Giovanna Pelà

Background: Identifying and addressing long-term health and societal challenges after COVID-19 is a research priority. Objectives: To create an international, multidisciplinary COVID-19 database, and synthesise long-term outcomes, predictors and costs. Design: Systematic identification of COVID-19 data sets and meta-analysis of individual participant data on long-term outcomes after COVID-19. Setting: Contributed data were collected in clinical, community and research settings. Interventions: Interventions from original studies were included as covariates in models. Data sources: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Web of Science, PsycInfo ^® (American Psychological Association, Washington, DC, USA), Cumulative Index to Nursing and Allied Health Literature, World Health Organization Global Index Medicus, Epistemonikos, LitCOVID; World Health Organization International Clinical Trials Registry Platform; ClinicalTrials.gov and supplementary searches for studies (November 2019–November 2021) were searched for studies on > 10 people from cohort, case-control, survey or randomised controlled trial studies, across any setting, describing validated assessment instruments, symptoms, hospitalisation, discharge destination or mortality beyond 28-days after COVID-19 onset. Data were extracted by two independent reviewers. Methods: Principal investigators contributed fully anonymised individual participant data. Demography, equity and symptoms were described. Assessment instruments were mapped to the International Classification of Functioning, Disability and Health. Factors associated with outcomes at 3–6 months, 9–12 months and beyond 12 months of index infection, for n > 500 individual participant data and > 1 data set were described using ratio of difference, point estimates, odds ratio and 95% confidence interval, as appropriate. The Mixed Methods Appraisal Tool described study quality; models were appraised using a Grading of Recommendations Assessment, Development and Evaluation-informed approach; heterogeneity was described using I ² . Outcome measures: Included overall perception of health, multidomain cognitive function, anxiety, depression, stress, post-traumatic stress disorder, fatigue, strength, walking ability, mobility, coping with daily life, breathlessness, mortality, later hospitalisation and health-related quality of life. Results: PRECIOUS collated 116 data sets from 40 countries (individual participant data = 62,849), comprising 20 randomised controlled trials, 13 case-control, 60 cohort 2 longitudinal, 1 survey and 20 other study types. Participants’ median age was 58 years interquartile range (45–68); 34,185 (54.4%) were female; 158 unique symptoms and 137 unique assessment instruments were captured, predominantly describing International Classification of Function, Disability and Health-body functions. Women had poorer outcomes across 30/37 models, compared with men. In 15/37 models, pre-existing lung disease and increasing age were associated with poorer outcomes; hospitalisation, diabetes and chronic kidney disease were each associated with poorer outcomes in 8/37 models. Initial hospitalisation resulted in lower health-related quality of life that did not recover for up to 2 years after initial infection. Heterogeneity was low in 34/37 models; 22/37 models were of moderate and 11/37 were of low quality. Limitations: Use of secondary data limits available covariates, outcomes and time points to those included in primary data sets; evidence was primarily based on high-income countries. There was a lack of data on longer-term healthcare resource use to estimate the costs to the healthcare system. Conclusions: PRECIOUS contributes to the overall picture of long-term COVID-19 outcomes beyond the long-COVID condition and highlights poorer long-term outcomes in women and people with pre-existing comorbidities. Future work: Evidence gaps included healthcare resource use, isolation, loneliness, societal participation and return to work outcomes. Data are needed on the role of health inequity on long-term outcomes. Study registration: This study is registered as PROSPERO (CRD42020224323, IRAS ID: 293578). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR132895) and is published in full in Health and Social Care Delivery Research ; Vol. 14, No. 29. See the NIHR Funding and Awards website for further award information.

Background: Frail, sarcopenic older individuals have high risk of cardiovascular events and require multidomain interventions. The cross-talk between cardiac and skeletal muscle mass is crucial to maintain physical independence in this specific population. The aim of the study was to evaluate, in a selected sample of frail, sarcopenic older adults, the influence of a two-year multimodal intervention, composed by exercise program and nutritional counseling, compared to a lifestyle education program, on echocardiographic parameters and the relationship between left ventricular mass and skeletal muscle. Methods: One-hundred subjects, among those enrolled in the SPRINTT trial at Frailty Clinic of the University-Hospital of Parma, underwent cardiac examination as part of the ancillary protocol CARDIOSPRINTT. Eighty-two participants completed the protocol and attended the final visit after approximately 25 months from enrolment. Results: We did not find significant changes in the intervention group compared with the control one. However, we captured the longitudinal effects of cardiovascular aging, including the reduction of left ventricular volumes and an impairment of systolic and diastolic function of both ventricles. We found a significant relationship between left ventricular mass and skeletal muscle mass, suggesting the existence of cardiac-skeletal muscle axis. This relationship was not independent of age, body mass index or systolic blood pressure. Conclusions: Our findings suggest that among frail, sarcopenic patients with different degree of mobility impairment, a multimodal intervention is necessary to improve cardiac health and counteract the cardiovascular aging. Modulating the cardiac-skeletal muscle axis may represent a novel and promising target for preventing cardio-sarcopenia.

Aged heart is more prone to develop cardiovascular diseases including arrhythmias. The age-related electrical remodeling of the heart results in specific electrophysiological alterations in male and female rats. Males could experience more challenging adaptations as they age. They show prolongations of atrial and ventricular activation, ventricular repolarization, and refractoriness. Aged females display alterations in ventricular activation. Arrhythmias are more likely to occur in aged animals with males being more susceptible to spontaneous and induced arrhythmias.

Purpose Frail and sarcopenic older individuals are high-risk population of cardiovascular events requiring multidomain intervention. The cross-talk between cardiac and skeletal muscle mass is crucial to maintain physical independence in this specific population. The aim of the study was to evaluate, in a selected sample of frail and sarcopenic older adults, the influence of two-year exercise program and nutritional counseling (MCI group) compared to lifestyle education (HALE group) on echocardiographic parameters and on the relationship between cardiac and skeletal muscle mass. Methods One-hundred subjects, among those enrolled in the SPRINTT trial at Frailty Clinic of University-Hospital of Parma site, underwent cardiological examination as part of the ancillary protocol (CARDIOSPRINTT). 82 participants (46 MCI and 36 HALE) completed the protocol and attended the final visit after approximately 25 months. Results We did not find not significant changes in the intervention group compared with HALE group. However, we captured the longitudinal effects of CV aging, including the reduction of left ventricular volume and an impairment of systolic and diastolic function of both ventricles. We found, as in the baseline, a significant relationship between LVM and SMM (r=0.571, p<0.001) suggesting the existence of cardiac muscle-skeletal muscle axis. This relationship was not independent of age, BMI or systolic blood pressure. ConclusionOur findings suggest that among frail patients with different degree of mobility impairment a personalized exercise protocol is necessary to improve cardiac health and counteract the cardiovascular aging. The modulation of cardiac-muscle axis, is an intriguing target for preventing or delaying the cardio-sarcopenia.

Background: There is no gold standard in diagnosing SAD. Indicators of SAD are considered: (a) a value 0.07 kPa·s·L−1 (R5-R20+). Aim and Objectives: The aim of the study was to ascertain, in asthmatic patients, whether spirometry and IOS indicators agree in detecting SAD. We also assessed the relationship between spirometry and IOS indicators and clinical features of asthma. Methods: We prospectively recruited adult asthmatic patients. Anthropometric and clinical characteristics were recorded. All patients performed spirometry and IOS tests. Results: We enrolled 301 asthmatic patients (179 females; mean age 50 ± 16 years) with normal to moderately severe degree of airway obstruction; 91% were non-smokers, 74% were atopic, 28% had an exacerbation in the previous year, and 18% had a poor asthma control by ACT. SAD was diagnosed in 62% of patients through FEF+, in 40% through FEV3/FEV6+ and in 41% through R5-R20+. κ values were 0.49 between FEF+ and FEV3/FEV6+, 0.20 between FEF+ and R5-R20+, 0.07 between FEV3/FEV6+ and R5-R20+. R5-R20+ but not FEF+ and FEV3/FEV6+ was significantly associated with ACT score (p < 0.05). Conclusions: Our study shows that in mild to moderately severe asthmatic patients, spirometry and IOS indicators are complementary in diagnosing SAD. Additionally, IOS indicator, but not spirometry ones, was related to asthma control.

The effects of excitability, refractoriness, and impulse conduction have been independently related to enhanced arrhythmias in the aged myocardium in experimental and clinical studies. However, their combined arrhythmic effects in the elderly are not yet completely understood. Hence, the aim of the present work is to relate relevant cardiac electrophysiological parameters to enhanced arrhythmia vulnerability in the in vivo senescent heart. We used multiple-lead epicardial potential mapping in control (9-month-old) and aged (24-month-old) rat hearts. Cardiac excitability and refractoriness were evaluated at numerous epicardial test sites by means of the strength-duration curve and effective refractory period, respectively. During sinus rhythm, durations of electrogram intervals and waves were prolonged in the senescent heart, compared with control, demonstrating a latency in tissue activation and recovery. During ventricular pacing, cardiac excitability, effective refractory period, and dispersion of refractoriness increased in the aged animal. This scenario was accompanied by impairment of impulse propagation. Moreover, both spontaneous and induced arrhythmias were increased in senescent cardiac tissue. Histopathological evaluation of aged heart specimens revealed connective tissue deposition and perinuclear myocytolysis in the atria, while scattered microfoci of interstitial fibrosis were mostly present in the ventricular subendocardium. This work suggests that enhanced arrhythmogenesis in the elderly is a multifactorial process due to the joint increase in excitability and dispersion of refractoriness in association with enhanced conduction inhomogeneity. The knowledge of these electrophysiological changes will possibly contribute to improved prevention of the age-associated increase in cardiac arrhythmias.

Background: Long-term sequelae, called Long-COVID (LC), may occur after SARS-CoV-2 infection, with unexplained dyspnoea as the most common symptom. The breathing pattern (BP) analysis, by means of the ratio of the inspiratory time (T_I) during the tidal volume (V_T) to the total breath duration (T_I/T_TOT) and by the V_T/T_I ratio, could further elucidate the underlying mechanisms of the unexplained dyspnoea in LC patients. Therefore, we analysed T_I/T_TOT and V_T/T_I at rest and during maximal exercise in LC patients with unexplained dyspnoea, compared to a control group. Methods: In this cross-sectional study, we enrolled LC patients with normal spirometry, who were required to perform a cardio-pulmonary exercise test (CPET) for unexplained dyspnoea, lasting at least 3 months after SARS-CoV-2 infection. As a control group, we recruited healthy age and sex-matched subjects (HS). All subjects performed spirometry and CPET, according to standardized procedures. Results: We found that 42 LC patients (23 females) had lower maximal exercise capacity, both in terms of maximal O₂ uptake (VO₂peak) and workload, compared to 40 HS (22 females) (p < 0.05). LC patients also showed significantly higher values of T_I/T_TOT at rest and at peak, and lower values in V_T/T_I at peak (p < 0.05). In LC patients, values of T_I/T_TOT at peak were significantly related to ∆PETCO₂, i.e., the end-tidal pressure of CO₂ at peak minus the one at rest (p < 0.05). When LC patients were categorized by the T_I/T_TOT 0.38 cut-off value, patients with T_I/T_TOT > 0.38 showed lower values in VO₂peak and maximal workload, and greater values in the ventilation/CO₂ linear relationship slope than patients with T_I/T_TOT ≤ 0.38 (p < 0.05). Conclusions: Our findings show that LC patients with unexplained dyspnoea have resting and exertional BP more prone to diaphragmatic fatigue, and less effective than controls. Pulmonary rehabilitation might be useful to revert this unpleasant condition.