONNECT intervention. Conclusions and Relevance: This cluster randomized clinical trial found that a primary palliative care intervention that was delivered by oncology nurses did not improve patient-reported outcomes at 3 months. Primary palliative care interventions with a higher dose intensity may be beneficial for most patients with advanced cancer who lack access to palliative care specialists. Trial Registration: ClinicalTrials.gov Identifier: NCT02712229.

3.
Clin Drug Investig ; 41(10): 885-894, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34480725

RESUMO

BACKGROUND AND OBJECTIVE: Methicillin-resistant Staphylococcus aureus bloodstream infections (MRSAB) cause significant mortality, and often require extended antibiotic therapy. Vancomycin, the most common initial MRSAB treatment, carries significant monitoring burden and nephrotoxicity risks. Our objective was to compare the cost-effectiveness of vancomycin and other antibiotic regimens against MRSAB. METHODS: We estimated the cost-effectiveness of intravenous antibiotics (vancomycin, daptomycin, linezolid, ceftaroline/daptomycin) for Veterans Health Administration patients with MRSAB using an exploratory decision-tree model. Primary effectiveness outcome was composite of microbiological failure at 7 days and adverse drug event (ADE)-related discontinuation after at least 7 days. RESULTS: In base-case analyses, intravenous linezolid was the least expensive regimen at 4 and 6 weeks. Daptomycin was more expensive and more effective than linezolid, with an incremental cost-effectiveness ratio (ICER) of ~$13,000 (4 weeks) per composite failure avoided. With 6 weeks of treatment, daptomycin was more expensive and more effective than vancomycin (ICER ~$21,000 per composite failure avoided). Vancomycin and ceftaroline/daptomycin were dominated strategies at both 4 and 6 weeks. In one-way sensitivity analyses, vancomycin was favored when its microbiological failure risk was less than 20.1% (base-case: 27.2%), assuming a willingness to pay (WTP) threshold of $40,000/composite treatment failure avoided. In two-way sensitivity analyses, intravenous linezolid was favored if linezolid microbiological failure and ADE-related discontinuation rates were < 22.5% and < 17.3%, respectively. Daptomycin, vancomycin, and linezolid were favored in 50%, 31%, and 17% of 4-week probabilistic iterations, respectively, at $40,000 WTP. CONCLUSION: Daptomycin is likely less expensive and more effective than vancomycin or other initial regimens for MRSAB. More data are needed on the safety of linezolid against MRSAB.


Assuntos
Daptomicina , Staphylococcus aureus Resistente à Meticilina , Oxazolidinonas , Sepse , Infecções Estafilocócicas , Acetamidas/efeitos adversos , Antibacterianos/efeitos adversos , Análise Custo-Benefício , Humanos , Linezolida , Sepse/tratamento farmacológico , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/efeitos adversos
4.
J Comp Eff Res ; 10(15): 1133-1141, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34490786

RESUMO

Aim: Perform a cost-effectiveness analysis of addition of subcutaneous semaglutide versus empagliflozin to usual treatment for patients with Type 2 diabetes and cardiovascular disease in US setting. Materials & methods: A Markov decision model estimated the impact of each strategy using cardiovascular complication rates based on EMPA-REG and SUSTAIN-6 trials. Modeled cohorts were followed for 3 years at 1-month intervals beginning at age 66. Results: Compared with empagliflozin, semaglutide resulted in cost of US$19,964 per quality-adjusted life-year gained. In one-way sensitivity analysis, only semaglutide cost >US$36.25/day (base case US$18.04) resulted in empagliflozin being preferred at a willingness-to-pay threshold of US$50,000/quality-adjusted life-year gained. Conclusion: For patients with Type 2 diabetes and cardiovascular disease, semaglutide is likely more cost-effective than empagliflozin added to usual treatment.

5.
Geroscience ; 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34562202

RESUMO

Impairments in muscle microvascular function are associated with the pathogenesis of sarcopenia and cardiovascular disease. High-intensity interval training (HIIT) is an intervention by which a myriad of beneficial skeletal muscle/cardiovascular adaptations have been reported across age, including capillarisation and improved endothelial function. Herein, we hypothesised that HIIT would enhance muscle microvascular blood flow and vascular reactivity to acute contractile activity in older adults, reflecting HIIT-induced vascular remodelling. In a randomised controlled-trial, twenty-five healthy older adults aged 65-85 years (mean BMI 27.0) were randomised to 6-week HIIT or a no-intervention control period of an equal duration. Measures of microvascular responses to a single bout of muscle contractions (i.e. knee extensions) were made in the m. vastus lateralis using contrast-enhanced ultrasound during a continuous intravenous infusion of Sonovue™ contrast agent, before and after the intervention period, with concomitant assessments of cardiorespiratory fitness and resting blood pressure. HIIT led to improvements in anaerobic threshold (13.2 ± 3.4 vs. 15.3 ± 3.8 ml/kg/min, P < 0.001), dynamic exercise capacity (145 ± 60 vs. 159 ± 59 W, P < 0.001) and resting (systolic) blood pressure (142 ± 15 vs. 133 ± 11 mmHg, P < 0.01). Notably, HIIT elicited significant increases in microvascular blood flow responses to acute contractile activity (1.8 ± 0.63 vs. 2.3 ± 0.8 (arbitrary contrast units (AU), P < 0.01)), with no change in any of these parameters observed in the control group. Six weeks HIIT improves skeletal muscle microvascular responsiveness to acute contractile activity in the form of active hyperaemia-induced by a single bout of resistance exercise. These findings likely reflect reports of enhanced large vessel distensibility, improved endothelial function, and muscle capillarisation following HIIT. Moreover, our findings illustrate that HIIT may be effective in mitigating deleterious alterations in muscle microvascular mediated aspects of sarcopenia.

6.
FASEB J ; 35(9): e21830, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34342902

RESUMO

Muscle disuse leads to a rapid decline in muscle mass, with reduced muscle protein synthesis (MPS) considered the primary physiological mechanism. Here, we employed a systems biology approach to uncover molecular networks and key molecular candidates that quantitatively link to the degree of muscle atrophy and/or extent of decline in MPS during short-term disuse in humans. After consuming a bolus dose of deuterium oxide (D2 O; 3 mL.kg-1 ), eight healthy males (22 ± 2 years) underwent 4 days of unilateral lower-limb immobilization. Bilateral muscle biopsies were obtained post-intervention for RNA sequencing and D2 O-derived measurement of MPS, with thigh lean mass quantified using dual-energy X-ray absorptiometry. Application of weighted gene co-expression network analysis identified 15 distinct gene clusters ("modules") with an expression profile regulated by disuse and/or quantitatively connected to disuse-induced muscle mass or MPS changes. Module scans for candidate targets established an experimentally tractable set of candidate regulatory molecules (242 hub genes, 31 transcriptional regulators) associated with disuse-induced maladaptation, many themselves potently tied to disuse-induced reductions in muscle mass and/or MPS and, therefore, strong physiologically relevant candidates. Notably, we implicate a putative role for muscle protein breakdown-related molecular networks in impairing MPS during short-term disuse, and further establish DEPTOR (a potent mTOR inhibitor) as a critical mechanistic candidate of disuse driven MPS suppression in humans. Overall, these findings offer a strong benchmark for accelerating mechanistic understanding of short-term muscle disuse atrophy that may help expedite development of therapeutic interventions.


Assuntos
Proteínas Musculares/genética , Músculo Esquelético/fisiologia , Atrofia Muscular/genética , Doenças Musculares/genética , Biossíntese de Proteínas/genética , Transcriptoma/genética , Adulto , Humanos , Masculino , Força Muscular/genética , Adulto Jovem
7.
Front Immunol ; 12: 680334, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421895

RESUMO

Background: Inborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans. Objective: We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency. Methods: We assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells. Results: SOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients. Conclusions: SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients.

8.
J Surg Oncol ; 124(5): 801-809, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34231222

RESUMO

INTRODUCTION: Neoadjuvant therapy (NAT) is an emerging strategy for operable pancreatic ductal adenocarcinoma (PDAC). While NAT increases multimodal therapy completion, it risks functional decline and treatment dropout. We used decision analysis to determine optimal management of localized PDAC and consider risks faced by elderly patients. METHODS: A Markov cohort decision analysis model evaluated treatment options for a 60-year-old patient with resectable PDAC: (1) upfront pancreaticoduodenectomy or (2) NAT. One-way and probabilistic sensitivity analyses were performed. A subanalysis considered the scenario of a 75-year-old patient. RESULTS: For the base case, NAT offered an incremental survival gain of 4.6 months compared with SF (overall survival: 26.3 vs. 21.7 months). In one-way sensitivity analyses, findings were sensitive to recurrence-free survival for NAT patients undergoing adjuvant, probability of completing NAT, and probability of being resectable at exploration after NAT. On probabilistic analysis, NAT was favored in a majority of trials (97%) with a median survival benefit of 5.1 months. In altering the base case for the 75-year-old scenario, NAT had a survival benefit of 3.8 months. CONCLUSIONS: This analysis demonstrates a significant benefit to NAT in patients with localized PDAC. This benefit persists even in the elderly cohort.


Assuntos
Adenocarcinoma/terapia , Carcinoma Ductal Pancreático/terapia , Técnicas de Apoio para a Decisão , Cadeias de Markov , Terapia Neoadjuvante/mortalidade , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Terapia Combinada , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
9.
FASEB J ; 35(8): e21773, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34324735

RESUMO

Acute hypoxia has previously been suggested to potentiate resistance training-induced hypertrophy by activating satellite cell-dependent myogenesis rather than an improvement in protein balance in human. Here, we tested this hypothesis after a 4-week hypoxic vs normoxic resistance training protocol. For that purpose, 19 physically active male subjects were recruited to perform 6 sets of 10 repetitions of a one-leg knee extension exercise at 80% 1-RM 3 times/week for 4 weeks in normoxia (FiO2 : 0.21; n = 9) or in hypoxia (FiO2 : 0.135, n = 10). Blood and skeletal muscle samples were taken before and after the training period. Muscle fractional protein synthetic rate was measured over the whole period by deuterium incorporation into the protein pool and muscle thickness by ultrasound. At the end of the training protocol, the strength gain was higher in the hypoxic vs the normoxic group despite no changes in muscle thickness and in the fractional protein synthetic rate. Only early myogenesis, as assessed by higher MyoD and Myf5 mRNA levels, appeared to be enhanced by hypoxia compared to normoxia. No effects were found on myosin heavy chain expression, markers of oxidative metabolism and lactate transport in the skeletal muscle. Though the present study failed to unravel clearly the mechanisms by which hypoxic resistance training is particularly potent to increase muscle strength, it is important message to keep in mind that this training strategy could be effective for all athletes looking at developing and optimizing their maximal muscle strength.


Assuntos
Proteínas Musculares/metabolismo , Força Muscular/fisiologia , Músculo Esquelético/anatomia & histologia , Oxigênio/metabolismo , Treinamento de Força/métodos , Regulação da Expressão Gênica , Humanos , Masculino , Músculo Esquelético/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Satélites de Músculo Esquelético/fisiologia , Adulto Jovem
10.
Geroscience ; 43(4): 1567-1584, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34196903

RESUMO

Resistance exercise training (RET) is well-known to counteract negative age-related changes in both muscle and tendon tissue. Traditional RET consists of both concentric (CON) and eccentric (ECC) contractions; nevertheless, isolated ECC contractions are metabolically less demanding and, thus, may be more suitable for older populations. However, whether submaximal (60% 1RM) CON or ECC contractions differ in their effectiveness is relatively unknown. Further, whether the time course of muscle and tendon adaptations differs to the above is also unknown. Therefore, this study aimed to establish the time course of muscle and tendon adaptations to submaximal CON and ECC RET. Twenty healthy young (24.5 ± 5.1 years) and 17 older males (68.1 ± 2.4 years) were randomly allocated to either isolated CON or ECC RET which took place 3/week for 8 weeks. Tendon biomechanical properties, muscle architecture and maximal voluntary contraction were assessed every 2 weeks and quadriceps muscle volume every 4 weeks. Positive changes in tendon Young's modulus were observed after 4 weeks in all groups after which adaptations in young males plateaued but continued to increase in older males, suggesting a dampened rate of adaptation with age. However, both CON and ECC resulted in similar overall changes in tendon Young's modulus, in all groups. Muscle hypertrophy and strength increases were similar between CON and ECC in all groups. However, pennation angle increases were greater in CON, and fascicle length changes were greater in ECC. Notably, muscle and tendon adaptations appeared to occur in synergy, presumably to maintain the efficacy of the muscle-tendon unit.

12.
ChemMedChem ; 16(18): 2775-2780, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34096189

RESUMO

Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5-0.25) and minimum adjunctive concentration (MAC=128-32 µM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 µM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our "in house" permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram-negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram-negative antibacterials.

13.
Am J Prev Med ; 61(1): 28-36, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34148625

RESUMO

INTRODUCTION: Use of the 13-valent pneumococcal conjugate vaccine in nonimmunocompromised adults aged ≥65 years is controversial. Higher-valency conjugate vaccines (15-valent and 20-valent ) are under development; their potential cost effectiveness in older adults is unknown, particularly when potential indirect (herd immunity) effects from childhood vaccination are considered. METHODS: A Markov model estimated the cost effectiveness of current U.S. recommendations and alternative strategies using currently available and in-development pneumococcal conjugate vaccines in seniors. Separately, strategies using a hypothetical 20-valent vaccine adding the 7 most common disease-causing non-13-valent vaccine serotypes were considered. Sensitivity analyses were performed and alternative scenarios were examined. Data were gathered and the analyses were performed in 2020. RESULTS: In analyses considering only existing and in-development vaccines, sole 20-valent vaccine use cost $172,491/quality-adjusted life year gained compared with current U.S. recommendations under baseline assumptions (equal serotype effectiveness and no childhood vaccination indirect effects). Strategies using 15-valent vaccine were more costly and less effective. When 13-valent/20-valent vaccines were assumed ineffective against pneumococcal serotype 3 and 15-valent vaccine was fully effective, 15-valent vaccine cost $237,431/quality-adjusted life year gained. With indirect effects considered, 15-valent or 20-valent vaccine cost >$449,000/quality-adjusted life year gained. When adding hypothetical 20-valent vaccine under baseline assumptions, hypothetical 20-valent vaccine cost $139,348/quality-adjusted life year gained. CONCLUSIONS: In-development pneumococcal conjugate vaccines may be economically unreasonable in older adults, regardless of serotype effectiveness assumptions, particularly when considering potential indirect effects from use of those vaccines in children. Adult vaccines containing high-risk serotypes not contained in childhood vaccines may be more promising.


Assuntos
Infecções Pneumocócicas , Idoso , Criança , Análise Custo-Benefício , Humanos , Imunidade Coletiva , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Anos de Vida Ajustados por Qualidade de Vida , Vacinação , Vacinas Conjugadas
14.
Appl Physiol Nutr Metab ; 46(9): 1147-1151, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34181868

RESUMO

We explored the views of older (≥65 years) past and potential volunteers in regard to participating in physiology research during the COVID-19 pandemic. Using an online questionnaire and focus groups, we found that past volunteers (n = 55) were more likely to take part in both acute (p < 0.05) and chronic (p < 0.05) physiology studies, compared with potential future volunteers (n = 57). Both cohorts demonstrated a positive attitude towards volunteering during the COVID-19 pandemic, although concern was evident. Novelty: Volunteers demonstrated a positive attitude and also concern towards participating in physiology research during COVID-19.


Assuntos
Pesquisa Biomédica , COVID-19/epidemiologia , Pandemias , Fisiologia , Sujeitos da Pesquisa/psicologia , Voluntários/psicologia , Idoso , Atitude , Feminino , Grupos Focais , Humanos , Masculino , Motivação , SARS-CoV-2 , Inquéritos e Questionários
15.
Nature ; 596(7872): 417-422, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34192737

RESUMO

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.


Assuntos
Envelhecimento/imunologia , Vacinas contra COVID-19/imunologia , Imunidade , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Autoanticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Vacinas contra COVID-19/administração & dosagem , Feminino , Pessoal de Saúde , Humanos , Imunidade/genética , Imunização Secundária , Imunoglobulina A/imunologia , Switching de Imunoglobulina , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Memória Imunológica/imunologia , Inflamação/sangue , Inflamação/imunologia , Interferon gama/imunologia , Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Hipermutação Somática de Imunoglobulina , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Vacinação , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
16.
J Cachexia Sarcopenia Muscle ; 12(4): 866-879, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34060253

RESUMO

BACKGROUND: Declines in cardiorespiratory fitness (CRF) and fat-free mass (FFM) with age are linked to mortality, morbidity and poor quality of life. High-intensity interval training (HIIT) has been shown to improve CRF and FFM in many groups, but its efficacy in the very old, in whom comorbidities are present is undefined. We aimed to assess the efficacy of and physiological/metabolic responses to HIIT, in a cohort of octogenarians with comorbidities (e.g. hypertension and osteoarthritis). METHODS: Twenty-eight volunteers (18 men, 10 women, 81.2 ± 0.6 years, 27.1 ± 0.6 kg·m-2 ) with American Society of Anaesthesiology (ASA) Grade 2-3 status each completed 4 weeks (12 sessions) HIIT after a control period of equal duration. Before and after each 4 week period, subjects underwent body composition assessments and cardiopulmonary exercise testing. Quadriceps muscle biopsies (m. vastus lateralis) were taken to quantify anabolic signalling, mitochondrial oxidative phosphorylation, and cumulative muscle protein synthesis (MPS) over 4-weeks. RESULTS: In comorbid octogenarians, HIIT elicited improvements in CRF (anaerobic threshold: +1.2 ± 0.4 ml·kg-1 ·min-1 , P = 0.001). HIIT also augmented total FFM (47.2 ± 1.4 to 47.6 ± 1.3 kg, P = 0.04), while decreasing total fat mass (24.8 ± 1.3 to 24 ± 1.2 kg, P = 0.0002) and body fat percentage (33.1 ± 1.5 to 32.1 ± 1.4%, P = 0.0008). Mechanistically, mitochondrial oxidative phosphorylation capacity increased after HIIT (i.e. citrate synthase activity: 52.4 ± 4 to 67.9 ± 5.1 nmol·min-1 ·mg-1 , P = 0.005; membrane protein complexes (C): C-II, 1.4-fold increase, P = 0.002; C-III, 1.2-fold increase, P = 0.03), as did rates of MPS (1.3 ± 0.1 to 1.5 ± 0.1%·day-1 , P = 0.03). The increase in MPS was supported by up-regulated phosphorylation of anabolic signalling proteins (e.g. AKT, p70S6K, and 4E-BP1; all P < 0.05). There were no changes in any of these parameters during the control period. No adverse events were reported throughout the study. CONCLUSIONS: The HIIT enhances skeletal muscle mass and CRF in octogenarians with disease, with up-regulation of MPS and mitochondrial capacity likely underlying these improvements. HIIT can be safely delivered to octogenarians with disease and is an effective, time-efficient intervention to improve muscle mass and physical function in a short time frame.

17.
J Cachexia Sarcopenia Muscle ; 12(4): 973-982, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34060717

RESUMO

BACKGROUND: The assessment of muscle mass is a key determinant of the diagnosis of sarcopenia. We introduce for the first time an ultrasound imaging method for diagnosing sarcopenia based on changes in muscle geometric proportions. METHODS: Vastus lateralis muscle fascicle length (Lf) and thickness (Tm) were measured at 35% distal femur length by ultrasonography in a population of 279 individuals classified as moderately active elderly (MAE), sedentary elderly (SE) (n = 109), mobility impaired elderly (MIE) (n = 43), and in adult young controls (YC) (n = 60). The ratio of Lf/Tm was calculated to obtain an ultrasound index of the loss of muscle mass associated with sarcopenia (USI). In a subsample of elderly male individuals (n = 76) in which corresponding DXA measurements were available (MAE, n = 52 and SE, n = 24), DXA-derived skeletal muscle index (SMI, appendicular limb mass/height2 ) was compared with corresponding USI values. RESULTS: For both young and older participants, USI values were found to be independent of sex, height and body mass. USI values were 3.70 ± 0.52 for YC, 4.50 ± 0.72 for the MAE, 5.05 ± 1.11 for the SE and 6.31 ± 1.38 for the MIE, all significantly different between each other (P < 0.0001). Based on the USI Z-scores, with reference to the YC population, the 219 elderly participants were stratified according to their muscle sarcopenic status. Individuals with USI values within a range of 3.70 < USI ≥ 4.23 were classified as non-sarcopenic (prevalence 23.7%), those with USI values within 4.23 < USI ≥ 4.76 were classified as pre-sarcopenic (prevalence 23.7%), those with USI values within 4.76 < USI ≥ 5.29 were classified as moderately sarcopenic (prevalence 15.1%), those with USI values within range 5.29 < USI ≥ 5.82 were classified as sarcopenic (prevalence 27.9%), and those with USI values >5.82 were classified as severely sarcopenic (prevalence 9.6%). The DXA-derived SMI was found to be significantly correlated with USI (r = 0.61, P < 0.0001). Notably, the USI cut-off value for moderate sarcopenia (4.76 a.u.) was found to coincide with the DXA cut-off value of sarcopenia (7.26 kg/m2 ). CONCLUSIONS: We propose a novel, practical, and inexpensive imaging marker of the loss of muscle mass associated with sarcopenia, called the ultrasound sarcopenic index (USI), based on changes in muscle geometric proportions. These changes provide a useful 'signature of sarcopenia' and allow the stratification of individuals according to the presence and severity of muscle sarcopenia. We are convinced that the USI will be a useful clinical tool for confirming the diagnosis of sarcopenia, of which the assessment of muscle mass is a key-component.

18.
Vaccine ; 39(31): 4278-4282, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34167834

RESUMO

BACKGROUND: The COVID-19 pandemic is causing declines in childhood immunization rates. We examined potential COVID-19-related changes in pediatric 13-valent pneumococcal conjugate vaccine (PCV13) use, subsequent impact on childhood and adult pneumococcal disease rates, and how those changes might affect the favorability of PCV13 use in non-immunocompromised adults aged ≥65 years. METHODS: A Markov model estimated pediatric disease resulting from decreased PCV13 use in children aged <5 years; absolute decreases from 10 to 50% for 1-2 years duration were examined, assuming no catch-up vaccination and that decreased vaccination led to proportionate increases in PCV13 serotype pneumococcal disease in children and seniors. Integrating pediatric model output into a second Markov model examining 65-year-olds, we estimated the cost effectiveness of older adult pneumococcal vaccination strategies while accounting for potential epidemiologic changes from decreased pediatric vaccination. RESULTS: One year of 10-50% absolute decreases in PCV13 use in <5-year-olds increased pneumococcal disease by an estimated 4-19% in seniors; 2 years of decreased use increased senior rates by 8-38%. In seniors, a >53% increase in pneumococcal disease was required to favor PCV13 use in non-immunocompromised seniors at a $200,000 per quality-adjusted life-year gained threshold, which corresponded to absolute decreases in pediatric PCV13 vaccination of >50% over a 2-year period. In sensitivity analyses, senior PCV13 vaccination was unfavorable if absolute decreases in pediatric PCV13 receipt were within plausible ranges, despite model assumptions favoring PCV13 use in seniors. CONCLUSION: COVID-19-related decreases in pediatric PCV13 use would need to be both substantial and prolonged to make heightened PCV13 use in non-immunocompromised seniors economically favorable.


Assuntos
COVID-19 , Infecções Pneumocócicas , Idoso , Criança , Pré-Escolar , Análise Custo-Benefício , Humanos , Pandemias , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , SARS-CoV-2 , Vacinação , Vacinas Conjugadas
19.
Immunity ; 54(6): 1257-1275.e8, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051148

RESUMO

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Ativação Linfocitária/imunologia , SARS-CoV-2/imunologia , Biomarcadores , Linfócitos T CD8-Positivos/metabolismo , COVID-19/diagnóstico , COVID-19/genética , Citocinas/metabolismo , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Estudos Longitudinais , Ativação Linfocitária/genética , Fosforilação Oxidativa , Fenótipo , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Transcriptoma
20.
Geroscience ; 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34046811

RESUMO

Optimising approaches for measuring skeletal muscle mass and turnover that are widely applicable, minimally invasive and cost effective is crucial in furthering research into sarcopenia and cachexia. Traditional approaches for measurement of muscle protein turnover require infusion of expensive, sterile, isotopically labelled tracers which limits the applicability of these approaches in certain populations (e.g. clinical, frail elderly). To concurrently quantify skeletal muscle mass and muscle protein turnover i.e. muscle protein synthesis (MPS) and muscle protein breakdown (MPB), in elderly human volunteers using stable-isotope labelled tracers i.e. Methyl-[D3]-creatine (D3-Cr), deuterium oxide (D2O), and Methyl-[D3]-3-methylhistidine (D3-3MH), to measure muscle mass, MPS and MPB, respectively. We recruited 10 older males (71 ± 4 y, BMI: 25 ± 4 kg.m2, mean ± SD) into a 4-day study, with DXA and consumption of D2O and D3-Cr tracers on day 1. D3-3MH was consumed on day 3, 24 h prior to returning to the lab. From urine, saliva and blood samples, and a single muscle biopsy (vastus lateralis), we determined muscle mass, MPS and MPB. D3-Cr derived muscle mass was positively correlated to appendicular fat-free mass (AFFM) estimated by DXA (r = 0.69, P = 0.027). Rates of cumulative myofibrillar MPS over 3 days were 0.072%/h (95% CI, 0.064 to 0.081%/h). Whole-body MPB over 6 h was 0.052 (95% CI, 0.038 to 0.067). These rates were similar to previous literature. We demonstrate the potential for D3-Cr to be used alongside D2O and D3-3MH for concurrent measurement of muscle mass, MPS, and MPB using a minimally invasive design, applicable for clinical and frail populations.

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