Profiling Covid-19 patients with respect to level of severity: an integrated statistical approach.

A full understanding of the characteristics of Covid-19 patients with a better chance of experiencing poor vital outcomes is critical for implementing accurate and precise treatments. In this paper, two different advanced data-driven statistical approaches along with standard statistical methods have been implemented to identify groups of patients most at-risk for death or severity of respiratory distress. First, the tree-based analysis allowed to identify profiles of patients with different risk of in-hospital death (by Survival Tree-ST analysis) and severity of respiratory distress (by Classification and Regression Tree-CART analysis), and to unravel the role on risk stratification of highly dependent covariates (i.e., demographic characteristics, admission values and comorbidities). The ST analysis identified as the most at-risk group for in-hospital death the patients with age > 65 years, creatinine [Formula: see text] 1.2 mg/dL, CRP [Formula: see text] 25 mg/L and anti-hypertensive treatment. Based on the CART analysis, the subgroups most at-risk of severity of respiratory distress were defined by patients with creatinine level [Formula: see text] 1.2 mg/dL. Furthermore, to investigate the multivariate dependence structure among the demographic characteristics, the admission values, the comorbidities and the severity of respiratory distress, the Bayesian Network analysis was applied. This analysis confirmed the influence of creatinine and CRP on the severity of respiratory distress.

Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.

Physical and psychological sequelae at three months after acute illness in COVID-19 survivors.

BACKGROUND: Coronavirus disease 2019 (COVID-19) may leave behind an altered health status early after recovery. We evaluated the clinical status of COVID-19 survivors at three months after hospital discharge. METHODS: In this prospective observational cohort study, hospitalized patients aged ≥18 years, evaluated at one (M1) and three (M3) months post-discharge were enrolled. 251 patients (71.3% males, median [IQR] age 61.8 [53.5-70.7] years) were included. Median (IQR) time from discharge to M3 was 89 (79.5-101) days. Primary outcome was residual respiratory dysfunction (RRD), defined by tachypnea, moderate to very severe dyspnea, or peripheral oxygen saturation ≤95% on room air at M3. RESULTS: RRD was found in 30.4% of patients, with no significant difference compared with M1. Chronic obstructive pulmonary disease and length of stay were independent predictors of RRD at multivariable logistic regression (OR [95% CI]: 4.13 [1.17-16.88], P=0.033; OR [95% CI]: 1.02 [1.00-1.04], P=0.047, respectively). Obesity and C-reactive protein levels upon admission were additional predictors at regression tree analysis. Impaired quality of life (QoL) was reported by 53.2% of patients. Anxiety and insomnia were each present in 25.5% of patients, and PTSD in 22.4%. No difference was found between M1 and M3 in QoL, anxiety or PTSD. Insomnia decreased at M3. Current major psychiatric disorder as well as anxiety, insomnia and PSTD at M1 independently predicted PTSD at M3. CONCLUSIONS: Clinical damage may persist at three months after discharge in COVID-19 survivors. Post-recovery follow-up is an essential component of patient management.

Association between Perceived Health-Related Quality of Life and Depression with Frailty in the FRASNET Study.

Frailty is a major challenge facing the aging world. The phenotype of the frail subject is still far from being satisfactorily defined. We report data on mood, cognition, and quality of life (QoL) in relation to anamnestic factors, health, and socio-economic status in the FRASNET geriatric population (1204 subjects in stable health conditions), which is an observational cohort study that includes fairly balanced groups of Italian frail (421, 35%), pre-frail (449, 37.3%) and robust (334, 27.7%) subjects. A conditional inference tree analysis revealed a substantial influence of psychological variables on frailty. The physical indicator of QoL (Short Form Survey-36-Physical Component Summary, SF-36-PCS) was the predominant variable in the full model (threshold at 39.9, p < 0.001): higher frailty was found in subjects with a caregiver and lower SF-36-PCS. Frailty was also associated with the mental indicator of QoL (Short Form Survey-36-Mental Component Summary, SF-36-MCS), depression (Geriatric Depression Scale, GDS-15), leisure activities, and level of education. In support of the prominent role of inflammation in aging and mental illness, the SF-36-PCS score was correlated with the blood concentration of C-X-C motif chemokine ligand 10 (CXCL10) (r Pearson -0.355, p = 0.015), a critical signal in cell senescence and inflammaging, while the rs7567647 variant in FN1 gene encoding a glycoprotein in the extracellular matrix was significantly associated with frailty in a multivariable model (p = 0.0006). The perception of health-related QoL and subclinical depression contribute to frailty. Their assessment could improve the identification of older patients at increased risk of adverse outcomes.

α-Gal A missense variants associated with Fabry disease can lead to ER stress and induction of the unfolded protein response.

Anderson-Fabry Disease (FD) is an X-linked lysosomal disorder caused by mutations in GLA, the gene encoding the lysosomal hydrolase α-galactosidase A (α-Gal A), leading to accumulation of glycosphingolipids in the lysosomes. FD is a multisystemic disorder leading to progressive cardiovascular, cerebrovascular and kidney dysfunction. Phenotypes are divided in two main classes, classic or non-classic, depending on substrate accumulation, age at onset, disease manifestation, severity and progression. The more severe classical phenotype is generally associated with mutations leading to absent or strongly reduced α-Gal A activity, while mutations with higher residual activity generally lead to the non-classical one. Approximately 70% of the over 1,000 Fabry disease-associated mutations are missense mutations, some leading to endoplasmic reticulum (ER) retention of mutant protein. We hypothesized that such mutations could be associated, besides the well-known absence of α-Gal A function/activity, to a possible gain of function effect due to production of a misfolded protein. We hence expressed α-Gal A missense mutations in HEK293 GLA -/- cells and investigated the localization of mutant protein and induction of ER stress and of the unfolded protein response (UPR). We selected a panel of 7 missense mutations, including mutants shown to have residual or no activity in vitro. Immunofluorescence analysis showed that mutants with residual activity have decreased lysosomal localization compared with wild type, and partial retention in the ER, while missense mutants with no residual activity are fully retained in the ER. UPR (ATF6 branch) was significantly induced by all but two mutants, with clear correlation with the extent of ER retention and the predicted mutation structural effect. These data identify a new molecular pathway, associated with gain of function effect, possibly involved in pathogenesis of FD.

Inverse salt sensitivity: an independent risk factor for cardiovascular damage in essential hypertension.

OBJECTIVE: Salt sensitivity is a powerful risk factor for cardiovascular (CV) disease and mortality in both normotensive and hypertensive patients. We investigated the predictive value of the salt sensitivity phenotype in the development of CV events and hypertensive target organ damage (TOD) among essential hypertensive patients. METHODS: Eight hundred forty-four naive hypertensive patients were recruited and underwent an acute saline test during which blood pressure (BP) displayed either no substantial variation (salt-resistant, SR individuals), an increase (salt-sensitive, SS), or a paradoxical decrease (inverse salt-sensitive, ISS). Sixty-one patients with the longest monitored follow-up (median 16 years) for blood pressure and organ damage were selected for the present study. A clinical score for TOD development based on the severity and the age of onset was set up by considering hypertensive heart disease, cerebrovascular damage, microalbuminuria, and vascular events. RESULTS: CV events were significantly higher among SS and ISS than in SR patients. The relative risk of developing CV events was 12.67 times higher in SS than SR and 5.94 times higher in ISS than SR patients. The development of moderate to severe TOD was 10-fold higher in SS and over 15-fold higher in ISS than in SR patients. Among the three phenotypes, changes in plasma endogenous ouabain were linked with the blood pressure effects of saline. CONCLUSIONS: Salt sensitivity and inverse salt sensitivity appear to be equivalent risk factors for CV events. The response to an acute saline test is predictive of CV damage for newly identified ISS individuals.

[The FRASNET study: identification of clinical and social factors of renal failure in an elderly population].

Background. Chronic renal failure is an epidemic in elderly patients. Older population have an increased prevalence of frailty and sarcopenia, associated with a wide range of adverse health outcomes such as falls, hospitalization, disability. Aim. Describe the sociodemographic and clinical variables of an elderly Lombard population and identify predictors of renal insufficiency. Materials and methods. Cross-sectional observational study conducted in hospitals, in recreational centers for the elderly, in the Universities of the Third Age of the provinces of Milan and Monza-Brianza conducted through a convenience sampling of 1250 subjects over the age of 65. Results. The study identified living alone, annual individual income < € 10,000, polypharmacy, sarcopenia and frailty as predictors of chronic kidney failure. The sample has a mean eGFR of 71.74 mL/min/1.73m2 (SD ± 16.56). Older people living alone are more likely to develop CRI (P = 0.031, confidence interval, CI [1.031-1.905]) as well as having an income < € 10,000 (P = 0.002, CI [0.392-0.923]). Taking more than 11 drugs a day increases the probability of having chronic renal failure by 16 times (P = 0.012, CI [1.155-3.16]). Sarcopenia and frailty increase the likelihood of having chronic renal failure (CRI) (P = 0.001, CI [1.198-2.095]). Conclusions. Identifying predictors of chronic kidney failure is a key step in introducing preventive measures and providing better care to the elderly population.

Dissecting the Polygenic Basis of Primary Hypertension: Identification of Key Pathway-Specific Components.

INTRODUCTION AND OBJECTIVES: Genome-wide association studies have identified a high number of genetic loci associated with hypertension suggesting the presence of an underlying polygenic architecture. In this study, we aimed to dissect the polygenic component of primary hypertension searching also for pathway-specific components. METHODS: The polygenic risk score (PRS) models, based on the UK biobank genetic signals for hypertension status, were obtained on a target Italian case/control cohort including 561 cases and 731 hyper-normal controls from HYPERGENES, and were then applied to an independent validation cohort composed by multi-countries European-based samples including 1,284 cases and 960 hyper-normal controls. RESULTS: The resulting genome-wide PRS was capable of stratifying the individuals for hypertension risk by comparing between individuals in the last PRS decile and the median decile: we observed an odds ratio (OR) of 3.62, CI = [2.01, 6.32] (P = 9.01E-07) and 3.22, 95% CI = [2.06, 5.10] (P = 6.47E-08) in the target and validation cohorts, respectively. The relatively high case/control ORs across PRS quantiles corroborates the presence of strong polygenic components which could be driven by an enrichment of risk alleles within the cases but also by potential enrichment of protective alleles in the old normotensive controls. Moreover, novel pathway-specific PRS revealed an enrichment of the polygenic signal attributable to specific biological pathways. Among those the most significantly associated with hypertension status was the calcium signaling pathway together with other mainly related such as the phosphatidylinositol/inositol phosphate pathways. CONCLUSIONS: The development of pathway-specific PRS could prioritize biological mechanisms, according to their contribution to the genetic susceptibility, whose regulations might be a potential pharmacological preventive target.

Acute Kidney Injury at Hospital Admission for SARS-CoV-2 Infection as a Marker of Poor Prognosis: Clinical Implications for Triage Risk Stratification.

BACKGROUND/AIMS: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of effects, including acute kidney injury (AKI) in up to 40% of hospitalized patients. Given the established relationship between AKI and poor prognosis, whether AKI might be a prognostic indicator for patients admitted to the hospital for SARS-CoV-2 infection would allow for a straightforward risk stratification of these patients. METHODS: We analyzed data of 623 patients admitted to San Raffaele Hospital (Milan, IT) between February 25 and April 19, 2020, for laboratory-confirmed SARS-CoV-2 infection. Incidence of AKI at hospital admission was calculated, with AKI defined according to the KDIGO criteria. Multivariable Cox regression models assessed the association between AKI and overall mortality and admission to the intensive care unit (ICU). RESULTS: Overall, 108 (17%) patients had AKI at hospital admission for SARS-CoV-2 infection. After a median follow-up for survivors of 14 days (interquartile range: 8, 23), 123 patients died, while 84 patients were admitted to the ICU. After adjusting for confounders, patients who had AKI at hospital admission were at increased risk of overall mortality compared to those who did not have AKI (hazards ratio [HR]: 2.00; p = 0.0004), whereas we did not find evidence of an association between AKI and ICU admission (HR: 0.95; p = 0.9). CONCLUSIONS: These data suggest that AKI might be an indicator of poor prognosis for patients with SARS-CoV-2 infection, and as such, given its readily availability, it might be used to improve risk stratification at hospital admission.

[New year, new variant: drawing lessons from frail elderly people].

A recent study called FRASNET enrolled on a voluntary basis a cohort on 1240 elderly people. They were either patients of the Nephrology and Dialysis unit at San Raffaele hospital in Milan, guests of care homes, or members of cultural, social and recreational centers for the elderly in the wider Milan area. Demographic, anthropometric and biochemical data were collected, together with information on comorbidities and pharmacological therapies, psychophysical test results and biological samples. After the first wave of the SARS-Cov-2 pandemic, we have interviewed the members of this same cohort to gather information on possible coronavirus infections and evaluate the impact of the pandemic on frail patients. It emerged that the prevalence of SARS-Cov-2 infections was 0.7% within this cohort. This encouraging result seems to confirm the effectiveness of the measures taken at the start of the pandemic, especially social distancing and personal protective equipment.

Serum Irisin May Predict Cardiovascular Events in Elderly Patients With Chronic Kidney Disease Stage 3-5.

OBJECTIVE: Irisin is a circulating myokine released from skeletal muscles after physical exercise. Irisin production decreases during the course of chronic kidney disease (CKD) as a potential consequence of sarcopenia and physical inactivity. METHODS: This observational study explored the relationship of serum irisin with cardiovascular outcome in 79 patients with stage 3-5 CKD. RESULTS: Serum irisin was significantly higher in healthy subjects (n = 20) than that in CKD patients (7 ± 2 vs. 3.1 ± 0.9 µg/mL; P = .0001) and was higher in patients with CKD stage 3 (3.2 ± 1 µg/mL) than in patients at stage 4 and 5 taken together (n = 36, 2.8 ± 0.7 µg/mL, P = .05). Patients in the lowest serum irisin tertile had lower serum 1,25(OH)2D levels (21 ± 11 pg/mL) than patients in the middle (30 ± 13 pg/mL; P = .005) and the highest tertile (27 ± 14 pg/mL; P = .047). Patients in the highest tertile had lower Kauppila score (10.6 ± 6.9) than patients in the middle (11.8 ± 5.5; P = .007) and the lowest tertile (6.9 ± 6.8; P = .043). Twenty patients suffered from cardiovascular events during a 3-year follow-up. A Cox regression model using age, body weight, presence of diabetes mellitus, gender, Kauppila calcification score, serum values of FGF23 (as logarithm), phosphate, sclerostin, albumin and cholesterol, estimated glomerular filtration rate, and serum irisin tertiles as covariates showed that patients in the highest tertile of serum irisin had a lower cardiovascular risk than patients in the middle tertile (B, 2.38; odds ratio, 10.8; 95% confidence interval, 1.65-58.13; P = .013) or in the lowest tertile (B, 1.61; odds ratio, 5; 95% confidence interval, 1.09-22.83; P = .038). CONCLUSIONS: These findings suggest that serum irisin may be a marker of cardiovascular outcome in patients with CKD.

[Anti-angiogenic drugs and hypertension: from multidisciplinary collaboration to greater care].

Anti-angiogenic drugs are widely used in cancer therapy. Their main targets of action are the vascular endothelial growth factor (VEGF) and its receptors (VEGF-R). Anti-angiogenic drugs are used to reduce the growth of the tumor and its metastases by acting on the phenomenon of tumor neo-angiogenesis. However, they are known for their side effects such as hypertension, acute kidney injury (AKI), and congestive heart failure. Methods: retrospective study conducted on 57 consecutive patients known for ovarian cancer. Patients treated with Bevacizumab, as first-line, relapse, or maintenance treatment (2015-2022). Results: according to FIGO staging, 98.2% (56 out of 57) of the patients in the study had third degree disease (G3). 49% of patients developed hypertension after starting Bevacizumab therapy (82% grade 2 according to CTCAE v.5). 89% of hypertensive patients started treatment and its management was multidisciplinary with nephrological consultation in 68% of cases. Only 3 out of 57 women discontinued treatment due to hypertension, and in only one of them it was not possible to restart it. Conclusions: the evaluation of the patient by a multidisciplinary team (gynecologist and nephrologist) is essential to minimize the morbidity and mortality of patients, and to avoid the interruption of antineoplastic treatment.

Antihypertensive treatment guided by genetics: PEARL-HT, the randomized proof-of-concept trial comparing rostafuroxin with losartan.

We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10-11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (LSS and HSD3B1), EO transport (MDR1/ABCB1), adducin (ADD1 and ADD3); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 µg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6-19.0), P = 0.038 and 13.4 (25.4-2.5), P = 0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former (P = 0.038); this difference was abolished by rostafuroxin at 10-11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians.

Role of blood pressure dysregulation on kidney and mortality outcomes in COVID-19. Kidney, blood pressure and mortality in SARS-CoV-2 infection.

BACKGROUND: In February 2020 the corona virus disease 2019 (COVID-19) infection started spreading throughout Italy, hitting the Lombardy region very hard. Despite the high diffusion, only a subset of patients developed severe COVID-19: around 25% of them developed acute kidney injury (AKI) and one-third of them died. Elderly patients and patients with high comorbidities were identified as being at higher risk of severe COVID-19. METHODS: Our prospective observational cohort study includes 392 consecutive patients hospitalized for COVID-19 in Milan (median age 67 years, 75% male). We evaluated the relationship between blood pressure at presentation, presence of AKI at Emergency Department admission and during hospitalization, and total in-hospital mortality (24%). RESULTS: Although 58% of our study patients reported a history of hypertension (HYP) (86% on treatment), 30% presented with low blood pressure levels. Only 5.5% were diagnosed with AKI on admission; 75% of hypertensive patients discontinued therapy during hospitalization (only 20% were on treatment at discharge). Gender and hypertension were strongly associated with AKI at admission (odds ratio 11). Blood pressure was inversely correlated with increased risk of AKI upon admission, regardless of the severity of respiratory distress. Age over 65, history of hypertension, and severity of respiratory distress were the main predictors of AKI, which developed in 34.7% of cases during hospitalization. AKI was associated with increased in-hospital mortality. Hypertension and low blood pressure at presentation were the main predictors of in-hospital mortality, together with age over 65, baseline pulmonary involvement, and severity of illness. CONCLUSIONS: In patients hospitalized for COVID-19, hypertension and low blood pressure at presentation are important risk factors for AKI and mortality. Early reduction of antihypertensive therapy may improve outcomes in patients with SARS-CoV-2 infection.

Urinary proteomics reveals key markers of salt sensitivity in hypertensive patients during saline infusion.

BACKGROUND: Hypertension is a complex disease and is the major cause of cardiovascular complications. In the vast majority of individuals, the aetiology of elevated blood pressure (BP) cannot be determined, thus impairing optimized therapies and prognosis for individual patients. A more precise understanding of the molecular pathogenesis of hypertension remains a pressing priority for both basic and translational research. Here we investigated the effect of salt on naive hypertensive patients in order to better understand the salt intake-blood pressure relationship. METHODS: Patients underwent an acute saline infusion and were defined as salt-sensitive or salt-resistant according to mean blood pressure changes. Urinary proteome changes during the salt load test were analysed by a label-free quantitative proteomics approach. RESULTS: Our data show that salt-sensitive patients display equal sodium reabsorption as salt-resistant patients, as major sodium transporters show the same behaviour during the salt load. However, salt-sensitive patients regulate the renin angiotensin system (RAS) differently from salt-resistant patients, and upregulate proteins, as epidermal growth factor (EGF) and plasminogen activator, urokinase (PLAU), involved in the regulation of epithelial sodium channel ENaC activity. CONCLUSIONS: Salt-sensitive and salt-resistant subjects have similar response to a saline/volume infusion as detected by urinary proteome. However, we identified glutamyl aminopeptidase (ENPEP), PLAU, EGF and Xaa-Pro aminopeptidase 2 precursor XPNPEP2 as key molecules of salt-sensitivity, through modulation of ENaC-dependent sodium reabsorption along the distal tubule.

Pharmacological blockade of TNFα prevents sarcopenia and prolongs survival in aging mice.

Sarcopenia is a hallmark of aging. Inflammation due to increased generation of cytokines such as TNFα, IL-1ß and IL-6 has been implicated in the pathogenesis of sarcopenia. In skeletal muscle of C57BL/6 mice from 12 until 28 months of age, we observed a progressive reduction of myofiber cross sectional area, loss of type II fibers and infiltration by inflammatory cells. Muscle strength decreased in parallel. Pharmacological TNFα blockade by weekly subcutaneous injection of Etanercept from 16 to 28 months of age prevented atrophy and loss of type II fibers, with significant improvements in muscle function and mice lifespan. The effects on leukocyte recruitment were limited. These results provide a proof of principle that endogenous TNFα is sufficient to cause sarcopenia and to reduce animal survival, and open a novel perspective on novel potential pharmacological treatment strategies based on TNFα blockade to prevent the noxious events associated with aging.

Residual clinical damage after COVID-19: A retrospective and prospective observational cohort study.

Data on residual clinical damage after Coronavirus disease-2019 (COVID-19) are lacking. The aims of this study were to investigate whether COVID-19 leaves behind residual dysfunction, and identify patients who might benefit from post-discharge monitoring. All patients aged ≥18 years admitted to the Emergency Department (ED) for COVID-19, and evaluated at post-discharge follow-up between 7 April and 7 May, 2020, were enrolled. Primary outcome was need of follow-up, defined as the presence at follow-up of at least one among: respiratory rate (RR) >20 breaths/min, uncontrolled blood pressure (BP) requiring therapeutic change, moderate to very severe dyspnoea, malnutrition, or new-onset cognitive impairment, according to validated scores. Post-traumatic stress disorder (PTSD) served as secondary outcome. 185 patients were included. Median [interquartile range] time from hospital discharge to follow-up was 23 [20-29] days. 109 (58.9%) patients needed follow-up. At follow-up evaluation, 58 (31.3%) patients were dyspnoeic, 41 (22.2%) tachypnoeic, 10 (5.4%) malnourished, 106 (57.3%) at risk for malnutrition. Forty (21.6%) patients had uncontrolled BP requiring therapeutic change, and 47 (25.4%) new-onset cognitive impairment. PTSD was observed in 41 (22.2%) patients. At regression tree analysis, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) and body mass index (BMI) at ED presentation, and age emerged as independent predictors of the need of follow-up. Patients with PaO2/FiO2 <324 and BMI ≥33 Kg/m2 had the highest odds to require follow-up. Among hospitalised patients, age ≥63 years, or age <63 plus non-invasive ventilation or diabetes identified those with the highest probability to need follow-up. PTSD was independently predicted by female gender and hospitalisation, the latter being protective (odds ratio, OR, 4.03, 95% confidence interval, CI, 1.76 to 9.47, p 0.0011; OR 0.37, 95% CI 0.14 to 0.92, p 0.033, respectively). COVID-19 leaves behind physical and psychological dysfunctions. Follow-up programmes should be implemented for selected patients.

Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy.

BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations.

Post-COVID-19 follow-up clinic: depicting chronicity of a new disease.

BACKGROUND AND AIM OF THE WORK: The coronavirus disease-19 (COVID-19) outbreak is posing considerable challenges to healthcare systems and societies worldwide. While the knowledge on the acute phase of the disease has rapidly expanded, little is known on the consequences of COVID-19 following clinical remission. We set up a multidisciplinary COVID-19 follow-up outpatient clinic to identify and address the clinical needs of COVID-19 survivors. Here we describe the features of our follow-up programme. METHODS: The multidisciplinary assessment comprises a complete physical examination, respiratory evaluation (peripheral oxygen saturation, respiratory rate, dyspnoea assessment, lung ultrasound and pulmonary function), cardiovascular assessment (electrocardiography, echocardiography), nutritional assessment (anthropometrics, mini Nutritional Assessment screening tool), neurological examination including cognitive tests, and mental health assessment. All data are prospectively collected, and blood is sampled for biobanking. RESULTS: Since 7 April to 5 June, 2020, 453 out of the 1388 COVID-19 survivors managed at our University Hospital have been evaluated at the Outpatient COVID-19 Follow-up Clinic. The characteristics of the follow-up cohort are similar to those of the whole cohort of COVID-19 in terms of demographics, comorbidities, and COVID-19 severity upon ED presentation, indicating that the follow-up cohort is representative of the whole cohort. CONCLUSIONS: Continuous patient monitoring might give an answer to the numerous unsolved questions about what comes next in this pandemic and beyond. This will help physicians and researchers establish strategies to face future pandemics and develop preventative and therapeutic strategies for similar hyperinflammatory conditions.