BACKGROUNDA trial involving adults 50 years of age or older showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01 B adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older . METHODSThis randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50. RESULTSIn ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups. CONCLUSIONSIn our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older. ( 1020T h e ne w e ngl a nd jou r na l o f m e dicine H erpes zoster, or shingles, results from the reactivation of latent varicellazoster virus (VZV) and typically manifests as a vesicular, painful dermatomal rash.

anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

In this large, prospective, multinational cohort, more than one half of all cases of non-HACEK gram-negative bacillus endocarditis were associated with health care contact. Non-HACEK gram-negative bacillus endocarditis is not primarily a disease of injection drug users.

We appreciate the thoughtful comments of Drs Almonedro-Delia, Galvez-Acebal, and Rodriguez-Bano regarding our recent publication, "Association Between Surgical Indications, Operative Risk, and Clinical Outcome in Infective Endocarditis: a Prospective Study From the International Collaboration on Endocarditis." 1 These authors raise important issues for evaluating the impact of surgery on patient outcomes, particularly survival. We strongly agree that treatment selection bias and survivor bias are major issues when evaluating the impact of surgery on mortality and that the use of appropriate statistical methodologies is necessary to quantify an unbiased and causal association of the effect of surgical treatment on outcome. In our previous studies on the impact of surgery on mortality, we have used such methods, including propensity scores, 2 to account for selection bias and Cox proportional hazards models with surgery entered as a time-dependent covariate 3,4 for survivor bias adjustment. However, the objective of the current study was to evaluate the differences in clinical characteristics comparing patients treated with and without cardiac surgery for infective endocarditis, and to evaluate the relationship between surgical indications, operative risk (by using the Society of Thoracic Surgeons operative risk score), and outcome. Our results emphasize the relevance of specific surgical indications in treatment decisions in infective endocarditis, and the relationship between the Society of Thoracic Surgeons operative risk score and outcome, as well. The purpose of our study was not to determine the prognostic influence of surgery in comparison with medical therapy alone in infective endocarditis.

Mycobacterium ulcerans causes slowly progressive, destructive skin and soft tissue infections, known as Bairnsdale or Buruli ulcer (BU). Forty‐six delegates with experience in the management of BU attended a 1‐day conference in Melbourne on 10 February 2006, with the aim of developing a consensus approach to the diagnosis, treatment and control of BU. An initial draft document was extended and improved during a facilitated round table discussion. BU is an environmental infection that occurs in specific locations. The main risk factor for infection is contact with an endemic area. Prompt cleaning of abrasions sustained outdoors, wearing protective clothing, and avoiding mosquito bites may reduce an individual's risk of infection. BU can be rapidly and accurately diagnosed by polymerase chain reaction testing of ulcer swabs or biopsies. Best outcomes are obtained when the diagnosis is made early. To aid early diagnosis, health authorities should keep local populations informed of new outbreaks. BU is best treated with surgical excision, which, if possible, should include a small rim of healthy tissue. For small lesions this may be all that is required. However, there is a role for antibiotics for more extensive disease, and their use may allow more conservative surgery.

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.

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BackgroundHost factors and complications have been associated with higher mortality in infective endocarditis (IE). We sought to develop and validate a model of clinical characteristics to predict 6‐month mortality in IE.Methods and ResultsUsing a large multinational prospective registry of definite IE (International Collaboration on Endocarditis [ICE]–Prospective Cohort Study [PCS], 2000–2006, n=4049), a model to predict 6‐month survival was developed by Cox proportional hazards modeling with inverse probability weighting for surgery treatment and was internally validated by the bootstrapping method. This model was externally validated in an independent prospective registry (ICE‐PLUS, 2008–2012, n=1197). The 6‐month mortality was 971 of 4049 (24.0%) in the ICE‐PCS cohort and 342 of 1197 (28.6%) in the ICE‐PLUS cohort. Surgery during the index hospitalization was performed in 48.1% and 54.0% of the cohorts, respectively. In the derivation model, variables related to host factors (age, dialysis), IE characteristics (prosthetic or nosocomial IE, causative organism, left‐sided valve vegetation), and IE complications (severe heart failure, stroke, paravalvular complication, and persistent bacteremia) were independently associated with 6‐month mortality, and surgery was associated with a lower risk of mortality (Harrell's C statistic 0.715). In the validation model, these variables had similar hazard ratios (Harrell's C statistic 0.682), with a similar, independent benefit of surgery (hazard ratio 0.74, 95% CI 0.62–0.89). A simplified risk model was developed by weight adjustment of these variables.ConclusionsSix‐month mortality after IE is ≈25% and is predicted by host factors, IE characteristics, and IE complications. Surgery during the index hospitalization is associated with lower mortality but is performed less frequently in the highest risk patients. A simplified risk model may be used to identify specific risk subgroups in IE.