Background In this study we evaluated the incidence of invasive pulmonary aspergillosis among intubated patients with critical coronavirus disease 2019 (COVID-19) and evaluated different case definitions of invasive aspergillosis. Methods Prospective, multicentre study on adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation. All included participants underwent screening protocol for invasive pulmonary aspergillosis with bronchoalveolar lavage galactomannan and cultures performed on admission at 7 days and in case of clinical deterioration. Cases were classified as coronavirus associated pulmonary aspergillosis (CAPA) according to previous consensus definitions. The new definition was compared with putative invasive pulmonary aspergillosis (PIPA). Results A total of 108 patients were enrolled. Probable CAPA was diagnosed in 30 (27.7%) of patients after a median of 4 (2-8) days from intensive care unit (ICU) admission. Kaplan-Meier curves showed a significant higher 30-day mortality rate from ICU admission among patients with either CAPA (44% vs 19%, p= 0.002) or PIPA (74% vs 26%, p<0.001) when compared with patients not fulfilling criteria for aspergillosis. The association between CAPA [OR 3.53 (95%CI 1.29-9.67), P=0.014] or PIPA [OR 11.60 (95%CI 3.24-41.29) p<0.001] with 30-day mortality from ICU admission was confirmed even after adjustment for confounders with a logistic regression model. Among patients with CAPA receiving voriconazole treatment (13 patients, 43%) A trend toward lower mortality (46% vs 59% p=0.30) and reduction of galactomannan index in consecutive samples was observed. Conclusion We found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease

Objectives We aimed to develop and validate a risk score to predict severe respiratory failure (SRF) among patients hospitalized with coronavirus disease-2019 (COVID-19). Methods We performed a multicentre cohort study among hospitalized (>24 hours) patients diagnosed with COVID-19 from 22 February to 3 April 2020, at 11 Italian hospitals. Patients were divided into derivation and validation cohorts according to random sorting of hospitals. SRF was assessed from admission to hospital discharge and was defined as: Sp o 2 <93% with 100% Fi o 2 , respiratory rate >30 breaths/min or respiratory distress. Multivariable logistic regression models were built to identify predictors of SRF, β-coefficients were used to develop a risk score. Trial Registration NCT04316949 . Results We analysed 1113 patients (644 derivation, 469 validation cohort). Mean (±SD) age was 65.7 (±15) years, 704 (63.3%) were male. SRF occurred in 189/644 (29%) and 187/469 (40%) patients in the derivation and validation cohorts, respectively. At multivariate analysis, risk factors for SRF in the derivation cohort assessed at hospitalization were age ≥70 years (OR 2.74; 95% CI 1.66–4.50), obesity (OR 4.62; 95% CI 2.78–7.70), body temperature ≥38°C (OR 1.73; 95% CI 1.30–2.29), respiratory rate ≥22 breaths/min (OR 3.75; 95% CI 2.01–7.01), lymphocytes ≤900 cells/mm 3 (OR 2.69; 95% CI 1.60–4.51), creatinine ≥1 mg/dL (OR 2.38; 95% CI 1.59–3.56), C-reactive protein ≥10 mg/dL (OR 5.91; 95% CI 4.88–7.17) and lactate dehydrogenase ≥350 IU/L (OR 2.39; 95% CI 1.11–5.11). Assigning points to each variable, an individual risk score (PREDI-CO score) was obtained. Area under the receiver-operator curve was 0.89 (0.86–0.92). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 71.6% (65%–79%), 89.1% (86%–92%), 74% (67%–80%) and 89% (85%–91%), respectively. PREDI-CO score showed similar prognostic ability in the validation cohort: area under the receiver-operator curve 0.85 (0.81–0.88). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 80% (73%–85%), 76% (70%–81%), 69% (60%–74%) and 85% (80%–89%), respectively. Conclusion PREDI-CO score can be useful to allocate resources and prioritize treatments during the COVID-19 pandemic.

Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

Background and purpose — Several surgical approaches are used in primary total hip arthroplasty (THA). In this randomized controlled trial we compared gait, risk of fall, self-reported and clinical measurements between subjects after direct superior approach (DSA) versus posterolateral approach (PL) for THA. Patients and methods — Participants with DSA (n = 22; age 74 [SD 8.9]) and PL (n = 23; age 72 [7.7]) underwent gait analysis, risk of fall assessment and Timed Up and Go Test (TUG) before (PRE), 1 month (T1) and 3 months after (T3) surgery. Data on bleeding and surgical time was collected. Results — DSA resulted in longer surgical times (90 [14] vs. 77 [20] min) but lower blood loss (149 [66] vs. 225 [125] mL) than PL. DSA had lower risk of fall at T3 compared with T1 and higher TUG scores at T3 compared with T1 and PRE. PL improved balance at T3 compared with T1 and PRE. Spatiotemporal gait parameters improved over time for both DSA and PL with no inter-group differences, whereas DSA, regarding hip rotation range of motion, showed lower values at T3 and T1 compared with PRE and, furthermore, this group had lower values at T1 and T3 compared with PL. All foregoing comparisons are statistically signficant (p < 0.05) Interpretation — DSA showed longer surgical time and lower blood loss compared with PL and early improvements in TUG, spatiotemporal, and kinematic gait parameters, highlighting rapid muscle strength recovery.

Background: Dalbavancin is gaining interest in the treatment of complex osteoarticular (OA) infections. Objective: To conduct a population pharmacokinetic analysis of dalbavancin in a prospective cohort of adult patients with Gram-positive OA infections and to identify optimal dosing regimens for long term-treatment. Methods: Non-linear mixed-effects modelling was performed with Monolix. Monte Carlo simulations were performed with six dalbavancin regimens (1500mg at day 1; 1000mg at day 1 plus 500mg at day 8; 1500mg at day1 and 8; 1500mg at day1 and 8 plus 500, 1000 or 1500mg at day 36) to assess the PTA of three pharmacodynamic target of fAUC24h/MIC against S. aureus (>27.1, 53.3 and 111.1). Cumulative fraction of response (CFR) was calculated against MIC distribution of both MRSA and MSSA as well. Desirable PTAs and CFRs were ≥90%. Results: Fifteen patients provided 120 plasma concentrations. Most (73.3%) had prosthetic joint infections. Clinical cure rate was 87%. A two-compartment model with linear elimination well described the data. No covariate was retained in the final model. Pharmacokinetic dalbavancin estimates were 0.106L/h for CL and 36.4L for Vss. The tested dosing regimens granted desirable CFRs against S. aureus at the most effective PK/PD target for a period ranging 3-to-9 weeks. Conclusion: Giving a two 1500mg dosing regimen of dalbavancin one week apart may ensure efficacy against both MSSA and MRSA up to 5 weeks in patients with OA infections. Clinical assessment at that time may allow for considering whether or not an additional dose should be administered for prolonging effective treatment.

The non-negligible prevalence of MS among HIV-infected patients under cART requires a careful and periodic monitoring of its components, with particular attention to dyslipidemia and hypertension.

Nucleoside reverse transcriptase inhibitor (NRTI)- and protease inhibitor (PI)-sparing antiretroviral regimens may be useful in selected human immune deficiency virus (HIV)-infected patients with resistance or intolerance to these drug classes. This was an observational prospective study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted PI who switched to a dual regimen containing raltegravir plus etravirine. Patients were required not to have prior virological failure to raltegravir and to have efficacy of etravirine shown through the genotypic resistance assay in case of prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure. As a whole, 38 patients were enrolled. The mean duration of current regimen was 4.3 years, and the reason for simplification was toxicity in 29 patients and resistance to NRTIs in 9 patients. After switching, the percentage of patients with HIV RNA <20 copies/ml at week 48 was 81.6% in the intent-to-treat-exposed analysis. The switch led to a significant reduction in the mean serum triglyceride levels (-81.2 mg/dl), in the mean total cholesterol levels (-44.3 mg/dl), and in the prevalence of tubular proteinuria (-30.2%), with a significant increase in the mean phosphoremia (+0.52 mg/dl) and in both mean lumbar and femoral neck bone mineral density (+6.5% and +4.7%, respectively). Two patients (5.2%) had virological failure due to suboptimal adherence, and five subjects (13.1%) discontinued treatment due to adverse events. In our study, simplification to the dual-therapy raltegravir plus etravirine was associated with a good efficacy and tolerability, in addition to a favorable effect on kidney, bone, and serum lipids.

Purpose Current conservative treatments for knee OA provide limited benefits, with symptoms relief for a short amount of time. Regenerative medicine approaches such as the use of microfragmented adipose tissue (mFAT) showed promising results in terms of durable effects and the possibility to enhance tissue healing and counteract the progression of the pathology. Nevertheless, up to today, the large part of clinical data about mFAT use refers to uncontrolled studies, especially in the surgical setting. The purpose of this study was to evaluate the effectiveness of mFAT applied in association with arthroscopic debridement (AD) for the treatment of knee OA, in terms of symptoms relief and tissue healing. Methods This study is a prospective, randomized controlled clinical trial. 78 patients affected by knee OA grade 3–4 according to KL classification were randomly assigned to AD or AD + mFAT treatment groups. Clinical, radiological and serological assessments were performed at 6 months after treatment. Additional clinical evaluation was performed at the end of the study with an average follow-up of 26.1 ± 9.5 months. VAS, KOOS, WOMAC and SF-12 were also collected at both timepoints, KSS only at 6 months. Results Treatment with AD + mFAT improved functional scores at both 6 months (KOOS-PS: + 11.7 ± 20.2 vs + 24.4 ± 22.5, in AD and AD + mFAT, respectively, p = 0.024; KSS: + 14.9 ± 15.9 vs + 24.8 ± 23.5, in AD and AD + mFAT, respectively, p = 0.046) and 24-month follow-ups (KOOS-PS Functional subscale: − 2.0 ± 3.5 vs − 4.7 ± 4.2, in AD and AD + mFAT, respectively, p = 0.012). Lower T2-mapping scores were obtained in AD + mFAT-treated group in medial and lateral condyle compartments (p < 0.001). Slight increase was observed in the levels of a serum biomarker of cartilage deposition (PIIINP) in both groups at 6-month follow-up (p = 0.037). Conclusion mFAT improves functional outcome and MRI appearance when used in association with AD, therefore supporting its use in the treatment of knee OA in an arthroscopic setting.