Explore the vast range of titles available.

Background Peritoneal-based malignancy (PBM), especially peritoneal carcinomatosis from gastrointestinal malignancies traditionally carries a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC) have been shown to attain long median survival of 34–92 months and 5 year survival of 29–59 % in patients with favorable histopathological subtypes. Recurrence after CRS and HIPEC poses a management dilemma. This paper evaluates our institution’s experience with repeat CRS and HIPEC, its associated morbidity and outcomes. Methods One-hundred and thirty underwent CRS and HIPEC for PBM from April 2001 to June 2013. 49 had peritoneal recurrences, of which 24 had peritoneal only recurrence. 7 out of the 24 underwent a second CRS and HIPEC. Results Five females and two males with median age of 51 (37–63), underwent a second CRS and HIPEC. The primary malignancies were: 1 peritoneal mesothelioma, 3 appendiceal, 2 ovarian, and 1 colorectal cancers. Median peritoneal cancer indices for the initial and second CRS were 19 and 12, respectively. Completeness of cytoreduction score of 0 was achieved for all patients. Median hospitalization after second CRS and HIPEC was 12 days (7–60). 1 out of 7 (14 %) experienced grade 3 or 4 post-operative complications. There was no 30-day or inpatient mortality. Median follow-up was 13 months (1–97). Median disease-free interval between the first CRS and HIPEC to peritoneal recurrence was 20 months (14–87). Median disease-free survival of 6 months (1–97) was achieved after the second CRS and HIPEC. Six patients remained alive without disease and one passed away with disease. Two had recurrences at 12 and 71 months after second CRS and HIPEC, 1 died and the other, still alive, went on to have a third CRS. Conclusion Repeat CRS and HIPEC can achieve prolonged survival in selected patients with peritoneal-based malignancies, and can be performed with acceptable morbidity and mortality.

Generation of large amounts of genomic data is now feasible and cost-effective with improvements in next generation sequencing (NGS) technology. Ribonucleic acid sequencing (RNA-Seq) is becoming the preferred method for comprehensively characterising global transcriptome activity. Unique to cytoreductive surgery (CRS), multiple spatially discrete tumour specimens could be systematically harvested for genomic analysis. To facilitate such downstream analyses, laser capture microdissection (LCM) could be utilized to obtain pure cell populations. The aim of this protocol study was to develop a methodology to obtain high-quality expression data from matched primary tumours and metastases by utilizing LCM to isolate pure cellular populations. We demonstrate an optimized LCM protocol which reproducibly delivered intact RNA used for RNA sequencing and quantitative polymerase chain reaction (qPCR). After pathologic annotation of normal epithelial, tumour and stromal components, LCM coupled with cDNA library generation provided for successful RNA sequencing. To illustrate our framework’s potential to identify targets that would otherwise be missed with conventional bulk tumour sequencing, we performed qPCR and immunohistochemical technical validation to show that the genes identified were truly expressed only in certain sub-components. This study suggests that the combination of matched tissue specimens with tissue microdissection and NGS provides a viable platform to unmask hidden biomarkers and provides insight into tumour biology at a higher resolution.

RET fusion–positive lung cancer accounts for 1 to 2% of non–small-cell lung cancers. Among previously treated patients with RET fusion–positive lung cancer, 64% of those who received selpercatinib, a RET kinase inhibitor, had a response, and among previously untreated patients, 85% had a response. Approximately one third of the patients had adverse events of grade 3 or higher.

Neonatal infections cause a significant proportion of deaths in the first week of life, yet little is known about risk factors and pathways of transmission for early-onset neonatal sepsis globally. We aimed to estimate the risk of neonatal infection (excluding sexually transmitted diseases [STDs] or congenital infections) in the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period. We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, and the World Health Organization Regional Databases for studies of maternal infection, vertical transmission, and neonatal infection published from January 1, 1960 to March 30, 2013. Studies were included that reported effect measures on the risk of neonatal infection among newborns exposed to maternal infection. Random effects meta-analyses were used to pool data and calculate the odds ratio estimates of risk of infection. Eighty-three studies met the inclusion criteria. Seven studies (8.4%) were from high neonatal mortality settings. Considerable heterogeneity existed between studies given the various definitions of laboratory-confirmed and clinical signs of infection, as well as for colonization and risk factors. The odds ratio for neonatal lab-confirmed infection among newborns of mothers with lab-confirmed infection was 6.6 (95% CI 3.9-11.2). Newborns of mothers with colonization had a 9.4 (95% CI 3.1-28.5) times higher odds of lab-confirmed infection than newborns of non-colonized mothers. Newborns of mothers with risk factors for infection (defined as prelabour rupture of membranes [PROM], preterm <37 weeks PROM, and prolonged ROM) had a 2.3 (95% CI 1.0-5.4) times higher odds of infection than newborns of mothers without risk factors. Neonatal infection in the first week of life is associated with maternal infection and colonization. High-quality studies, particularly from settings with high neonatal mortality, are needed to determine whether targeting treatment of maternal infections or colonization, and/or prophylactic antibiotic treatment of newborns of high risk mothers, may prevent a significant proportion of early-onset neonatal sepsis. Please see later in the article for the Editors' Summary.

Pre-exposure prophylaxis (PrEP) is traditionally prescribed by HIV specialist physicians. Given finite specialist resources, there is a need to scale up PrEP delivery by decentralizing services via other healthcare professionals. We aimed to assess the feasibility of delivering PrEP to men who have sex with men (MSM) through primary care physicians and sexual health clinic nurses. We piloted a multi-component, implementation and dissemination research program to increase provision of PrEP through primary care physicians and sexual health clinic nurses in Toronto, Canada. Community-based organizations (CBOs) provided prospective participants with information cards that contained links to an online module on engaging providers in a conversation about PrEP. In our patient-initiated continuing medical education (PICME) strategy, participants saw their family doctors and gave them the card, which also contained a link to a Continuing Medical Education module. In the nurse-led strategy, participants visited one of two participating clinics to obtain PrEP. We administered an optional online questionnaire to patients and providers at baseline and six months. CBOs distributed 3043 cards. At least 339 men accessed the online module and 196 completed baseline questionnaires. Most (55%) intended to visit nurses while 21% intended to consult their physicians. Among 45 men completing follow-up questionnaires at 6 months, 31% reported bringing cards to their physicians and obtaining PrEP through them; sexual health clinics delivered PrEP to 244 patients. Participants who went through the PICME approach reported no changes in relationships with their providers. Nurses showed fidelity to PrEP prescribing guidelines. Nurse-led PrEP and patient-initiated continuing medical education (PICME) for primary care physicians are feasible strategies to increase PrEP uptake. Nurse-led PrEP delivery was preferred by most patients.

Background Matings between male Aedes aegypti mosquitoes infected with w AlbB strain of Wolbachia and wild-type females yield non-viable eggs, thereby suppressing Ae. aegypti abundance in the field. We evaluated the spillover efficacy of releasing w AlbB-infected Ae. aegypti male mosquitoes to suppress dengue in sites adjacent to release sites (spillover sites). Methods The protocol of a two-arm cluster-randomised test-negative controlled trial (cRCT) was specified and emulated using a nationally representative dengue test-negative/positive database of 454,437 individuals reporting for febrile illness to primary or secondary care in public healthcare institutions. Spillover intervention sites were defined by geolocating locations which were adjacent to, i.e. shared geographical borders with, actual Wolbachia intervention sites. We built a cohort of individuals who resided in spillover sites versus a comparator control group who resided in sites which did not receive Wolbachia interventions. We emulated a constrained randomisation protocol used in cRCTs to balance dengue risk between spillover and control arms in the pre-intervention period. We matched individuals reporting for testing in intervention and control groups by calendar time and a high-dimensional battery of sociodemographic, environmental and anthropogenic variables. Intention-to-treat analysis was conducted to estimate the protective efficacy against dengue given spillover Wolbachia exposure. Results The final cohort consisted of 2354 matched individuals residing in Wolbachia spillover and control sites for at least 3 months in the study period. Compared to the controls, individuals residing in spillover sites for 3 or more months were associated with a 45% (OR: 0.55, 95% CI: 0.42‒0.74) reduction in risk of contracting dengue. Higher durations of spillover Wolbachia exposure also modestly increased protective efficacies. Compared to the control arm, the proportion of virologically confirmed dengue cases was lower in the spillover arm overall and across each subgroup. Protective efficacies were found across all years, age and sex subgroups. Conclusions Our results demonstrated the potential of Wolbachia -mediated sterility for reducing the risk of contracting dengue even in sites which were not directly treated by the intervention.

In 2015/2016, Canada’s largest provinces implemented publicly-funded human papillomavirus (HPV) vaccination programs for gay, bisexual, and other men who have sex with men (GBM) ≤ 26 years old. We sought to describe HPV vaccine uptake among GBM and determine barriers and facilitators to vaccine initiation with a focus on healthcare access and utilization. Engage is a cohort study among GBM aged 16 + years in three Canadian cities recruited from 2017 to 2019 via respondent driven sampling (RDS). Men completed a comprehensive questionnaire at baseline. By publicly-funded vaccine eligibility (≤26 years old = eligible for vaccination, ≥27 years old = ineligible), we described HPV vaccine uptake (initiation = 1 + dose, completion = 3 doses) and explored factors associated with vaccine initiation using Poisson regression. All analyses were weighted with the RDS-II Volz-Heckathorn estimator. Across the three cities, 26–35% and 14–21% of men ≤ 26 years and 7–26% and 2–9% of men ≥ 27 years initiated and completed HPV vaccination, respectively. Vaccine initiation was significantly associated with STI/HIV testing or visiting a HIV care specialist in the past six months (≤26: prevalence ratio[PR] = 2.15, 95% confidence interval[CI] 1.06–4.36; ≥27: PR = 2.73, 95%CI 1.14–6.51) and past hepatitis A or B vaccination (≤26: PR = 2.88, 95%CI 1.64–5.05; ≥27: PR = 2.03, 95%CI 1.07–3.86). Among men ≥ 27 years old, vaccine initiation was also positively associated with accessing PrEP, living in Vancouver or Toronto, but negatively associated with identifying as Latin American and increasing age. Vaccine initiation was twice as likely among men ≥ 27 years with private insurance versus no insurance. Sixty-five to 74% of men eligible for publicly-funded vaccine across the three cities remained unvaccinated against HPV by 2019. High vaccine cost may partly explain even lower uptake among men ≥ 27 years old. Men seeking sexual health care were more likely to initiate vaccination; bundling vaccination with these services may help improve HPV vaccine uptake.

Background This trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Singapore, with the aim of measuring the efficacy of male Wolbachia -infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting with all four dengue serotypes in circulation. The trial commenced in July 2022 and is expected to conclude in September 2024. The original study protocol was published in December 2022. Here, we describe amendments that have been made to the study protocol since commencement of the trial. Methods The key protocol amendments are (1) addition of an explicit definition of Wolbachia exposure for residents residing in intervention sites based on the duration of Wolbachia exposure at point of testing, (2) incorporation of a high-dimensional set of anthropogenic and environmental characteristics in the analysis plan to adjust for baseline risk factors of dengue transmission, and (3) addition of alternative statistical analyses for endpoints to control for post hoc imbalance in cluster-based environmental and anthropogenic characteristics. Discussion The findings from this study will provide the first experimental evidence for the efficacy of releasing male- Wolbachia infected mosquitoes to reduce dengue incidence in a cluster-randomised controlled trial. The trial will conclude in 2024 and results will be reported shortly thereafter. Trial registration ClinicalTrials.gov, identifier: NCT05505682. Registered on 16 August 2022. Retrospectively registered. Last updated 11 November 2023.

Abstract Background Matings between male Aedes aegypti mosquitoes infected with wAlbB strain of Wolbachia and wildtype females yield non-viable eggs. We evaluated the efficacy of releasing wAlbB-infected Ae. aegypti male mosquitoes to suppress dengue. Methods We specified the protocol of a two-arm cluster-randomized test-negative controlled trial (cRCT) and emulated it using a nationally representative test-negative/positive database of individuals reporting for febrile illness to any public hospital, general practitioner or polyclinic. We retrospectively built a cohort of individuals who reside in Wolbachia locations vs a comparator control group who do not reside in Wolbachia locations, using a nationally representative database of all individuals whom report for febrile illness and were tested for dengue at the Environmental Health Institute/hospital laboratories/commercial diagnostic laboratories, through general practitioner clinic, polyclinic or public/private hospital from epidemiological week (EW) 1 2019 to EW26 2022. We emulated a constrained randomization protocol used in cRCTs to balance dengue risk between intervention and control arms in the pre-intervention period. We used the inverse probability weighting approach to further balance the intervention and control groups using a battery of algorithmically selected sociodemographic, environmental and anthropogenic variables. Intention-to-treat analyses were conducted to estimate the risk reduction of dengue given Wolbachia exposure. Results Intention-to-treat analyses revealed that, compared with controls, Wolbachia releases for 3, 6 and ≥12 months was associated to 47% (95% confidence interval: 25–69%), 44% (33–77%) and 61% (38–78%) protective efficacy against dengue, respectively. When exposed to ≥12 months of Wolbachia releases, protective efficacies ranged from 49% (13–72%) to 77% (60–94%) across years. The proportion of virologically confirmed dengue cases was lower overall in the intervention arm. Protective efficacies were found across all years, age and sex subgroups, with higher durations of Wolbachia exposure associated to greater risk reductions of dengue. Conclusion Results demonstrated that Wolbachia-mediated sterility can strengthen dengue control in tropical cities, where dengue burden is the greatest.

Background Gay, bisexual and other men who have sex with men (gbMSM) in Canada continue to experience high rates of incident HIV. Pre-exposure prophylaxis (PrEP, the regular use of anti-HIV medication) reduces HIV acquisition and could reduce incidence. However, there are too few physicians with expertise in HIV care to meet the projected demand for PrEP. To meet demand and achieve greater public health impact, PrEP delivery could be ‘decentralized’ by incorporating it into front-line prevention services provided by family physicians (FPs) and sexual health clinic nurses. Methods This PrEP decentralization project will use two strategies. The first is an innovative knowledge dissemination approach called ‘Patient-Initiated CME’ (PICME), which aims to empower individuals to connect their family doctors with online, evidence-based, continuing medical education (CME) on PrEP. After learning about the project through community agencies or social/sexual networking applications, gbMSM interested in PrEP will use a uniquely coded card to access an online information module that includes coaching on how to discuss their HIV risk with their FP. They can provide their physician a link to the accredited CME module using the same card. The second strategy involves a pilot implementation program, in which gbMSM who do not have a FP may bring the card to designated sexual health clinics where trained nurses can deliver PrEP under a medical directive. These approaches will be evaluated through quantitative and qualitative methods, including: questionnaires administered to patients and physicians at baseline and at six months; focus groups with patients, FPs, and sexual health clinic staff; and review of sexual health clinic charts. The primary objective is to quantify the uptake of PrEP achieved using each decentralization strategy. Secondary objectives include a) characterizing barriers and facilitators to PrEP uptake for each strategy, b) assessing fidelity to core components of PrEP delivery within each strategy, c) measuring patient-reported outcomes including satisfaction with clinician-patient relationships, and d) conducting a preliminary costing analysis. Discussion This study will assess the feasibility of a novel strategy for disseminating knowledge about evidence-based clinical interventions, and inform future strategies for scale-up of an underutilized HIV prevention tool.