GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed.

Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering.

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.

Burden of Disease in PWH Harboring a Multidrug-Resistant Virus: Data From the PRESTIGIO Registry.

BACKGROUND: Currently, no data are available on the burden of morbidity and mortality in people with HIV-1 (PWH) harboring a 4-class drug-resistant (4DR) virus (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase strand transfer inhibitors). The study aimed to assess the incidence of clinical events and death in this population. METHODS: This was a cohort study on PWH from the PRESTIGIO Registry with a documented 4DR virus. Burden of disease was defined as the occurrence of any new event including an AIDS-defining event (ADE) or non-AIDS-defining event (NADE) or death from any cause after 4DR evidence (baseline). Cox regression models evaluated factors associated with the risk of new clinical events/death. RESULTS: Among 148 PWH followed for a median (interquartile range) of 47 (32-84) months after 4DR evidence, 38 PWH had 62 new events or died from any cause (incidence rate, 9.12/100 person-years of follow-up; 95% CI = 6.85-11.39): 12 deaths (6 AIDS-related and 6 non-AIDS-related), 18 ADEs, 32 NADEs; 20 of the 38 NADEs (45%) of the incident clinical events were malignancies. The 4-year cumulative incidence of death was 6% (95% CI, 3%-13%), and that of ≥1 event or death was 22% (95% CI, 16%-31%). A higher risk of new clinical events/death was more likely in PWH with previous clinical events (adjusted hazard ratio [aHR], 2.67; 95% CI, 1.07-6.67) and marginally associated with lower baseline CD4+/CD8+ ratio (aHR, 0.82; 95% CI, 0.65-1.02). CONCLUSIONS: PWH harboring 4DR have a high burden of disease with a worrying incidence of malignancies, strongly advising for close prevention and monitoring interventions as well as access to innovative therapeutic strategies, especially in people with a history of clinical events and low CD4+/CD8+ ratio.

A whole family-based physical activity promotion intervention: findings from the families reporting every step to health (FRESH) pilot randomised controlled trial.

INTRODUCTION: This study assessed the feasibility and acceptability of FRESH (Families Reporting Every Step to Health), a theory-based child-led family physical activity (PA) intervention delivered online. We also assessed the preliminary effectiveness of the intervention on outcomes of interest and whether pre-specified criteria were met to progress to a full-scale definitive trial. METHODS: In a three-armed randomised pilot trial, 41 families (with a 7-11-year-old index child) were allocated to a: 'family' (FAM), 'pedometer-only' (PED), or a no-treatment control (CON) arm. The FAM arm received access to the FRESH website, allowing participants to select step challenges to 'travel' to target cities around the world, log their steps, and track progress as families virtually globetrot. FAM and PED arms also received family sets of pedometers. All family members could participate in the evaluation. Physical (e.g., fitness, blood pressure), psychosocial (e.g., social support), behavioural (e.g., objectively-measured PA), and economic (e.g., expenditure for PA) data were collected at baseline, 8- and 52-weeks. RESULTS: At 8- and 52-weeks, 98 and 88% of families were retained, respectively. Most children liked participating in the study (> 90%) and thought it was fun (> 80%). Compared to the PED (45%) and CON (39%) arms, a higher percentage of children in the FAM (81%) arm reported doing more activities with their family. Adults agreed that FRESH encouraged their family do more PA and made their family more aware of the amount of PA they do. No notable between-group differences were found for childrens' minutes in moderate-to-vigorous PA. Sizeable changes of 9.4 (95%CI: 0.4, 18.4) and 15.3 (95%CI: 6.0, 24.5) minutes in moderate-to-vigorous PA was found for adults in the FAM group compared to those in the PED or CON groups, respectively. No other notable differences were found. CONCLUSION: This study demonstrates feasibility and acceptability of the FRESH intervention. All progression criteria were at least partially satisfied. However, we failed to recruit the target sample size and did not find a signal of effectiveness on PA particularly long-term or in children. Further refinements are required to progress to a full-scale trial. TRIAL REGISTRATION: This study was prospectively registered ( ISRCTN12789422 ) on 16/03/2016.

Quality of life in the FOXFIRE, SIRFLOX and FOXFIRE-global randomised trials of selective internal radiotherapy for metastatic colorectal cancer.

Selective internal radiotherapy (SIRT) is a liver-directed treatment involving the injection of yttrium-90 microspheres into the blood supply of liver tumours. There are very few studies assessing health-related quality of life (HRQOL) in patients treated with SIRT. Patients with liver metastases from colorectal cancer (CRC) were randomised in the FOXFIRE (FFr; ISRCTN83867919), SIRFLOX (SF; NCT00724503) and FOXFIRE-Global (FFrG; NCT01721954) trials of first-line oxaliplatin-fluorouracil (FOLFOX) chemotherapy combined with SIRT versus FOLFOX alone. HRQOL was assessed using the three-level EQ-5D, European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) and EORTC Colorectal Liver Metastases cancer module (EORTC QLQ-LMC21) at baseline, ≤3 months, 6 months, 12 months and annually thereafter from randomisation, and at disease progression. Analyses were conducted on an intention-to-treat basis. In total, 554 patients were randomised to SIRT + FOLFOX and 549 patients to FOLFOX alone. HRQOL was statistically significant lower in SIRT + FOLFOX patients ≤3 months after SIRT administration in all three instruments, particularly global health, physical and role functioning and symptoms of fatigue, nausea/vomiting and appetite loss. By accepted thresholds, these differences were deemed not clinically important. Differences between SIRT + FOLFOX and FOLFOX alone over the 2-year follow up and at disease progression were also not clinically important. Although there is some decrease in HRQOL for up to 3 months following SIRT, the addition of SIRT to FOLFOX chemotherapy does not change HRQOL to a clinically important degree in metastatic CRC patients.

Fever of unknown origin (FUO): which are the factors influencing the final diagnosis? A 2005-2015 systematic review.

BACKGROUND: The differential diagnosis of Fever of Unknown Origin (FUO) is very extensive, and includes infectious diseases (ID), neoplasms and noninfectious inflammatory diseases (NIID). Many FUO remain undiagnosed. Factors influencing the final diagnosis of FUO are unclear. METHODS: To identify factors associated with FUO diagnostic categories, we performed a systematic review of classical FUO case-series published in 2005-2015 and including patients from 2000. Moreover, to explore changing over time, we compared these case-series with those published in 1995-2004. RESULTS: Eighteen case-series, including 3164 patients, were included. ID were diagnosed in 37.8% of patients, NIID in 20.9%, and neoplasm in 11.6%, FUO were undiagnosed in 23.2%. NIIDs significantly increased over time. An association exists between study country income level and ID (increasing when the income decreases) and undiagnosed FUO (increasing when the income increases); even if not significant, the use of a pre-defined Minimal Diagnostic Work-up to qualify a fever as FUO seems to correlate with a lower prevalence of infections and a higher prevalence of undiagnosed FUO. The multivariate regression analysis shows significant association between geographic area, with ID being more frequent in Asia and Europe having the higher prevalence of undiagnosed FUO. Significant associations were found with model of study and FUO defining criteria, also. CONCLUSIONS: Despite advances in diagnostics, FUO still remains a challenge, with ID still representing the first cause. The main factors influencing the diagnostic categories are the income and the geographic position of the study country.

HPV infection and pre-neoplastic cervical lesions among 321 HIV+ women in Florence, Italy, 2006-2016: prevalence and associated factors.

Women living with HIV (WLWH) are at higher risk for HPV-related malignancies. To estimate the factors associated to HPV infection and to pre-neoplastic cervical lesions, we observed 321 WLWH in an HIV care-centre in Florence, Italy. In 2006-2016, WLWH followed at S. Maria Annunziata Hospital underwent to gynaecological examination including HPV-test, Pap-smear, colposcopy and, if needed, cervical biopsy. Demographical and clinical information were collected and linear logistic regression was performed. Among 321 WLWH, 161 (50.2%) resulted HPV+. Multiple genotypes were identified in 35%, and cancer high-risk genotypes in 61%. Younger age, not-caucasic origin, increasing number of partners, and shorter duration of HIV are associated with HPV infection. A colposcopy was performed in 154 HIV+/HPV+ women: histological lesions were present in 47 (30%). Among these, CIN1, CIN2 and CIN3 were present in 16, 4, and 1 patients, respectively. Being caucasic, smoking 1-20 cigarettes/day, having 2 partners in the last year, and being an injective-drug-user are associated with cervical lesions. The use of bi-valent, 4-valent and 9-valent HPV vaccines would potentially prevent lesions in 19%, 33%, and 48%. Among WLWH efficaciously in care for HIV, demographic and behavioral factors mainly contribute to acquisition of HPV and to development of cervical lesions.

The societal burden of chronic liver diseases: results from the COME study.

OBJECTIVE: Chronic liver diseases (CLDs) impose a significant socioeconomic burden on patients and the healthcare system, but to what extent remains underexplored. We estimated costs and health-related-quality-of-life (HRQoL) among patients with CLDs at different stages and with different aetiologies. DESIGN: A cost-of-illness study was conducted. Direct costs, productivity loss and HRQoL were estimated in patients with chronic hepatitis, cirrhosis hepatocellular carcinoma (HCC) or where orthotopic liver transplantation (OLT) had been performed, for hepatitis C virus (HCV) infection, hepatitis B virus (HBV) infection, or in those with liver disease from other causes. Patients were retrospectively observed for 6 months. The societal perspective was adopted to calculate costs. RESULTS: In total, 1088 valid patients (median age=59.5 years, 60% men) were enrolled. 61% had chronic hepatitis, 20% cirrhosis, 8% HCC and 12% underwent OLT. HCV infection was identified in 52% and HBV infection in 29% of the patients. Adjusted mean direct costs increased from <€200/patient-month in HCV-infected patients with hepatitis to >€3000/patient-month in HBV infected patients with OLT. Antiviral treatment was the cost driver in patients with hepatitis, while hospital costs were the driver in the other subgroups. Absenteeism increased from HBV-infected patients with hepatitis (0.7 day/patient-month) to patients with OLT with other aetiologies (3.7 days/patient-month). HRQoL was on average more compromised in cirrhosis and patients with HCC, than in hepatitis and patients with OLT. HBV-infected patients generated higher direct costs, patients with other aetiologies generated the highest productivity loss and HCV-infected patients reported the worst HRQoL levels. CONCLUSIONS: The present study can be considered a benchmark for future research and to guide policies aimed at maximising the cost-effective of the interventions.

Comparing the performance of the standard EQ-5D 3L with the new version EQ-5D 5L in patients with chronic hepatic diseases.

PURPOSE: To assess the performance of the EQ-5D-5L version compared with the standard EQ-5D-3L in a clinical setting targeted at patients with chronic hepatic diseases (CHDs). METHODS: We introduced the 5L descriptive system into a cost-of-illness study involving patients with different CHDs. The patients completed a questionnaire including the two versions of the EQ-5D, together with other questions related to their condition. We tested the feasibility, the level of inconsistency, the redistribution properties among consistent responses, the ceiling effect, the discriminative power, and the convergent validity of the 5L compared with the 3L system. RESULTS: A total of 1,088 valid patients were recruited: 62% male, 19-89 (median = 59) years old. Patients had chronic hepatitis from HCV (31.8%) or HBV infections (29.3%) or other causes (7.8%), 20.4% had cirrhosis, 11.9% underwent liver transplantation, and 7.8% had hepatic carcinoma. Less than 1% of EQ-5D-5L were returned blank, and 1.6% or less of missing values were calculated on the dimensions of the partially completed questionnaires. The proportion and weight of inconsistent responses (i.e., 3L responses that were at least two levels away from the 5L responses) was 2.9% and 1.2 on average, respectively. Regarding redistribution, 57-65% of the patients answering level 2 with the 3L version redistributed their responses to levels 2 or 4 with the 5L version. A relative 7% reduction of the ceiling effect was found. Furthermore, the absolute informativity increased but the relative informativity slightly decreased in every domain, and the convergent validity with the VAS improved. CONCLUSIONS: In a clinical setting involving CHD patients, the EQ-5D-5L was shown to be feasible and with promising levels of performance. Our findings suggest that the 5L performs better in at least some of the properties analyzed, and encourage further research to also test other psychometric properties of this new version of the EQ-5D.

Systematic literature review on economic implications and pharmacoeconomic issues of psoriatic arthritis.

The introduction of anti tumour necrosis factors-α (TNF-α) agents has greatly advanced the management of psoriatic arthritis (PsA). Functional disability in patients with PsA may result in significant impairment of Quality of Life (QoL), psychosocial disability and productivity loss. Although many patients respond adequately to methotrexate and other therapies, in patients who have incomplete responses, anti TNF-α agents reduce inflammation and minimise joints damage, increasing functional capacity and QoL, and decreasing the progression rate of structural damage in peripheral joints. Because of the high costs associated to anti TNF-α agents therapy, an increasing number of economic evaluations have been performed over the last few years, and several cost-of-illness and cost-effectiveness studies have been published concerning use of anti TNF-α agents in management of PsA. We performed a systematic literature review to better understand the pharmacoeconomic perspective of PsA. The pharmacoeconomic studies analysed have demonstrated the high socioeconomic burden of PsA and that TNF-α blockers treatment options provide value for money in the musculoskeletal and cutaneous manifestations of psoriatic disease.

Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease.

The European Network for Infectious Diseases (EUNID) is a network of clinicians, public health epidemiologists, microbiologists, infection control, and critical-care doctors from the European member states, who are experienced in the management of patients with highly infectious diseases. We aim to develop a consensus recommendation for infection control during clinical management and invasive procedures in such patients. After an extensive literature review, draft recommendations were amended jointly by 27 partners from 15 European countries. Recommendations include repetitive training of staff to ascertain infection control, systematic use of cough and respiratory etiquette at admission to the emergency department, fluid sampling in the isolation room, and analyses in biosafety level 3/4 laboratories, and preference for point-of-care bedside laboratory tests. Children should be cared for by paediatricians and intensive-care patients should be cared for by critical-care doctors in high-level isolation units (HLIU). Invasive procedures should be avoided if unnecessary or done in the HLIU, as should chest radiography, ultrasonography, and renal dialysis. Procedures that require transport of patients out of the HLIU should be done during designated sessions or hours in secure transport. Picture archiving and communication systems should be used. Post-mortem examination should be avoided; biopsy or blood collection is preferred.

Patient to patient transmission of hepatitis B virus: a systematic review of reports on outbreaks between 1992 and 2007.

BACKGROUND: Hepatitis B outbreaks in healthcare settings are still a serious public health concern in high-income countries. To elucidate the most frequent infection pathways and clinical settings involved, we performed a systematic review of hepatitis B virus outbreaks published between 1992 and 2007 within the EU and USA. METHODS: The research was performed using two different databases: the PubMed Database and the Outbreak Database, the worldwide database for nosocomial outbreaks. Selection of papers was carried out using the Quorom algorithm, and to avoid selection biases, the inclusion criteria were established before the articles were identified. RESULTS: Overall, 30 papers were analyzed, reporting on 33 hepatitis B virus outbreaks that involved 471 patients, with 16 fatal cases. Dialysis units accounted for 30.3% of outbreaks followed by medical wards (21.2%), nursing homes (21.2%), surgery wards (15.2), and outpatient clinics (12.1%). The transmission pathways were: multi-vial drugs (30.3%), non-disposable multi-patient capillary blood sampling devices (27.2%), transvenous endomyocardial biopsy procedures (9.1%), and multiple deficiencies in applying standard precautions (9.1%). CONCLUSION: The analysis of transmission pathways showed that some breaches in infection control measures, such as administration of drugs using multi-vial compounds and capillary blood sampling, are the most frequent routes for patient-to-patient transmission of hepatitis B virus. Moreover some outbreak reports underlined that heart-transplant recipients are at risk of contracting hepatitis B virus infection during the transvenous endomyocardial biopsy procedure through indirect contact with infected blood as a result of environmental contamination. To prevent transmission, healthcare workers must adhere to standard precautions and follow fundamental infection control principles, such as the use of sterile, single-use, disposable needles and avoiding the use of multi-vial compounds in all healthcare settings including outpatient settings.

Fever of unknown origin: a systematic review of the literature for 1995-2004.

BACKGROUND: Fever of unknown origin (FUO) identifies a pattern of fever with temperature higher than 38.3 degrees C on several occasions over more than 3 weeks, in which the diagnosis remains uncertain after an initial diagnostic work-up. The identification of the cause of FUO is a challenge in clinical practice despite recent advances in diagnostic techniques. There are more than 200 reported causes of FUO and they can be classified in four diagnostic categories: infections, neoplasms, non-infectious inflammatory diseases and miscellaneous. METHODS: We performed a systematic research of the literature on classical FUO to retrieve the review articles and case series published from 1995 to 2004, including articles from developing countries. The case series were reviewed to identify the tests commonly used both to qualify a fever as FUO and to determine the cause of the FUO, and to design an updated flow chart for the diagnosis of classical FUO. RESULTS AND CONCLUSIONS: No standardized diagnostic strategy could be determined. The diagnostic process should be guided by the potential diagnostic clues (PDCs) emerging from the history, physical examination and baseline tests. A standardized flow chart can be applied only in absence of PDCs or when the PDCs are contradictory.Nuclear medicine techniques are a valuable aid in the search for the origin of FUO due to bacterial infections or in the absence of PDCs.

[Cutaneous myiasis from Cordylobia anthropophaga in a traveller returning from Senegal: a case study]. / Miasi cutanea da Cordylobia anthropophaga in un viaggiatore di ritorno dal Senegal.

Myiasis is the infestation of human or animal tissues by fly larvae. The disease is widespread especially in tropical countries. Here we report a case of myiasis due to Cordylobia anthropophaga that occurred in a traveller returning from Senegal. This case has some peculiar characteristics, regarding the site of the lesion and the clinical presentation.