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Background: Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19, but its association with mortality is unclear. We reviewed published literature for evidence of an association between HCQ (with or without azithromycin (AZM)) and total mortality in COVID-19 patients. Methods: Articles were retrieved until April 29th, 2021 by searching in seven databases. Data were combined using the general-variance-based method. Results: A total of 25 cohort studies (N=41,339 patients) and 11 randomized clinical trials (RCTs; N=8,709) were found. The use of HCQ was not associated with mortality in meta-analysis of RCTs (pooled risk ratio (PRR): 1.08, 95%CI: 0.97-1.20; I2=0%), but it was associated with 20% lower mortality risk (PRR=0.80, 95%CI: 0.69-0.93; I2=80%) in pooling of cohort studies. The negative association with mortality was mainly apparent by pooling cohort studies that used lower doses of HCQ (���400 mg/day; PRR=0.69, 95%CI: 0.57-0.87). Use of HCQ+AZM (11 studies) was associated with 25% non-statistically significant lower mortality risk (PPR=0.75; 0.51-1.10; P=0.15). Use of HCQ was not associated with severe adverse events (PRR=1.12, 95%CI: 0.88-1.44; I2=0%). Conclusions: HCQ use was not associated with mortality in COVID-19 patients in pooling results from RCTs (high level of certainty of evidence), but it was associated with 20% mortality reduction when findings from observational studies were combined (low level of certainty of evidence). The reduction of mortality was mainly apparent in observational studies where lower doses of HCQ were used. These findings might help disentangling the debate on HCQ use in COVID-19.

Background The outpatient setting is a key scenario for the implementation of antimicrobial stewardship (AMS) activities, considering that overconsumption of antibiotics occurs mainly outside hospitals. This publication is the result of a joint initiative by the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks, which is aimed at formulating a set of target actions for linking surveillance data with AMS activities in the outpatient setting. Methods A scoping review of the literature was carried out in three research areas: AMS leadership and accountability; antimicrobial usage and AMS; antimicrobial resistance and AMS. Consensus on the actions was reached through a RAND-modified Delphi process involving over 40 experts in infectious diseases, clinical microbiology, AMS, veterinary medicine or public health, from 18 low-, middle- and high-income countries. Results Evidence was retrieved from 38 documents, and an initial 25 target actions were proposed, differentiating between essential or desirable targets according to clinical relevance, feasibility and applicability to settings and resources. In the first consultation round, preliminary agreement was reached for all targets. Further to a second review, 6 statements were re-considered and 3 were deleted, leading to a final list of 22 target actions in the form of a practical checklist. Conclusions This White Paper is a pragmatic and flexible tool to guide the development of calibrated surveillance-based AMS interventions specific to the outpatient setting, which is characterized by substantial inter- and intra-country variability in the organization of healthcare structures, maintaining a global perspective and taking into account the feasibility of the target actions in low-resource settings.

BACKGROUND: On May 12, 2020, a symposium titled "Liability of healthcare professionals and institutions during COVID-19 pandemic" was held in Italy with the participation of national experts in malpractice law, hospital management, legal medicine, and clinical risk management. The symposium's rationale was the highly likely inflation of criminal and civil proceedings concerning alleged errors committed by health care professionals and decision makers during the COVID-19 pandemic. Its aim was to identify and discuss the main issues of legal and medicolegal interest and thus to find solid solutions in the spirit of preparedness planning. METHODS: There were 5 main points of discussion: (A) how to judge errors committed during the pandemic because of the application of protocols and therapies based on no or weak evidence of efficacy, (B) whether hospital managers can be considered liable for infected health care professionals who were not given adequate personal protective equipment, (C) whether health care professionals and institutions can be considered liable for cases of infected inpatients who claim that the infection was transmitted in a hospital setting, (D) whether health care institutions and hospital managers can be considered liable for the hotspots in long-term care facilities/care homes, and (E) whether health care institutions and hospital managers can be considered liable for the worsening of chronic diseases. RESULTS AND CONCLUSION: Limitation of the liability to the cases of gross negligence (with an explicit definition of this term), a no-fault system with statal indemnities for infected cases, and a rigorous methodology for the expert witnesses were proposed as key interventions for successfully facing future proceedings.

Objective: This study investigates the effectiveness and tolerability of switching to a darunavir/cobicistat (DRV/c)-based antiretroviral regimen from a ritonavir-boosted protease inhibitor (PI/r)-based regimen in virologically suppressed HIV-positive patients. DRV trough values were also investigated. Setting: Prospective, multicenter, single-country, noninterventional cohort study. Methods: This study included patients on a PI/r-based ART for at least 12 months having plasma HIV-1 RNA

The BQ.1 SARS-CoV-2 variant, also known as Cerberus, is one of the most recent Omicron descendant lineages. Compared to its direct progenitor BA.5, BQ.1 carries out some additional spike mutations in some key antigenic site which confer it further immune escape ability over other circulating lineage. In such a context, here we performed a genome-based survey aimed to obtain an as complete as possible nuance of this rapidly evolving Omicron subvariant. Genetic data suggests that BQ.1 represents an evolutionary blind background, lacking of the rapid diversification which is typical of a dangerous lineage. Indeed, the evolutionary rate of BQ.1 is very similar to that of BA.5 (7.6 × 10−4and 7 × 10−4subs/site/year, respectively), which is circulating by several months. Bayesian Skyline Plot reconstruction, indicates low level of genetic variability, suggesting that the peak has been reached around September 3, 2022. Structure analyses performed by comparing the properties of BQ.1 and BA.5 RBD indicated that the impact of the BQ.1 mutations on the affinity for ACE2 may be modest. Likewise, immunoinformatic analyses showed modest differences between the BQ.1 and the BA5 potential B-cells epitope. In conclusion, genetic and structural analysis on SARS-CoV-2 BQ.1 suggest that, it does not show evidence about its particular dangerous or high expansion capability. The monitoring genome-based must continue uninterrupted for a better understanding of its descendant and all other lineages.

The COVID-19 pandemic continues to have a threatening impact on a global scale, largely due to the emergence of newly SARS-CoV-2 variants. The Mu (PANGO lineage B.1.621), was first identified in Colombia in January 2021 and was classified as a variant of interest (VOI) in August 2021, due to a constellation of mutations that likely-mediate an unexpectedly enhanced immune resistance to inactivated vaccine-elicited antibodies. Despite recent studies suggesting that the Mu variant appears to have less infectivity than the Delta variant, here we examined the structural effect of the Mu spike protein mutations and predicted the potential impact on infectivity of the Mu variant compared with the Delta and Delta plus spike protein.

The occurrence of COVID-19 pandemic had a significant negative effect on health care systems over the last year. Health care providers were forced to focus mainly on COVID-19 patients, neglecting in many cases equally important diseases, both acute and chronic. Therefore, also screening and diagnostic strategies for HIV could have been significantly impaired. This retrospective, multicenter, observational study aimed at assessing the number and characteristics of new HIV/AIDS diagnoses during COVID-19 pandemic in Italy and compared characteristics of people living with HIV at diagnosis between pre- and post-COVID-19 era (2019 vs 2020). Our results showed a significant reduction of HIV diagnoses during pandemic. By contrast, people living with HIV during pandemic were older and were diagnosed in earlier stage of disease (considering CD4+ T cell count) compared to those who were diagnosed the year before. Moreover, there was a significant decrease of new HIV diagnoses among men who have sex with men, probably for the impact of social distancing and restriction applied by the Italian Government. Late presentation incidence, if numbers in 2020 were lower than those in 2019, is still an issue. Routinely performing HIV testing in patients with suspected SARS-CoV-2 infection is identifying and linking to care underdiagnosed people living with HIV earlier. Thus, combined tests (HIV and SARS-CoV-2) should be implemented in patients with SARS-CoV-2 symptoms overlapping HIV's ones. Lastly, our results lastly showed how urgent implementation of a national policy for HIV screening is necessary.

Among the more recently identified SARS-CoV-2 Variants of Interest (VOI) is the Lambda variant, which emerged in Peru and has rapidly spread to South American regions and the US. This variant remains poorly investigated, particularly regarding the effects of mutations on the thermodynamic parameters affecting the stability of the Spike protein and its Receptor Binding Domain. We report here an in silico study on the potential impact of the Spike protein mutations on the immuno-escape ability of the Lambda variant. Bioinformatics analysis suggests that a combination of shortening the immunogenic epitope loops and the generation of potential N-glycosylation sites may be a viable adaptation strategy, potentially allowing this emerging viral variant to escape from host immunity.

The impact of inappropriate empirical antibiotic therapy (IEAT) on the outcome of severe infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-Ent) remains unclear. Current evidence is limited by study design and lack of confounder control. The main objective of this study was to define the outcome of severe infections due to ESBL-Ent according to clinical parameters and place of infection acquisition. Adult hospitalised patients with ESBL-Ent infections were included in a 3-year multicentre prospective study. Primary outcomes were IEAT rates and crude mortality of severe infections, adjusted by place of acquisition [community-acquired infection (CAI), healthcare-associated infection (HCAI) and hospital-acquired infection (HAI)]. Among 729 patients, 519 (71.2%) were diagnosed with HAI, 176 (24.1%) with HCAI and 34 (4.7%) with CAI. Moreover, 32.9% of patients received IEAT; higher rates of IEAT were observed in pneumonia (23%) and deep surgical site infections (19%). HCAIs were more frequently associated with IEAT than HAIs (48.3% vs. 27.9%; OR = 1.7, 95% CI 1.2–2.4). The overall mortality rate for severe infections (n = 264) was 12.1% and was significantly higher in HCAIs (20%) than HAIs (10%) (RR = 2.3, 95% CI 1.01–5.3). IEAT significantly increased the risk of mortality in bloodstream infections (RR = 8.3, 95% CI 2–46.3). Rates of IEAT and overall mortality of ESBL-Ent severe infections were higher in HCAIs than HAIs. Prompt diagnosis of patients with severe HCAIs due to ESBL-Ent is essential since these infections receive high rates of IEAT and significantly higher mortality than HAIs [ClinicalTrials.gov Identifier: NCT00404625].

OBJECTIVES Two-drug antiretroviral regimens based on lamivudine (3TC) plus either a protease inhibitor (PI) or dolutegravir (DTG) are becoming increasingly popular in switch strategies. Our goal was to derive a predictive score for virological failure (VF). METHODS We retrospectively analysed data for a cohort of 587 virologically suppressed (HIV RNA

ObjectivesOur aim was to investigate the durability of different initial regimens in patients starting ART with CD4+ counts 5 log10 copies/mL.MethodsThis was a retrospective study of HIV-infected patients prospectively followed in the ICONA cohort. Those who started ART with boosted protease inhibitors (bPIs), NNRTIs or integrase strand transfer inhibitors (InSTIs), with CD4+ 5 log10 copies/mL, were included. The primary endpoint was treatment failure (TF), a composite endpoint defined as virological failure (VF, first of two consecutive HIV-RNA >50 copies/mL after 6 months of treatment), discontinuation of class of the anchor drug or death. Independent associations were investigated by Poisson regression analysis in a model including age, gender, mode of HIV transmission, CDC stage, HCV and HBV co-infection, pre-treatment HIV-RNA, CD4+ count and CD4+/CD8+ ratio, ongoing opportunistic disease, fibrosis FIB-4 index, estimated glomerular filtration rate, haemoglobin, platelets, neutrophils, calendar year of ART initiation, anchor drug class (treatment group) and nucleos(t)ide backbone.ResultsA total of 1195 patients fulfilled the inclusion criteria: 696 started ART with a bPI, 315 with an InSTI and 184 with an NNRTI. During 2759 person-years of follow up, 642 patients experienced TF. Starting ART with bPIs [adjusted incidence rate ratio (aIRR) (95% CI) 1.62 (1.29–2.03) versus starting with NNRTIs; P ConclusionsIn patients starting ART with 5 log10 HIV-RNA copies/mL, the durability of regimens based on InSTIs was longer than that of NNRTI- and bPI-based regimens.

Introduction A hypercoagulable condition was described in patients with coronavirus disease 2019 (COVID-19) and proposed as a possible pathogenic mechanism contributing to disease progression and lethality. Aim We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients. Methods In a retrospective observational study, 2,574 unselected patients hospitalized in 30 clinical centers in Italy from February 19, 2020 to June 5, 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection were analyzed. The primary endpoint in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores. Results Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% confidence interval: 0.49–0.74; E-value = 2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation. Conclusion In-hospital heparin treatment was associated with a lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomized clinical trials are eagerly awaited to provide clear-cut recommendations.

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February–May 2020). Patients’ characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction ( p < 0.001 ). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.

Background A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae. Methods We retrospectively analyzed observational data on use and outcomes of CAZ-AVI therapy for infections caused by Klebsiella pneumoniae carbapenemase–producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens versus CAZ-AVI monotherapy. Results The cohort comprised 577 adults with bloodstream infections (n = 391) or nonbacteremic infections involving mainly the urinary tract, lower respiratory tract, and intra-abdominal structures. All received treatment with CAZ-AVI alone (n = 165) or with ≥1 other active antimicrobials (n = 412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs 25.0%, P = .79). In multivariate analysis, mortality was positively associated with presence at infection onset of septic shock (P = .002), neutropenia (P < .001), or an INCREMENT score ≥8 (P = .01); with lower respiratory tract infection (LRTI) (P = .04); and with CAZ-AVI dose adjustment for renal function (P = .01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P = .006). All associations remained significant after propensity score adjustment. Conclusions CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug’s seemingly more limited efficacy in LRTIs and potential survival benefits of prolonging CAZ-AVI infusions to ≥3 hours.

Lineage B.1.617+, also known as G/452R.V3 and now denoted by WHO with the Greek letters δ and κ, is a recently described SARS‐CoV‐2 variant under investigation first identified in October 2020 in India. As of May 2021, three sublineages labeled as B.1.617.1 (κ), B.1.617.2 (δ), and B.1.617.3 have been already identified, and their potential impact on the current pandemic is being studied. This variant has 13 amino acid changes, three in its spike protein, which are currently of particular concern: E484Q, L452R, and P681R. Here, we report a major effect of the mutations characterizing this lineage, represented by a marked alteration of the surface electrostatic potential (EP) of the receptor‐binding domain (RBD) of the spike protein. Enhanced RBD‐EP is particularly noticeable in the B.1.617.2 (δ) sublineage, which shows multiple replacements of neutral or negatively charged amino acids with positively charged amino acids. We here hypothesize that this EP change can favor the interaction between the B.1.617+ RBD and the negatively charged ACE2, thus conferring a potential increase in the virus transmission., Highlights Lineage B.1.617.2, is a recently described SARS‐CoV‐2 VOC first identified in October 2020 in India.Three sublineages labeled as B.1.617.1, B.1.617.2, and B.1.617.3 have been already identified.Enhanced RBD‐EP is particularly noticeable in the B.1.617.2 VOC which shows multiple replacements of neutral or negatively charged amino acids with positively charged amino acids.

We investigated SARS-CoV-2 transmission dynamics in Italy, one of the countries hit hardest by the pandemic, using phylodynamic analysis of viral genetic and epidemiological data. We observed the co-circulation of multiple SARS-CoV-2 lineages over time, which were linked to multiple importations and characterized by large transmission clusters concomitant with a high number of infections. Subsequent implementation of a three-phase nationwide lockdown strategy greatly reduced infection numbers and hospitalizations. Yet we present evidence of sustained viral spread among sporadic clusters acting as “hidden reservoirs” during summer 2020. Mathematical modelling shows that increased mobility among residents eventually catalyzed the coalescence of such clusters, thus driving up the number of infections and initiating a new epidemic wave. Our results suggest that the efficacy of public health interventions is, ultimately, limited by the size and structure of epidemic reservoirs, which may warrant prioritization during vaccine deployment., Giovanetti et al. examine SARS-CoV-2 transmission dynamics in Italy using phylodynamic analysis of viral genetic and epidemiological data. They present evidence to suggest that the efficacy of public health interventions is limited by the size and structure of epidemic reservoirs, which may influence vaccination programmes.

Background : The COVID-19 pandemic affected healthcare systems worldwide. Predictive models developed by Artificial Intelligence (AI) and based on timely, centralized and standardized real world patient data could improve management of COVID-19 to achieve better clinical outcomes. The objectives of this manuscript are to describe the structure and technologies used to construct a COVID-19 Data Mart architecture and to present how a large hospital has tackled the challenge of supporting daily management of COVID-19 pandemic emergency, by creating a strong retrospective knowledge base, a real time environment and integrated information dashboard for daily practice and early identification of critical condition at patient level. This framework is also used as an informative, continuously enriched data lake, which is a base for several on-going predictive studies. Methods : The information technology framework for clinical practice and research was described. It was developed using SAS Institute software analytics tool and SAS® Vyia® environment and Open-Source environment R ® and Python ® for fast prototyping and modelling. The included variables and the source extraction procedures were presented. Results : The Data Mart covers a retrospective cohort of 2634 patients with SARS-CoV-2 infection. People who died were older, had more comorbidities, reported more frequently dyspnea at onset, had higher d-dimer, C-reactive protein and urea nitrogen. The dashboard was developed to support the management of COVID-19 patients at three levels: hospital, single ward and individual care level. Interpretation : The COVID-19 Data Mart based on integration of a large collection of clinical data and an AI-based integrated framework has been developed, based on a set of automated procedures for data mining and retrieval, transformation and integration, and has been embedded in the clinical practice to help managing daily care. Benefits from the availability of a Data Mart include the opportunity to build predictive models with a machine learning approach to identify undescribed clinical phenotypes and to foster hospital networks. A real-time updated dashboard built from the Data Mart may represent a valid tool for a better knowledge of epidemiological and clinical features of COVID-19, especially when multiple waves are observed, as well as for epidemic and pandemic events of the same nature (e. g. with critical clinical conditions leading to severe pulmonary inflammation). Therefore, we believe the approach presented in this paper may find several applications in comparable situations even at region or state levels. Finally, models predicting the course of future waves or new pandemics could largely benefit from network of DataMarts.

Bloodstream infections (BSIs) are a major cause of mortality in elderly. Objective of the study is to identify factors predictive of mortality in old and oldest old patients.This is a single centre retrospective observational study, including all patients admitted to Fondazione Policlinico A. Gemelli university hospital and diagnosed with BSI. Patients were stratified into three groups according to age: adult (A), younger than 65; old (O), aged between 65 and 80; oldest old (OO), older than 80. Primary outcome was 30-day in-hospital mortality. Secondary outcomes were duration of antimicrobial therapy (DOT) and length of hospital stay (LOS).Of the 1034 patients included in the study, 346 were in group A, 447 in group O and 241 in group OO. The rate of 30-day mortality raised from 6.9% (24/346) in group A to 10.8% (84/447) in group O and 33.2% (80/241) in group OO (p0.01), while DOT and LOS significantly decreased moving from adults to oldest old (p0.01). Methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus spp were both independently correlated to an increased 30-day mortality risk selectively in patients older than 80 (MRSA: HR 2.37, p=0.03; Enterococcus spp: HR 2.44, p=0.01).BSIs have a high impact on survival in old and oldest old patients. BSIs by gram-positive pathogens, in particular MRSA and Enterococcus spp, should be a wake-up call for physicians, who should focus efforts on adequate and prompt antibiotic and support treatment.

Objectives Surgical antibiotic prophylaxis (SAP) represents a major indication of antibiotic consumption worldwide. The present study aims to report the results of an enabling, long-term AMS intervention conducted between 2013 and 2019 on an Italian University Hospital performing more than 40.000 surgical interventions per year. Methods SAP inappropriateness was defined according to the ASHP guidelines and divided in four main categories: indication, selection and dosing, duration, timing. Between 2013 and 2019, we conducted a continuative AMS intervention over 14 surgical departments that included enablement, review of selected clinical records and feedback. Results We collected a total of 789 SAP prescribed to 735 patients (mean age 56.7 ± 17.8y). Overall, guideline adherence improved from 36.6% (n = 149) at baseline to 57.9% (n = 221) post-intervention (P P indication (from 58.5 to 93.2%), selection and dosing (from 58.5 to 80.6%), timing (from 92.4 to 97.6%), duration (from 71 to 80.1%). Conclusions Though results cannot be generalized to all hospital populations, enabling AMS interventions may be effective in establishing a sustained improvement in SAP appropriateness rates. Once identified the main causes of SAP inappropriateness, tailored AMS interventions for each department may be beneficial. Further studies are needed to evaluate specific outcomes as incidence of surgical site infections and antimicrobial resistance.

Background and aims There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death. Methods and results Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6–14.7 for age ≥85 vs 18–44 y); HR = 4.7; 2.9–7.7 for estimated glomerular filtration rate levels, Highlights • Impaired renal function, elevated C-reactive protein and advanced age were major indicators of death in COVID-19 patients. • These associations were substantially homogenous across all sub-groups analysed. • No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. • Death rates were higher in the Northern as opposed to Central-Southern Italian regions.

Over the last months, pandemic SARS‐CoV‐2 caused a significant challenge for clinicians. Unfortunately, no approved and validated treatments are available. Intravenous tocilizumab, an antirheumatic drug, seems to be promising in counteracting cytokine storm caused by SARS‐CoV‐2 infection with associated clinical improvements. We report herein a case series of patients with COVID‐19 pneumonia who were treated with tocilizumab administrated, for the first time, subcutaneously with good clinical and radiological outcomes. This article is protected by copyright. All rights reserved.

Background Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19. Objective We set-up a multicenter Italian collaboration to investigate the relationship between HCQ therapy and COVID-19 in-hospital mortality. Methods In a retrospective observational study, 3,451 unselected patients hospitalized in 33 clinical centers in Italy, from February 19, 2020 to May 23, 2020, with laboratory-confirmed SARS-CoV-2 infection, were analyzed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received HCQ with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores, with the addition of subgroup analyses. Results Out of 3,451 COVID-19 patients, 76.3% received HCQ. Death rates (per 1,000 person-days) for patients receiving or not HCQ were 8.9 and 15.7, respectively. After adjustment for propensity scores, we found 30% lower risk of death in patients receiving HCQ (HR=0.70; 95%CI: 0.59 to 0.84; E-value=1.67). Secondary analyses yielded similar results. The inverse association of HCQ with inpatient mortality was particularly evident in patients having elevated C-reactive protein at entry. Conclusions HCQ use was associated with a 30% lower risk of death in COVID-19 hospitalized patients. Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19.

Italy is one of the countries on track with the WHO's agenda to eliminate hepatitis C virus (HCV) by 2030. Healthcare facilities play a crucial role in seeking patients who are infected but have not yet been treated. We assessed the effectiveness of a recall strategy, named 'Telepass' project, for patients exposed to HCV infection who have not yet been linked to care in a large tertiary care centre. The 'Telepass' project was structured in two phases: (a) a retrospective analysis first identified all anti-HCV-positive subjects among patients who underwent pre-operative assessment in the facility in the course of one year; (b) a following prospective phase, aimed to recall patients in need either of further diagnostic tests (ie HCV-RNA) or treatment. A total of 12246 records of patients tested for HCV antibodies were reviewed. The overall prevalence of anti-HCV-positive subjects was 1.83% (224/12246) with a male/female ratio of 2.07. Out of the 224 anti-HCV-positive patients, 123 (54.91%) did not have documented HCV-RNA tests and were therefore selected for recall. Of these, 123 were reachable and 26 (21.13%) were successfully linked to care. Ten patients (38.46%) tested HCV-RNA positive and initiated treatment with direct-acting antivirals (DAAs). The Telepass study highlights that a recall strategy starting from internal hospital databases can help identify patients with chronic HCV infection who have not yet been linked to care, and provides an epidemiological insight into the prevalence of HCV infection in Italy in the late DAAs era.

To the Editor,In this journal Hou et al. recently reported their experience on clinical aggravation in COVID-19 patients [1]. Patients with disease progression were more likely to have various comp...

Objective The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID−19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418 ) to retrospectively investigate the relationship between RAAS inhibitors and COVID−19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies. Methods We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting–enzyme inhibitors (ACE I) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method. Results Out of 4069 COVID−19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID−19 treatments: 0.96, 95% confidence interval 0.77–1.20 and HR = 0.89, 0.67–1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78–1.26 and HR = 0.88, 0.65–1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID−19 adult patients, 9700 with hypertension) confirmed the absence of association. Conclusions In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID−19 patients.

Italy is the first western country suffering heavy SARS‐CoV‐2 transmission and disease impact after Covid‐19 pandemia started in China. Even though the presence of mutations on spike glycoprotein and nucleocapsid in Italian isolates has been reported, the potential impact of these mutations on viral transmission has not been evaluated. We have compared SARS‐CoV‐2 genome sequences from Italian patients with virus sequences from Chinese patients. We focussed upon three non‐synonimous mutations of genes coding for S(one) and N (two) viral proteins present in Italian isolates and absent in Chinese ones, using various bio‐informatic tools. Amino acid analysis and changes in three‐dimensional protein structure suggests the mutations reduce protein stability and, particularly for S1 mutation, the enhanced torsional ability of the molecule could favour virus binding to cell receptor(s). This theoretical interpretation awaits experimental and clinical confirmation. This article is protected by copyright. All rights reserved.

• Clinicians are looking for a reliable prognostic marker for patients with COVID-19. • In our cohort, clinical improvement was predicted by younger age and a NLR below 3. • Transfer to ICU was instead predicted by a NLR over 4 (p=0.046). • NLR is a fast, widely available and relatively inexpensive assessment. • NLR may be a useful tool in the early screening of patients with COVID-19.

Este artículo se encuentra disponible en la siguiente URL: https://www.frontiersin.org/articles/10.3389/fpubh.2020.00284/full En este artículo también participan: Luciano Violante, Roberto Cauda, Carlo Petrini, Antonio Abbate, Rossana Alloni, Josepmaria Argemi, Josep Argemí Renom, Anna De Benedictis, France Galerneau, Giampaolo Ghilardi, Janet Palmer Hafler, Magdalena Linden, Alfredo Marcos, Andrea Onetti Muda, Marco Pandolfi, Thierry Pelaccia, Mario Picozzi, Ruben Oscar Revello, Giovanna Ricci, Robert Rohrbaugh, Patrizio Rossi, Ascanio Sirignano, Antonio Gioacchino Spagnolo, Trevor Stammers, Lourdes Velázquez, Evandro Agazzi y Mark Mercurio.

Background SARS-CoV-2 is a new coronavirus that has spread globally, infecting more than 150000 people, and being declared pandemic by the WHO. We provide here bio-informatic, evolutionary analysis of 351 available sequences of its genome with the aim of mapping genome structural variations and the patterns of selection. Methods A Maximum likelihood tree has been built and selective pressure has been investigated in order to find any mutation developed during the SARS-CoV-2 epidemic that could potentially affect clinical evolution of the infection. Finding We have found in more recent isolates the presence of two mutations affecting the Non-Structural Protein 6 (NSP6) and the Open Reding Frame10 (ORF 10) adjacent regions. Amino acidic change stability analysis suggests both mutations could confer lower stability of the protein structures. Interpretation One of the two mutations, likely developed within the genome during virus spread, could affect virus intracellular survival. Genome follow-up of SARS-CoV-2 spread is urgently needed in order to identify mutations that could significantly modify virus pathogenicity.

Objectives To assess the impact of switching to dolutegravir plus lamivudine maintenance therapy on the HIV cellular reservoir size. Patients and methods This was a prospective, longitudinal, matched, controlled study. We enrolled virologically suppressed patients on stable three-drug ART who switched at baseline (BL) to dolutegravir/lamivudine (DT group) or maintained triple therapy (TT group); subjects in the TT group were matched 1:1 with those in the DT group according to age, gender, years since HIV diagnosis, years on ART and anchor drug. Total blood-associated HIV DNA levels were assessed by droplet digital PCR at BL and after 48 weeks (T48). Results were expressed as log10 HIV DNA copies/106 leucocytes. Results We enrolled 40 patients in the DT group and 40 in the TT group; the two groups were homogeneous for all main characteristics except nadir CD4 cell count. At BL, HIV DNA levels were comparable between the DT and TT groups: 2.27 (IQR 1.97–2.47) and 2.26 (IQR 2.05–2.61) log10 HIV DNA copies/106 leucocytes, respectively. Change in HIV DNA load from BL to T48 was −0.105 (IQR −0.384 to 0.121, P = 0.041) in the DT group and −0.132 (IQR −0.362 to 0.046, P = 0.005) in the TT group, with a comparable decline observed between the two groups (P = 0.821). A higher HIV DNA decline was associated with higher BL CD4/CD8 ratio. Conclusions Maintenance therapy with dolutegravir/lamivudine had the same impact as the triple regimen on HIV DNA levels after 48 weeks of treatment. These data seem to support the effectiveness of a dolutegravir/lamivudine dual regimen in controlling the magnitude of the cellular reservoir (www.clinicaltrials.gov, number NCT02836782).

Objectives: To evaluate the impact of high-dose (HD) carbapenem-based combination therapy on clinical outcome in patients with monomicrobial carbapenem-resistant Klebsiella pneumoniae (CR-KP) bloodstream-infection (BSI). Methods: Post hoc analysis of all adult patients with CR-KP BSI who were treated with a combination antibiotic regimen, collected over a six-year period in six large Italian teaching hospitals. To control for confounding effects of HD carbapenem combination on 14-day mortality, a multivariate Cox regression analysis was performed. Due to imbalances between patients, a propensity score for receiving HD carbapenem was added to the model. Results: 595 patients with CR-KP BSI were analysed, 77% of isolates showed a carbapenem MIC ≥16 mg/L, 428 (71.9%) received HD carbapenem-based combination therapy. Overall, 127 patients (21.3%) died within 14 days after BSI onset. Multivariate analysis showed the Charlson comorbidity index (HR 1.31, 95%CI 1.20–1.43, P < 0.001), septic shock at BSI onset (HR 3.14, 95%CI 2.19–4.50, P < 0.001), and colistin-resistant strain (HR 1.52, 95%CI 1.02–2.24, P = 0.03) were independently associated with 14-day mortality, whereas admission to surgical ward (HR 0.44, 95%CI 0.25–0.78, P = 0.005) and HD carbapenem use (HR 0.69, 95%CI 0.47–1.00, P = 0.05) were protective factors. When adjusted for the propensity score, HD carbapenem use showed a greater protective effect (HR 0.64, 95%CI 0.43–0.95, P = 0.03). Stratifying the model for carbapenem MIC, the benefit of HD carbapenem was also observed for strains with carbapenem MIC ≥16 mg/L. Conclusions: In patients receiving combination therapy for CR-KP BSI, the use of HD carbapenem seems to be associated with better outcome, even in the presence of high-level carbapenem resistance.

The introduction of generic antiretroviral medications in developing countries has resulted in significant CD4 cell restoration, HIV viral decline, and a noteworthy reduction in the time to initiation of therapy. Projection models have also predicted significant cost saving associated with the extensive diffusion of generic antiretrovirals in developed countries. However, some uncertainties on generics have recently been raised. These concerns mainly relate to the adequacy of the study design for bioequivalence testing, the potential for uncontrolled switching from one generic to another, and the loss of adherence if patients switched from fixed-dose coformulations to single components in order to incorporate the new generic drugs. In the present review, we deal with current evidence and potential controversial issues regarding generic antiretrovirals and their underlying economic implications and provide some proposals on how to favor the widespread diffusion of generics in HIV medicine. This may be particularly relevant considering that the safe, systematic switch from patented to generic antiretrovirals could potentially guarantee access to therapies for HIV-infected patients worldwide and lead to money savings that would compensate the expenditure increase resulting from new, innovative HIV drugs. .

Purpose: Pyogenic spondylodiscitis (PS) is still burdened by a high rate of orthopedic and neurological complications. Despite the rising incidence, the choice of a proper orthopedic treatment is often delayed by the lack of clinical data. The aim of this study was to propose a clinical-radiological classification of pyogenic spondylodiscitis to define a standard treatment algorithm. Methods: Based on data from 250 patients treated from 2008 to 2015, a clinical-radiological classification of pyogenic spondylodiscitis was developed. According to primary classification criteria (bone destruction or segmental instability, epidural abscesses and neurological impairment), three main classes were identified. Subclasses were defined according to secondary criteria. PS without segmental instability or neurological impairment was treated conservatively. When significant bone loss or neurological impairment occurred, surgical stabilization and/or decompression were performed. All patients underwent clinical and radiological 2-year follow-up. Results: Type A PS occurred in 84 patients, while 46 cases were classified as type B and 120 as type C. Average time of hospitalization was 51.94 days and overall healing rate was 92.80%. 140 patients (56.00%) were treated conservatively with average time of immobilization of 218.17 ± 9.89 days. Both VAS and SF-12 scores improved across time points in all classes. Residual chronic back pain occurred in 27 patients (10.80%). Overall observed mortality was 4.80%. Conclusions: Standardized treatment of PS is highly recommended to ensure patients a good quality of life. The proposed scheme includes all available orthopedic treatments and helps spine surgeons to significantly reduce complications and costs and to avoid overtreatment.

Background: Clostridioides difficile infection (CDI) is a risk factor for bloodstream infections (BSI). Fecal microbiota transplantation (FMT) is more effective than antibiotics in treating recurrent CDI, but its efficacy in preventing CDI-related BSI is uncertain. Objective: To assess incidence of primary BSI in patients with recurrent CDI treated with FMT compared with patients treated with antibiotics. Design: Prospective cohort study. FMT and antibiotic treated patients were matched using propensity score. Setting: Single academic medical center. Patients: 290 inpatients with recurrent CDI; 57 patients per treatment in matched cohort. Interventions: FMT or antibiotics. Measurements: Our primary outcome was the development of primary BSI within a 90-day follow-up. Secondary outcomes were length of hospitalization, and overall survival (OS) at 90 days. Results: 109 patients were treated with FMT, and 181 received antibiotics. Five patients in the FMT group and 40 in the antibiotic group developed BSI. Due to differences in the patients treated with FMT and antibiotics in a number of baseline characteristics including the number of recurrences and CDI severity, comparative analyses were limited to the matched cohort. Subjects in the FMT group experienced a 23% lower risk of developing BSI (95% confidence interval 10-35%), 14 fewer days of hospitalization (95% confidence interval 9-20 days), and a 32% increase in OS (95% confidence interval 16-47%) compared with the antibiotic group. Limitations: Non-randomized study with potential for unmeasured/residual confounding. Limited generalizability of the propensity score-matched cohort. Conclusion: In a propensity score-matched cohort, patients with recurrent CDI treated with FMT were less likely to develop primary BSI.

We report a case of a 13-year-old immunocompetent male with multifocal tubercular osteomyelitis involving several spinal segments, small bones of the hands, and the scalp, who started with progressively back pain and enlarging painful swelling on the palms of hands, fatigue, and irregular fever. All the hand lesions were firm, mildly tender, and covered by ulcerated skin with serous discharge from the site. Magnetic resonance showed lesions of the right fifth metacarpal, of the right intermediate phalanx of the fourth finger, of the left second metacarpal, and of most vertebral bodies of the cervical, dorsal, lumbar, and sacral spine. The nucleic acid amplification test and the final culture from the drainage of the hands' lesion were positive for Mycobacterium tuberculosis. The patient received a standard antitubercular treatment for 12 months with clinical improvement.

Both cognitive diseases and alexithymia may be associated with HIV. Moreover, alexithymia has been linked to cardiovascular (CV) diseases. Our aim was to explore the prevalence of alexithymia and its associations with neurocognitive disorders (HAND) and CV risk factors in a well-controlled HIV-positive population. We consecutively enrolled 140 HIV-positive individuals on antiretroviral therapy and 35 healthy subjects matched for age, education and gender. In all participants alexithymia was explored by the 20-item Toronto Alexithymia Scale. For HIV-positive subjects also data about CV risk factors were collected, and a comprehensive neuropsychological examination was administered; HAND was defined according to Frascati criteria. Patients and controls did not differ in the proportion of alexithymic status (10% vs. 11%; p=0.761). Among HIV-positive patients, alexithymic participants presented a higher prevalence of diabetes (21% vs. 3%, p=0.035) and hypertension (36% vs. 13%, p= 0.037) compared to non-alexithymic. About 30% (n=41) of HIV-positive patients met criteria for asymptomatic HAND. Alexithymia was not independently associated with a higher risk of HAND (p=0.189). Analyzing each cognitive domain, alexithymia showed an independent association with an abnormal performance (OR 1.08; p=0.037) only in psychomotor speed. In conclusion, in the context of a well-controlled HIV infection, we found a low prevalence of alexithymia comparable to healthy controls. Alexithymia was linked to higher risk of CV disease in the HIV-positive population, but with a rate similar to that previously estimated in the HIV-negative alexithymic. Finally, alexithymia was clearly associated to cognitive impairment only in the psychomotor speed domain, suggesting a common fronto-striatal system dysregulation.

Postprint

Our objective was to evaluate factors associated with recurrence in patients with 027+ and 027- Clostridium difficile infection (CDI).Patients with CDI observed between January and December 2014 in six hospitals were consecutively included in the study. The 027 ribotype was deduced by the presence of tcdB, tcdB, cdt genes and the deletion Δ117 in tcdC (Xpert® C. difficile/Epi). Recurrence was defined as a positive laboratory test result for C. difficile more than 14 days but within 8 weeks after the initial diagnosis date with reappearance of symptoms. To identify factors associated with recurrence in 027+ and 027- CDI, a multivariate analysis was performed in each patient group. Subdistributional hazard ratios (sHRs) and 95% confidence intervals (95%CIs) were calculated.Overall, 238 patients with 027+ CDI and 267 with 027- CDI were analysed. On multivariate analysis metronidazole monotherapy (sHR 2.380, 95%CI 1.549-3.60, p0.001) and immunosuppressive treatment (sHR 3.116, 95%CI 1.906-5.090, p0.001) were factors associated with recurrence in patients with 027+ CDI. In this patient group, metronidazole monotherapy was independently associated with recurrence in both mild/moderate (sHR 1.894, 95%CI 1.051-3.410, p 0.033) and severe CDI (sHR 2.476, 95%CI 1.281-4.790, p 0.007). Conversely, non-severe disease (sHR 3.704, 95%CI 1.437-9.524, p 0.007) and absence of chronic renal failure (sHR 16.129, 95%CI 2.155-125.000, p 0.007) were associated with recurrence in 027- CDI.Compared to vancomycin, metronidazole monotherapy appears less effective in curing CDI without relapse in the 027+ patient group, independently of disease severity.

Background Ceftazidime-avibactam (CAZ-AVI) has been approved in Europe for the treatment of complicated intra-abdominal and urinary tract infections, as well as hospital-acquired pneumonia, and for gram-negative infections with limited treatment options. CAZ-AVI displays in vitro activity against Klebsiella pneumoniae carbapenemase (KPC) enzyme producers, but clinical trial data on its efficacy in this setting are lacking. Methods We retrospectively reviewed 138 cases of infections caused by KPC-producing K. pneumoniae (KPC-Kp) in adults who received CAZ-AVI in compassionate-use programs in Italy. Case features and outcomes were analyzed, and survival was then specifically explored in the large subcohort whose infections were bacteremic. Results The 138 patients started CAZ-AVI salvage therapy after a first-line treatment (median, 7 days) with other antimicrobials. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died. Thirty-day mortality among the 104 patients with bacteremic KPC-Kp infections was significantly lower than that of a matched cohort whose KPC-Kp bacteremia had been treated with drugs other than CAZ-AVI (36.5% vs 55.8%, P = .005). Multivariate analysis of the 208 cases of KPC-Kp bacteremia identified septic shock, neutropenia, Charlson comorbidity index ≥3, and recent mechanical ventilation as independent predictors of mortality, whereas receipt of CAZ-AVI was the sole independent predictor of survival. Conclusions CAZ-AVI appears to be a promising drug for treatment of severe KPC-Kp infections, especially those involving bacteremia.

Our aim was to better explore the association between liver fibrosis (LF) and neurocognitive impairment (NCI) in people living with HIV (PLWH).We performed a cross-sectional cohort study by consecutively enrolling PLWH at two clinical centers. All subjects underwent a comprehensive neuropsychological battery; NCI was defined as having a pathological performance (1.5 SD below the normative mean) on at least two cognitive domains. LF was explored using FIB4 index; in a subgroup of PLWH, LF was also assessed by transient elastography.A total of 386 subjects were enrolled, of whom 17 (4.4%) had FIB4 3.25. In the subgroup of PLWH (N = 127) performing also liver transient elastography, 14 (11%) had liver stiffness 14 kPa. Overall, 47 subjects (12%) were diagnosed with NCI. At multivariate regression analyses, participants with FIB4 1.45 showed a higher risk of NCI in comparison with those with lower values (aOR 3.04, p = 0.044), after adjusting for education (aOR 0.71, p 0.001), past AIDS-defining events (aOR 2.91, p = 0.014), CD4 cell count, past injecting drug use (IDU), HIV-RNA 50 copies/mL, and HCV co-infection. Also a liver stiffness 14 kPa showed an independent association with a higher risk of NCI (aOR 10.13, p = 0.041). Analyzing any single cognitive domain, a higher risk of abnormal psychomotor speed was associated with a liver stiffness 14 kPa (aOR 223.17, p = 0.019) after adjusting for education (aOR 0.57, p = 0.018), HIV-RNA 50 copies/mL (aOR 0.01, p = 0.007), age, past IDU, and HCV co-infection.In PLWH, increased LF, estimated through non-invasive methods, was associated to a higher risk of NCI independently from HCV status.

Here we evaluated hospitalisation rates and associated risk factors of human immunodeficiency virus (HIV)-infected individuals who were followed up in an Italian reference hospital from 1998 to 2016. Incidence rates (IR) of hospitalisations were calculated for five study periods from 1998 to 2016. The random-effects Poisson regression model was used to assess risk factors for hospitalisation including demographic and clinical characteristics. To consider that more events may occur for the same subject, multiple failure-time data analysis was also performed for selected causes using the Cox proportional hazards model. We evaluated 2031 patients. During 13 173 person-years (py) of follow-up, 3356 hospital admissions were carried out for 756 patients (IR: 255 per 1000 py). IR decreased significantly over the study period, from 634 in 1998–2000 to 126 per 1000 py in 2013–2016. Major declines were detected for AIDS-defining events, non-HIV/AIDS-related infections and neurological diseases. Older age, female sex, longer HIV duration and HCV coinfection were associated with a higher hospitalisation risk, whereas higher CD4 nadir and antiretroviral therapy were associated with a reduced risk. Influence of advanced HIV disease markers declined over time. Hospitalisation rates decreased during the study period in most causes. The relative weight of hospitalisations for non-AIDS-related tumours, cardiovascular, respiratory and kidney diseases increased during the study period, whereas those for AIDS-defining events declined.