BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. DESIGN: Phase III double-blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989). MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion). RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group. CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Cutoffs for white-coat and masked blood pressure effects: an ambulatory blood pressure monitoring study.

The values used to define white-coat and masked blood pressure (BP) effects are usually arbitrary. This study aimed at investigating the accuracy of various cutoffs based on the differences (ΔBP) between office BP (OBP) and 24h-ambulatory BP monitoring (ABPM) to identify white-coat (WCH) and masked (MH) hypertension, which are phenotypes coupled with adverse prognosis. This cross-sectional study included 11,350 [Derivation cohort; 45% men, mean age = 55.1 ± 14.1 years, OBP = 132.1 ± 17.6/83.9 ± 12.5 mmHg, 24 h-ABPM = 121.6 ± 11.4/76.1 ± 9.6 mmHg, 25% using antihypertensive medications (AH)] and 7220 (Validation cohort; 46% men, mean age = 58.6 ± 15.1 years, OBP = 136.8 ± 18.7/87.6 ± 13.0 mmHg, 24 h-ABPM = 125.5 ± 12.6/77.7 ± 10.3 mmHg; 32% using AH) unique individuals who underwent 24 h-ABPM. We compared the sensitivity, specificity, positive and negative predictive values and area under the curve (AUC) of diverse ΔBP cutoffs to detect WCH (ΔsystolicBP/ΔdiastolicBP = 28/17, 20/15, 20/10, 16/11, 15/9, 14/9 mmHg and ΔsystolicBP = 13 and 10 mmHg) and MH (ΔsystolicBP/ΔdiastolicBP = -14/-9, -5/-2, -3/-1, -1/-1, 0/0, 2/2 mmHg and ΔsystolicBP = -5 and -3mmHg). The 20/15 mmHg cutoff showed the best AUC (0.804, 95%CI = 0.794-0.814) to detect WCH, while the 2/2 mmHg cutoff showed the highest AUC (0.741, 95%CI = 0.728-0.754) to detect MH in the Derivation cohort. Both cutoffs also had the best accuracy to detect WCH (0.767, 95%CI = 0.754-0.780) and MH (0.767, 95%CI = 0.750-0.784) in the Validation cohort. In secondary analyses, these cutoffs had the best accuracy to detect individuals with higher and lower office-than-ABPM grades in both cohorts. In conclusion, the 20/15 and 2/2 mmHg ΔBP cutoffs had the best accuracy to detect hypertensive patients with WCH and MH, respectively, and can serve as indicators of marked white-coat and masked BP effects derived from 24 h-ABPM.

Effect of Dietary Supplementation with Organic Silicon on the Growth Performance, Blood Biochemistry, Digestive Enzymes, Morphohistology, Intestinal Microbiota and Stress Resistance in Juvenile Hybrid Tilapia (Oreochromis mossambicus × Oreochromis niloticus).

In recent decades, interest has been aroused worldwide in the use of silicon in nutrition; however, information on its effect on nutrition and metabolism of fish is limited. The objective of the research was to evaluate the effect of dietary supplementation with organic silicon on the growth performance, blood biochemistry, digestive enzymes, morphohistology and intestinal microbiota and stress resistance in hybrid Tilapia (Oreochromis mossambicus × Oreochromis niloticus). Methodologically, six levels of organic silicon (DOS) [control (0), 10, 20, 30, 40 and 50 mg·kg-1] were used to feed juvenile fish (initial weight 7.51 ± 0.25 g) grown for eight weeks in 18 aquariums (15 fish/aquarium). The results indicated that growth performance showed differences (p < 0.05) for specific growth rate, feed conversion and survival. Triglycerides, cholesterol and glucose, transaminases and digestive enzymes were significantly influenced by DOS levels. The histological study confirmed that the administered diets did not cause damage and induced significant morphological changes in the proximal intestine. The 16S rRNA gene sequencing analysis of the gut microbiota showed a high diversity and richness of OTU/Chao-1, with Fusobacteria, Proteobacteria, Bacteroidetes and Acidobacteria predominating in the DOS treatments compared to the control (p < 0.05). Induction of hypoxia stress after the feeding period showed a significant relative survival rate of 83.33% in fish fed 50 mg·kg-1. It is concluded that the DOS treatments performed better than the control treatment in most of the variables analysed. DOS had no negative effects on the fish. The results showed that up to 50 mg·kg-1 DOS improved digestive, metabolic and growth performance in hybrid Tilapia.

Economic valuation of Harmful Algal Blooms (HAB): Methodological challenges, policy implications, and an empirical application.

This paper presents a literature review on the economic valuation of Harmful Algal Bloom (HAB) impacts, identifying methodological challenges, policy implications, and gaps. Unlike previous literature reviews, we are particularly interested in determining whether the economic valuations of HABs have included a policy analysis. Our paper provides a conceptual framework that allows us to evaluate whether applications of economic studies of HABs are consistent with a well-defined economic welfare analysis. It links methodologies and techniques with welfare measures, data types, and econometric methods. Based on this literature review, we present an example of economic valuation that closes the gap between policy analysis and valuation methodology. We use a stated preferences study to estimate a "seafood price premium" to create a fund to support monitoring systems and for damage compensation to producers in the presence of HABs. Results show that most economic studies on HAB valuation do not consider any cost-benefit analysis of a defined policy intervention. The predominant economic valuation methodology uses market information to estimate a proxy for welfare measure of the impact of HABs (loss revenue, sales, exports). Moreover, nonuse and indirect use values are ignored in the literature, while stated preference methodologies are underrepresented. Finally, results from 1293 surveys found that people are willing to pay an increase in the price of mussels to support a policy that informs on HAB. However, the lack of institutional trust affects the probability of paying negatively.

Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes.

In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mitosis, DNA damage response including nucleotide excision repair, ATM- and ATR-mediated damage response, homologous repair and non-homologous end joining. VCP variants cause multisystem proteinopathy, and pathology can arise in several tissue types such as skeletal muscle, bone, brain, motor neurons, sensory neurons and possibly cardiac muscle, with the disease course being challenging to predict.

Determination of prognostic markers for COVID-19 disease severity using routine blood tests and machine learning.

The need for the identification of risk factors associated to COVID-19 disease severity remains urgent. Patients' care and resource allocation can be potentially different and are defined based on the current classification of disease severity. This classification is based on the analysis of clinical parameters and routine blood tests, which are not standardized across the globe. Some laboratory test alterations have been associated to COVID-19 severity, although these data are conflicting partly due to the different methodologies used across different studies. This study aimed to construct and validate a disease severity prediction model using machine learning (ML). Seventy-two patients admitted to a Brazilian hospital and diagnosed with COVID-19 through RT-PCR and/or ELISA, and with varying degrees of disease severity, were included in the study. Their electronic medical records and the results from daily blood tests were used to develop a ML model to predict disease severity. Using the above data set, a combination of five laboratorial biomarkers was identified as accurate predictors of COVID-19 severe disease with a ROC-AUC of 0.80 ​±â€‹ 0.13. Those biomarkers included prothrombin activity, ferritin, serum iron, ATTP and monocytes. The application of the devised ML model may help rationalize clinical decision and care.

Structure-based computational design of antibody mimetics: challenges and perspectives.

The design of antibody mimetics holds great promise for revolutionizing therapeutic interventions by offering alternatives to conventional antibody therapies. Structure-based computational approaches have emerged as indispensable tools in the rational design of those molecules, enabling the precise manipulation of their structural and functional properties. This review covers the main classes of designed antigen-binding motifs, as well as alternative strategies to develop tailored ones. We discuss the intricacies of different computational protein-protein interaction design strategies, showcased by selected successful cases in the literature. Subsequently, we explore the latest advancements in the computational techniques including the integration of machine and deep learning methodologies into the design framework, which has led to an augmented design pipeline. Finally, we verse onto the current challenges that stand in the way between high-throughput computer design of antibody mimetics and experimental realization, offering a forward-looking perspective into the field and the promises it holds to biotechnology.

Effectiveness of the fourth dose of COVID-19 vaccines against severe COVID-19 among adults 40 years or older in Brazil: a population-based cohort study.

Background: The emergence of COVID-19 variants with immune scape and the waning of primary vaccine schemes effectiveness have prompted many countries to indicate first and second booster COVID-19 vaccine doses to prevent severe COVID-19. However, current available evidence on second booster dose effectiveness are mostly limited to high-income countries, older adults, and mRNA-based vaccination schemes scenarios. We aimed to investigate the relative vaccine effectiveness (rVE) of the fourth dose compared to three doses for severe COVID-19 outcomes in Brazil; and compare the rVE of a fourth dose with an mRNA vaccine compared to adenovirus-based product in the same settings. Methods: We performed a target emulated trial using a population-based cohort of individuals aged 40 years or older who have received a homologous primary scheme of CoronaVac, ChAdOx1, or BNT162b2, and any third dose product and were eligible for the fourth dose in Brazil. The primary outcome was COVID-19 associated hospitalization or death. We built Cohort A matching individuals vaccinated with a fourth dose to individuals who received three doses to estimate the rVE of the fourth dose. We built Cohort B, a subset of Cohort A, matching mRNA-based (mRNA) to adenovirus-based fourth dose vaccinated individuals to compare their relative hazards for severe COVID-19. Findings: 46,693,484 individuals were included in Cohort A and 6,763,016 in Cohort B. 45% of them were aged between 40 and 60 years old, and 48% between 60 and 79 years old. In Cohort A, the most common previous series was a ChAdOx1 two-dose followed by BNT162b2 (44%), and a CoronaVac two-dose followed by a BNT162b2 (36%). Among those fourth dose vaccinated, 36.9% received ChAdOx1, 32.7% Ad26.COV2.S, 25.8% BNT162b2, and 4.7% CoronaVac. In Cohort B, among those who received an adenovirus fourth dose, 53.7% received ChAdOx1 and 46.3% received Ad26.COV2.S. The estimated rVE for the primary outcome of four doses compared to three doses was 44.1% (95% CI 42.3-46.0), with some waning during follow-up (rVE 7-60 days 46.8% [95% CI 44.4-49.1], rVE after 120 days 33.8% [95% CI 18.0-46.6]). Among fourth dose vaccinated individuals, mRNA-based vaccinated individuals had lower hazards for hospitalization or death compared to adenovirus-vaccinated individuals (HR 0.81, 95% CI 0.75-0.87). After 120 days, no difference in hazards between groups was observed (HR 1.35, 95% CI 0.93-1.97). Similar findings were observed for hospitalization and death separately, except no evidence for differences between fourth dose brands for death in Cohort B. Interpretation: In a heterogeneous scenario of primary and first booster vaccination combinations, a fourth dose provided meaningful and durable protection against severe COVID-19 outcomes. Compared to adenovirus-based booster, a fourth dose wild-type mRNA vaccine was associated with immediate lower hazards of hospitalization or death unsustained after 120 days. Funding: None.

Microplastics in seafood: Consumer preferences and valuation for mitigation technologies.

Microplastics, an emerging pollutant, have garnered widespread attention due to potential repercussions on human health and the environment. Given the critical role of seafood in food security, growing concerns about microplastics might be detrimental to meeting future global food demand. This study employed a discrete choice experiment to investigate Chilean consumers' preferences for technology aimed at mitigating microplastic levels in mussels. Using a between-subjects design with information treatments, we examined the impact of informing consumers about potential human health and environmental effects linked to microplastics pollution on their valuation for the technology. We found that the information treatments increased consumers' willingness to pay for mussels. Specifically, consumers were willing to pay a premium of around US$ 4 for 250 g of mussel meat with a 90 % depuration efficiency certification. The provision of health impact information increased the price premium by 56 %, while the provision of environmental information increased it by 21 %. Furthermore, combined health and environmental information significantly increased the probability of non-purchasing behavior by 22.8 % and the risk perception of microplastics for human health by 5.8 %. These results emphasized the critical role of information in shaping consumer preferences and provided evidence for validating investment in research and development related to microplastic pollution mitigation measures.

Estimation of genetic parameters for maintenance energy requirements and residual feed intake in Nellore cattle.

We estimated heritabilities and genetic and phenotypic correlation estimates for maintenance energy requirements (NEmR), residual feed intake (RFI), growth, carcass and reproductive indicator traits, using data from 41 feed efficiency trials in Brazil, comprising 4381 males and females. Continuous traits were analysed using a linear animal model and threshold traits were analysed using a threshold animal model. The heritability estimates were low for RFI (0.190) and NEmR (0.193); other heritabilities were mainly moderate (growth and carcass traits) or high (sexual precocity traits). The genetic correlation of RFI with NEmR was high (0.701). The genetic correlations of NEmR were low with carcass and reproductive traits, and moderate with growth traits. Thus, selection to improve weaning weight and female sexual precocity indicator traits would not affect maintenance energy requirement. Genetic selection to reduce maintenance energy requirements is feasible and would also reduce DMI and RFI. Selection to improve RFI can be used to identify animals with lower maintenance energy requirements. Long-term selection to reduce RFI and NEmR would have favourable effects on yearling weight, carcass muscle indicator traits and female sexual precocity. Genetic (co)variance component estimates for NEmR, in conjunction with economic values of selection criteria, may be used to develop novel approaches for genetic selection to improve efficiency of beef production.

Identification and characterization of a nonbiological small-molecular mimic of a Zika virus conformational neutralizing epitope.

Antigenic similarities between Zika virus (ZIKV) and other flaviviruses pose challenges to the development of virus-specific diagnostic tools and effective vaccines. Starting with a DNA-encoded one-bead-one-compound combinatorial library of 508,032 synthetic, non-natural oligomers, we selected and characterized small molecules that mimic ZIKV epitopes. High-throughput fluorescence-activated cell sorter-based bead screening was used to select molecules that bound IgG from ZIKV-immune but not from dengue-immune sera. Deep sequencing of the DNA from the "Zika-only" beads identified 40 candidate molecular structures. A lead candidate small molecule "CZV1-1" was selected that correctly identifies serum specimens from Zika-experienced patients with good sensitivity and specificity (85.3% and 98.4%, respectively). Binding competition studies of purified anti-CZV1-1 IgG against known ZIKV-specific monoclonal antibodies (mAbs) showed that CZV1-1 mimics a nonlinear, neutralizing conformational epitope in the domain III of the ZIKV envelope. Purified anti-CZV1-1 IgG neutralized infection of ZIKV in cell cultures with potencies comparable to highly specific ZIKV-neutralizing mAbs. This study demonstrates an innovative approach for identification of synthetic non-natural molecular mimics of conformational virus epitopes. Such molecular mimics may have value in the development of accurate diagnostic assays for Zika, as well as for other viruses.

In vitro and ex vivo activity of the fluoroquinolone DC-159a against mycobacteria.

Antimicrobial resistance is a global health problem. In 2021, it was estimated almost half a million of multidrug-resistant tuberculosis (MDR-TB) cases. Besides, non-tuberculous mycobacteria (NTM) are highly resistant to several drugs and the emergence of fluoroquinolone (FQ) resistant M. tuberculosis (Mtb) is also a global concern making treatments difficult and with variable outcome. The aim of this study was to evaluate the activity of the FQ, DC-159a, against Mtb and NTM and to explore the cross-resistance with the currently used FQs.A total of 12 pre-extensively drug-resistant (XDR) Mtb, 2 XDR, 36 fully drug susceptible strains and 41 NTM isolates were included to estimate the in vitro activity of DC-159a, moxifloxacin (MOX) and levofloxacin (LX), using minimal inhibitory and bactericidal concentration (MIC and MBC). The activity inside the human macrophages and pulmonary epithelial cells were also determined.DC-159a was active in vitro and ex vivo against mycobacteria. Besides, it was more active than MOX/LX. Moreover, no cross-resistance was evidenced between DC-159a and LX/MOX as DC-159a could inhibit Mtb and MAC strains that were already resistant to LX/MOX.DC-159a could be a possible candidate in new therapeutic regimens for MDR/ XDR-TB and mycobacterioses cases.

Factors influencing adverse events following COVID-19 vaccination.

Various novel platform technologies have been used for the development of COVID-19 vaccines. In this nested cohort study among healthcare workers in Australia and Brazil who received three different COVID-19-specific vaccines, we (a) evaluated the incidence of adverse events following immunization (AEFI); (b) compared AEFI by vaccine type, dose and country; (c) identified factors influencing the incidence of AEFI; and (d) assessed the association between reactogenicity and vaccine anti-spike IgG antibody responses. Of 1302 participants who received homologous 2-dose regimens of ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech) or CoronaVac (Sinovac), 1219 (94%) completed vaccine reaction questionnaires. Following the first vaccine dose, the incidence of any systemic reaction was higher in ChAdOx1-S recipients (374/806, 46%) compared with BNT162b2 (55/151, 36%; p = 0.02) or CoronaVac (26/262, 10%; p < 0.001) recipients. After the second vaccine dose, the incidence of any systemic reaction was higher in BNT162b2 recipients (66/151, 44%) compared with ChAdOx1-S (164/806, 20%; p < 0.001) or CoronaVac (23/262, 9%; p < 0.001) recipients. AEFI risk was higher in younger participants, females, participants in Australia, and varied by vaccine type and dose. Prior COVID-19 did not impact the risk of AEFI. Participants in Australia compared with Brazil reported a higher incidence of any local reaction (170/231, 74% vs 222/726, 31%, p < 0.001) and any systemic reaction (171/231, 74% vs 328/726, 45%, p < 0.001), regardless of vaccine type. Following a primary course of ChAdOx1-S or CoronaVac vaccination, participants who did not report AEFI seroconverted at a similar rate to those who reported local or systemic reactions. In conclusion, we found that the incidence of AEFI was influenced by participant age and COVID-19 vaccine type, and differed between participants in Australia and Brazil.

Assessing the incorporation of latent variables in the estimation of the value of a statistical life.

For many years, the economic literature has recognized the role of attitudes, beliefs, and perceptions in estimating the value of a statistical life (VSL). However, few applications have attempted to include them. This article incorporates the perceived controllability and concern about traffic and cardiorespiratory risks to estimate VSL using a hybrid choice model (HCM). The HCM allows us to include unobserved heterogeneity and improve behavioral realism explicitly. Using data from a choice experiment conducted in Santiago, Chile, we estimate a VSL of US$3.78 million for traffic risks and US$2.06 million for cardiorespiratory risks. We found that higher controllability decreases the likelihood that the respondents would be willing to pay for risk reductions in both risks. On the other hand, concern about these risks decreases the willingness to pay for traffic risk reductions but increases it for cardiorespiratory risk reductions.

Bilateral Combined Rhegmatogenous and Tractional Retinal Detachments Due to Persistent High-Titer Syphilis.

A 23-year-old man developed bilateral rhegmatogenous retinal detachments secondary to high-titer ocular syphilis. The patient's titer increased four-fold after completing a 14-day course of intravenous penicillin (IVP). He underwent bilateral pars plana vitrectomy with silicone oil fill in both eyes. In this article, the authors propose an updated treatment method for patients with advanced ocular syphilis that includes oral doxycycline for 30 days following 14 days of IVP to optimally minimize the patient's infectious burden. Following surgery and this new treatment regime, this patient's best-corrected visual acuity 10 weeks postoperatively measured 20/50 in the right eye and 20/30 in the left eye. This case highlights a rare but devastating complication of ocular syphilis. We suggest the addition of oral doxycycline to IVP for patients with syphilis titers ≥ 1:256, HIV co-infection, and presence of posterior retinitis. [Ophthalmic Surg Lasers Imaging Retina 2024;55:46-50.].

Evolutionary deletions within the SARS-CoV-2 genome as signature trends for virus fitness and adaptation.

Coronaviruses are large RNA viruses that can infect and spread among humans and animals. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019, has evolved since its first detection in December 2019. Deletions are a common occurrence in SARS-CoV-2 evolution, particularly in specific genomic sites, and may be associated with the emergence of highly competent lineages. While deletions typically have a negative impact on viral fitness, some persist and become fixed in viral populations, indicating that they may confer advantageous benefits for the virus's adaptive evolution. This work presents a literature review and data analysis on structural losses in the SARS-CoV-2 genome and the potential relevance of specific signatures for enhanced viral fitness and spread.

Oxidative Stress Levels and DNA Repair Kinetics in Senescent Primary Human Fibroblasts Exposed to Chronic Low Dose Rate of Ionizing Radiation.

BACKGROUND: Exposure to low dose rate (LDR) radiation may accelerate aging processes. Previously, we identified numerous LDR-induced pathways involved in oxidative stress (OS) and antioxidant systems, suggesting that these pathways protect against premature senescence (PS). This study aimed to investigate if there are differences between young replicative senescent (RS) and PS cells considering DNA repair kinetics, OS, and DNA damage localized in the telomeres. METHODS: We established PS cells by culturing and passaging young primary fibroblasts exposed to LDR. Then, RS cells were established by culturing and passaging young fibroblasts until they stopped proliferating. Senescence was characterized by analyzing telomere length and senescence-associated ß-galactosidase (SA-ß-gal) staining. DNA damage and repair were evaluated with γH2AX foci formation; telomere identification was carried out using the fluorescence in situ hybridization (FISH) probe; and oxidative stress was assessed by measuring 8-oxo-dG in the medium. RESULTS: The data indicate the following: young cells have a better ability to cope with LDR-induced oxidative stress; RS and PS have higher steady-state levels of DNA damage; RS have slower DNA repair kinetics; and PS/RS have elevated levels of telomeric DNA damage. CONCLUSION: Our main conclusion is that PS and RS differ regarding DNA repair kinetics and SA-ß-gal levels.

Long-term oncological and surgical outcomes after Video Endoscopic Inguinal Lymphadenectomy (VEIL) in patients with penile cancer

ABSTRACT Objective: To report outcomes from the largest multicenter series of penile cancer patients undergoing video endoscopic inguinal lymphadenectomy (VEIL). Materials and Methods: Retrospective multicenter analysis. Authors of 21 centers from the Penile Cancer Collaborative Coalition-Latin America (PeC-LA) were included. All centers performed the procedure following the same previously described standardized technique. Inclusion criteria included penile cancer patients with no palpable lymph nodes and intermediate/high-risk disease and those with non-fixed palpable lymph nodes less than 4 cm in diameter. Categorical variables are shown as percentages and frequencies whereas continuous variables as mean and range. Results: From 2006 to 2020, 210 VEIL procedures were performed in 105 patients. Mean age was 58 (45-68) years old. Mean operative time was 90 minutes (60-120). Mean lymph node yield was 10 nodes (6-16). Complication rate was 15.7%, including severe complications in 1.9% of procedures. Lymphatic and skin complications were noted in 8.6 and 4.8% of patients, respectively. Histopathological analysis revealed lymph node involvement in 26.7% of patients with non-palpable nodes. Inguinal recurrence was observed in 2.8% of patients. 10y- overall survival was 74.2% and 10-y cancer specific survival was 84.8%. CSS for pN0, pN1, pN2 and pN3 were 100%, 82.4%, 72.7% and 9.1%, respectively. Conclusion: VEIL seems to offer appropriate long term oncological control with minimal morbidity. In the absence of non-invasive stratification measures such as dynamic sentinel node biopsy, VEIL emerged as the alternative for the management of non-bulky lymph nodes in penile cancer.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial.

Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.