No consistent evidence of decreased exposure to varicella-zoster virus among older adults in countries with universal varicella vaccination

Background Universal varicella vaccination might reduce opportunities for varicella-zoster virus (VZV) exposure and protective immunological boosting, thus increasing herpes zoster incidence in latently infected adults. Here, we assessed humoral and cell-mediated immunity (CMI), as markers of VZV exposure, from adults aged ≥50 years. Methods We repurposed data from placebo recipients in a large multinational clinical trial (ZOE-50, NCT01165177). Countries were clustered based on their varicella vaccination programme characteristics, as having high, moderate or low VZV circulation. Anti-VZV antibody geometric mean concentrations, median frequencies of VZV-specific CD4 T cells and percentages of individuals with increases in VZV-specific CD4 T cell frequencies were compared across countries and clusters. Sensitivity analyses using a variable number of timepoints and different thresholds were also performed for CMI data. Results VZV-specific humoral immunity from 17 countries (12 high, two moderate, three low circulation) varied significantly between countries (p<0·0001) but not by VZV circulation. No significant differences were identified in VZV-specific CMI between participants from two high versus one low circulation countries. In 3/5 sensitivity analyses, increases in CMI were more frequent in high VZV circulation countries (0.03≤p<0.05). Conclusions We found no consistent evidence of reduced VZV exposure among older adults in countries with universal varicella vaccination.

Implantation of autologous Expanded Mesenchymal Stromal Cells in Hip Osteonecrosis through Percutaneous Forage: Evaluation of the Operative Technique

Bone forage to treat early osteonecrosis of the femoral head (ONFH) has evolved as the channel to percutaneously deliver cell therapy into the femoral head. However, its efficacy is variable and the drivers towards higher efficacy are currently unknown. The aim of this study was to evaluate the forage technique and correlate it with the efficacy to heal ONFH in a multicentric, multinational clinical trial to implant autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSCs). Methods: In the context of EudraCT 2012-002010-39, patients with small and medium-sized (mean volume = 13.3%, range: 5.4 to 32.2) ONFH stage II (Ficat, ARCO, Steinberg) C1 and C2 (Japanese Investigation Committee (JIC)) were treated with percutaneous forage and implantation of 140 million BM-hMSCs in a standardized manner. Postoperative hip radiographs (AP—anteroposterior and lateral), and MRI sections (coronal and transverse) were retrospectively evaluated in 22 patients to assess the femoral head drilling orientation in both planes, and its relation to the necrotic area. Results: Treatment efficacy was similar in C1 and C2 (coronal plane) and in anterior to posterior (transverse plane) osteonecrotic lesions. The drill crossed the sclerotic rim in all cases. The forage was placed slightly valgus, at 139.3 ± 8.4 grades (range, 125.5–159.3) with higher dispersion (f = 2.6; p = 0.034) than the anatomical cervicodiaphyseal angle. Bonferroni’s correlation between both angles was 0.50 (p = 0.028). More failures were seen with a varus drill positioning, aiming at the central area of the femoral head, outside the weight-bearing area (WBA) (p = 0.049). In the transverse plane, the anterior positioning of the drill did not result in better outcomes (p = 0.477). Conclusion: The forage drilling to deliver cells should be positioned within the WBA in the coronal plane, avoiding varus positioning, and central to anterior in the transverse plane. The efficacy of delivered MSCs to regenerate bone in ONFH could be influenced by the drilling direction. Standardization of this surgical technique is desirable.

Fidaxomicin for the treatment of Clostridioides difficile in children

Fidaxomicin is an oral narrow-spectrum novel 18-membered macrocyclic antibiotic that was initially approved in 2011 by the US FDA for the treatment of Clostridioides difficile infections (CDI) in adults. In February 2020, the FDA approved fidaxomicin for the treatment of CDI in children age >6 months. In adults, fidaxomicin is as efficacious as vancomycin in treating CDI and reduces the risk of recurrent CDI. An investigator-blinded, randomized, multicenter, multinational clinical trial comparing the efficacy and safety of fidaxomicin with vancomycin in children was recently published confirming similar findings as previously reported in adults. Fidaxomicin is the first FDA-approved treatment for CDI in children and offers a promising option for reducing recurrent CDI in this population.

Linagliptin and pioglitazone combination therapy versus monotherapy with linagliptin or pioglitazone: A randomised, double-blind, parallel-group, multinational clinical trial

Linagliptin plus pioglitazone single-pill combinations were evaluated. Patients ( n = 936) with insufficient glycaemic control, despite lifestyle interventions, were randomised for 30 weeks to either monotherapy with linagliptin 5 mg; pioglitazone 15, 30 or 45 mg; or single-pill combination with linagliptin 5 mg plus pioglitazone 15, 30 or 45 mg. An extension (⩽54 weeks) planned to evaluate linagliptin plus pioglitazone 30 or 45 mg single-pill combinations was not completed due to a protocol amendment. Adjusted mean (95% confidence interval) differences in HbA1c change from baseline at week 30 for linagliptin plus pioglitazone 15, 30 and 45 mg were −0.17% (−0.41, 0.07), −0.37% (−0.60, −0.14) and −0.41% (−0.64, −0.18) versus pioglitazone monotherapies, respectively, and −0.44% (−0.67, −0.20), −0.68% (−0.91, −0.44) and −0.89% (−1.12, −0.66) versus linagliptin monotherapy, respectively. Single-pill combinations were generally well tolerated. Hypoglycaemia frequency was ⩽1.5% per group. Linagliptin plus pioglitazone combinations were efficacious, with safety profiles comparable to the individual monotherapies.