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Background:The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. Methods:In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. Findings:156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30–44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3(IQR 349–828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2–9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. Interpretation:Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital.

Objectives Some estrogen metabolites are associated with increased breast cancer risk, while others are protective. Research efforts have focused on modifiable factors, including bioactive compounds found in food or supplements, promoting estrogen profiles with anti-cancer properties. EstroSense® is a nutraceutical product with bioactive compounds, including Indole-3-carbinol and green-tea catechins, which may favourably affect estrogen profiles. This study was conducted to determine if EstroSense use, compared to placebo, promotes a higher urinary 2-hydroxyestrone:16α-hydroxyestrone ratio (2-OHE1:16α-OHE1), a biomarker associated with a lowered risk of breast cancer. Methods A total of 148 premenopausal women were recruited from British Columbia, Canada to participate in a randomized, double-blind, cross-over, multicentre, placebo-controlled study in which women were randomized to a treatment sequence that consisted of either EstroSense®, followed by placebo or vice-versa. The women were instructed to consume three capsules per day of EstroSense® or the placebo for three menstrual cycles (∼12 weeks). The primary outcome was the measurement of 2-OHE1:16α-OHE1 in casual samples at baseline and after each treatment phase. Results After 12 weeks of intervention, the mean (95% CI) urinary 2-OHE1:16α-OHE1 was 4.55 (2.69, 6.42) (p Conclusions EstroSense use led to markedly higher urinary 2-OHE1:16α-OHE1 than the placebo, a biomarker associated with a lower risk of breast cancer. Registration http://clinicaltrials.gov (NCT02385916).

Background: Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin-induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL. Methods: Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan-Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy. Results: In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%), with a rapid increase observed to 27% (95% CI, 21%-35%) at 3 months and to 61% (95% CI, 53%-69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%-62%; P 2 increase: hazard ratio [HR], 1.20; 95% CI, 1.01-1.41) vincristine (HR, 2.87; 95% CI, 1.89-4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17-2.95) further influenced CIHL development over time. Conclusions: In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co-)medication. These results highlight the need for audiological monitoring at each cisplatin cycle.

OBJECTIVES: To quantify the real-world survival benefit of re-resection vs no re-resection in patients diagnosed with T1 bladder cancer (BC) at the population level. PATIENTS AND METHODS: Retrospective population-wide observational cohort study based on pathology reports linked to health administrative data. We identified patients who were diagnosed with T1 BC in the province of Ontario (01/2001-12/2015) and used billing claims to ascertain whether they received re-resection within 2-10 weeks. The time-dependent effect of re-resection on survival outcomes was modelled by Cox proportional hazards regression (unadjusted and adjusted for numerous assumed patient- and surgeon-level confounding variables). Effect measures were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We identified 7666 patients of which 2162 (28.7%) underwent re-resection after a median (interquartile range) time of 45 (35-56) days. Patients who received re-resection were less likely to die from any causes (HR 0.68, 95% CI 0.63-0.74, P

Following the report of an excess in paediatric cases of severe acute hepatitis of unknown aetiology by the United Kingdom (UK) on 5 April 2022, 427 cases were reported from 20 countries in the World Health Organization European Region to the European Surveillance System TESSy from 1 January 2022 to 16 June 2022. Here, we analysed demographic, epidemiological, clinical and microbiological data available in TESSy. Of the reported cases, 77.3% were 5 years or younger and 53.5% had a positive test for adenovirus, 10.4% had a positive RT-PCR for SARS-CoV-2 and 10.3% were coinfected with both pathogens. Cases with adenovirus infections were significantly more likely to be admitted to intensive care or high-dependency units (OR = 2.11; 95% CI: 1.18–3.74) and transplanted (OR = 3.36; 95% CI: 1.19–9.55) than cases with a negative test result for adenovirus, but this was no longer observed when looking at this association separately between the UK and other countries. Aetiological studies are needed to ascertain if adenovirus plays a role in this possible emergence of hepatitis cases in children and, if confirmed, the mechanisms that could be involved.

Summary Personalized cancer treatments based on the molecular profile of a patient’s tumor are an emerging and exciting class of treatments in oncology. As genomic tumor profiling is becoming more common, targeted treatments for specific molecular alterations are gaining traction. To discover new potential therapeutics that may apply to broad classes of tumors matching some molecular pattern, experimentalists and pharmacologists rely on high-throughput, in vitro screens of many compounds against many different cell lines. We propose a hierarchical Bayesian model of how cancer cell lines respond to drugs in these experiments and develop a method for fitting the model to real-world high-throughput screening data. Through a case study, the model is shown to capture nontrivial associations between molecular features and drug response, such as requiring both wild type TP53 and overexpression of MDM2 to be sensitive to Nutlin-3(a). In quantitative benchmarks, the model outperforms a standard approach in biology, with $\approx20\%$ lower predictive error on held out data. When combined with a conditional randomization testing procedure, the model discovers markers of therapeutic response that recapitulate known biology and suggest new avenues for investigation. All code for the article is publicly available at https://github.com/tansey/deep-dose-response.

The menstrual cycle is a key indicator of overall health for women of reproductive age. Previously, menstruation was primarily studied through survey results; however, as menstrual tracking mobile apps become more widely adopted, they provide an increasingly large, content-rich source of menstrual health experiences and behaviors over time. By exploring a database of user-tracked observations from the Clue app by BioWink GmbH of over 378,000 users and 4.9 million natural cycles, we show that self-reported menstrual tracker data can reveal statistically significant relationships between per-person cycle length variability and self-reported qualitative symptoms. A concern for self-tracked data is that they reflect not only physiological behaviors, but also the engagement dynamics of app users. To mitigate such potential artifacts, we develop a procedure to exclude cycles lacking user engagement, thereby allowing us to better distinguish true menstrual patterns from tracking anomalies. We uncover that women located at different ends of the menstrual variability spectrum, based on the consistency of their cycle length statistics, exhibit statistically significant differences in their cycle characteristics and symptom tracking patterns. We also find that cycle and period length statistics are stationary over the app usage timeline across the variability spectrum. The symptoms that we identify as showing statistically significant association with timing data can be useful to clinicians and users for predicting cycle variability from symptoms, or as potential health indicators for conditions like endometriosis. Our findings showcase the potential of longitudinal, high-resolution self-tracked data to improve understanding of menstruation and women’s health as a whole.

We explore how to quantify uncertainty when designing predictive models for healthcare to provide well-calibrated results. Uncertainty quantification and calibration are critical in medicine, as one must not only accommodate the variability of the underlying physiology, but adjust to the uncertain data collection and reporting process. This occurs not only on the context of electronic health records (i.e., the clinical documentation process), but on mobile health as well (i.e., user specific self-tracking patterns must be accounted for). In this work, we show that accurate uncertainty estimation is directly relevant to an important health application: the prediction of menstrual cycle length, based on self-tracked information. We take advantage of a flexible generative model that accommodates under-dispersed distributions via two degrees of freedom to fit the mean and variance of the observed cycle lengths. From a machine learning perspective, our work showcases how flexible generative models can not only provide state-of-the art predictive accuracy, but enable well-calibrated predictions. From a healthcare perspective, we demonstrate that with flexible generative models, not only can we accommodate the idiosyncrasies of mobile health data, but we can also adjust the predictive uncertainty to per-user cycle length patterns. We evaluate the proposed model in real-world cycle length data collected by one of the most popular menstrual trackers worldwide, and demonstrate how the proposed generative model provides accurate and well-calibrated cycle length predictions. Providing meaningful, less uncertain cycle length predictions is beneficial for menstrual health researchers, mobile health users and developers, as it may help design more usable mobile health solutions.

Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.

Prior research has shown that concordance with the guideline-endorsed recommendation to re-resect patients diagnosed with primary T1 bladder cancer (BC) is suboptimal. Therefore, the aim of this population-based study was to identify factors associated with re-resection in T1 BC.We linked province-wide BC pathology reports (January 2001 to December 2015) with health administrative data sources to derive an incident cohort of patients diagnosed with T1 BC in the province of Ontario, Canada. Re-resection was ascertained by a billing claim for transurethral resection within 2 to 8 weeks after the initial resection, accounting for system-related wait times. Multivariable logistic regression analysis accounting for the clustered nature of the data was used to identify various patient-level and surgeon-level factors associated with re-resection. P values0.05 were considered statistically significant (2-sided).We identified 7,373 patients who fulfilled the inclusion criteria. Overall, 1,678 patients (23%) underwent re-resection. Patients with a more aggressive tumor profile and individuals without sufficiently sampled muscularis propria as well as younger, healthier and socioeconomically advantaged patients were more likely to receive re-resection (all p0.05). In addition, more senior, lower volume and male surgeons were less likely to perform re-resection for their patients (all p0.05).Only a minority of all patients received re-resection within 2 to 8 weeks after initial resection. To improve the access to care for potentially underserved patients, we suggest specific knowledge translation/exchange interventions that also include equity aspects besides further promotion of evidence-based instead of eminence-based medicine.

INTRODUCTION AND OBJECTIVE:A second transurethral resection within 2 to 6 weeks after the initial resection (i.e. re-resection) is recommended for patients diagnosed with primary T1 bladder cancer ...

Background Medication management (MM) refers to all clinical activities that a pharmacist performs to ensure safe and effective medication therapy for patients. Objective To characterize pharmacist-driven MM services via retrospective analysis of real-world data collected in a community pharmacy in British Columbia (BC), Canada. Methods This was a retrospective longitudinal study from January 2014–December 2015. Patient demographics, clinical problems, identified drug-related problems (DTPs), and pharmacists' interventions were summarized using descriptive statistics. The relationship between DTPs and the clinical conditions, as well as DTPs and the interventions, were analyzed. Other outcomes included: the relationship between patients’ age and visit time with the number of DTPs; the number of clinical conditions; and the number of interventions. Results 1,572 patients received MM (mean visit time = 29.1 min). 2,133 DTPs were identified, which resulted in 7176 recommended interventions. The clinical problems most frequently encountered were cardiovascular (20%), and mental (15.7%). The most frequently identified DTP was “needs additional therapy” (61.8%), while the most frequently initiated or recommended interventions were education (43.4%), and changing therapy (21.6%). Elderly patients with multiple comorbidities had more DTPs and required more interventions and even when no DTPs were identified, some patients still received counselling and education in these visits. Conclusion Using real-world data, this research demonstrated that patients benefit from identification and resolution of DTPs through pharmacists-driven MM programs.

Objective: Concurrent mental and substance use disorders or dual diagnosis are highly prevalent among individuals experiencing homelessness. Studies have indicated that dual diagnosis leads to poor...

Background Decision makers are facing growing challenges in prioritizing drugs for reimbursement because of soaring drug costs and increasing pressures on financial resources. In addition to cost and effectiveness, payers are using other values to dictate which drugs are prioritized for funding, yet there are limited data on the Canadian public’s priorities. Objectives To measure the relative societal importance of values considered most relevant in informing drug reimbursement decisions in a representative sample of Canadians. Methods An online survey of 2539 Canadians aged 19 years and older was performed in which 13 values used in drug funding prioritization were ranked and then weighted using an analytic hierarchy process. Results Canadians value safe and efficacious drugs that have certainty of evidence. The values ranked in the top 5 by most of our subjects were potential effect on quality of life (65.4%), severity of the disease (62.6%), ability of drug to work (61.1%), safety (60.5%), and potential to extend life (49.4%). Values related to patient or disease characteristics such as rarity, socioeconomic status, and health and lifestyle choices held the lowest rankings and weights. Conclusions Canadians value, above all, treatment-related factors (eg, efficacy and safety) and disease-related factors (eg, severity and equity). Decision makers are currently using additional justifications to prioritize drugs for reimbursement, such as rarity and unmet need, which were not found to be highly valued by Canadians. Decision makers should integrate the public’s values into a Canadian reimbursement framework for prioritization of drugs competing for limited funds.

A second transurethral resection of the bladder tumor (TURBT) within 2 - 6 weeks after initial TURBT is thought to have diagnostic, therapeutic, and prognostic benefits in T1 bladder cancer (BC). However, little is known about the real-world uptake of this guideline-endorsed intervention. We aimed (1) to measure re-resection rates over time, (2) to investigate if a guideline revision (April 2008) explicitly endorsing re-resection within 2 - 6 weeks in all T1 BC patients led to an increase in re-resection rates, and (3) to investigate the uptake among different groups of surgeons.Province-wide BC pathology reports (January 2001 to December 2015; Ontario, Canada) were linked with health administrative data to (1) identify primary cases of T1 BC and to (2) ascertain whether these patients received re-resection. The resulting patients were then aggregated into quarterly time series and investigated by descriptive analysis, interventional autoregressive moving average (ARIMA) modeling, and Poisson regression analysis.A cohort of 7,373 patients was aggregated into a time series. We observed a linear increase in re-resection rates from 8.4% in 2001 to 28.3% in 2015. An actual effect of the guideline revision in April 2008 on re-resection rates could not be detected (P = 0.41). However, we observed a rather heterogeneous uptake behavior among different groups of surgeons. Specifically, female surgeons, more junior surgeons, high-volume surgeons, Canadian graduates, and surgeons without an academic affiliation were all independently more likely to re-resect their patients (all P-values0.05 in adjusted analysis).Re-resection rates in primary T1 BC increased between 2001 and 2015 in the province of Ontario regardless of the guideline revision in April 2008. Our study demonstrates that the uptake of this guideline-endorsed intervention varies among different groups of surgeons and therefore warrants further research to identify barriers to change that can be addressed by tailored interventions.

ObjectivesPatients requiring haemodialysis are at increased risk of serious illness with SARS-CoV-2 infection. To improve the understanding of transmission risks in six Scottish renal dialysis units, we utilised the rapid whole-genome sequencing data generated by the COG-UK consortium.MethodsWe combined geographical, temporal and genomic sequence data from the community and hospital to estimate the probability of infection originating from within the dialysis unit, the hospital or the community using Bayesian statistical modelling and compared these results to the details of epidemiological investigations.ResultsOf 671 patients, 60 (8.9%) became infected with SARS-CoV-2, of whom 16 (27%) died. Within-unit and community transmission were both evident and an instance of transmission from the wider hospital setting was also demonstrated.ConclusionsNear-real-time SARS-CoV-2 sequencing data can facilitate tailored infection prevention and control measures, which can be targeted at reducing risk in these settings.

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science., To help meet the ensuing demand for COVID-19 reagents, this article presents an openly available ‘coronavirus toolkit’ (https://mrcppu-covid.bio) and describes the generation and validation of these tools, including a simple SARS-CoV-2 reverse genetics system and a near-comprehensive panel of SARS-CoV-2 antibodies.

The second SARS virus, SARS-CoV-2, emerged in December 2019, and within a month was globally distributed. It was first introduced into Scotland in February 2020 associated with returning travellers and visitors. By March it was circulating in communities across the UK, and to control COVID-19 cases, and prevent overwhelming of the National Health Service (NHS), a ‘lockdown’ was introduced on 23rd March 2020 with a restriction of people’s movements. To augment the public health efforts a large-scale genome epidemiology effort (as part of the COVID-19 Genomics UK (COG-UK) consortium) resulted in the sequencing of over 5000 SARS-CoV-2 genomes by 18th August 2020 from Scottish cases, about a quarter of the estimated number of cases at that time. Here we quantify the geographical origins of the first wave introductions into Scotland from abroad and other UK regions, the spread of these SARS-CoV-2 lineages to different regions within Scotland (defined at the level of NHS Health Board) and the effect of lockdown on virus ‘success’. We estimate that approximately 300 introductions seeded lineages in Scotland, with around 25% of these lineages composed of more than five viruses, but by June circulating lineages were reduced to low levels, in line with low numbers of recorded positive cases. Lockdown was, thus, associated with a dramatic reduction in infection numbers and the extinguishing of most virus lineages. Unfortunately since the summer cases have been rising in Scotland in a second wave, with >1000 people testing positive on a daily basis, and hospitalisation of COVID-19 cases on the rise again. Examining the available Scottish genome data from the second wave, and comparing it to the first wave, we find that while some UK lineages have persisted through the summer, the majority of lineages responsible for the second wave are new introductions from outside of Scotland and many from outside of the UK. This indicates that, while lockdown in Scotland is directly linked with the first wave case numbers being brought under control, travel-associated imports (mostly from Europe or other parts of the UK) following the easing of lockdown are responsible for seeding the current epidemic population. This demonstrates that the impact of stringent public health measures can be compromised if following this, movements from regions of high to low prevalence are not minimised.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant., Graphical Abstract, Highlights • Increasing frequency of SARS-CoV-2 D614G is consistent with a selective advantage • Phylodynamic analyses do not show significantly different growth of D614G clusters • There is no association of D614G replacement with greater severity of infection • The D614G replacement is associated with higher viral loads and younger patient age, Analysis of the spread and frequency of SARS-CoV-2 D614G in the United Kingdom suggests a selective advantage for this strain that is associated with higher viral loads in younger patients but not higher COVID-19 clinical severity or mortality.

Introduction: Squamous cell carcinoma (SCC) of the penis is a rare disease comprising 1% of all male cancer. Options for the management of cT1-T2 cN0 penile SCC include partial penectomy (PP), considered the standard, and brachytherapy (BT), which offers acceptable local disease control and organ preservation. The purpose of our study was to assess and describe the oncological outcome for both treatments in a tertiary care center. Methods: We performed a contemporary retrospective study of patients with early-stage penile cancer treated surgically or by BT at a tertiary center between 2000 and 2016. Demographic, management, and followup data were obtained from an institutional database. Descriptive statistics and survival analysis using Kaplan-Meier plots were calculated. Local and regional recurrences were compared in both groups (BT vs. PP). Results: A total of 51 patients with cT1-T2N0 penile SCC treated with BT (35) and PP (16) were analyzed. Median followup was 37.1 (13.9–68) and 25.4 months (18–52.3) for the BT and PP group, respectively. Recurrence developed in seven (20%) patients treated with BT. Median time to recurrence was 35.2 months (range 2.9–95.8). No recurrences were reported in patients treated with PP. Forty-four (86.2%) patients were alive with no evidence of disease at the last followup. Overall survival was 62.7%. Complications after primary tumor treatment were urethral stenosis (15.7%), penile necrosis (7.8%), and local infection (2%). Conclusions: PP provides acceptable local control with organ preservation in early-stage penile SCC. BT was able to offer organ preservation in 69% of men. Future prospective studies are needed to compare other organ-conserving treatment modalities with PP.

Introduction: Prior research demonstrated an association between surgical case volume and survival in muscle-invasive bladder cancer (BC). This relationship, however, has not been investigated in the setting of T1 BC so far. Therefore, we investigated whether a higher surgical case volume of T1 BC translates into improved survival outcomes. Methods: Province-wide pathology reports (January 2002 to December 2015) were linked with health administrative data to identify patients diagnosed with T1 BC. For each patient, we determined the T1 case volume of the involved surgeon by benchmarking (percentile) her/him against his/her colleagues during a lookback period of one year. The volume-outcome (overall survival) relationship was then investigated by Cox proportional hazards regression (unadjusted and adjusted for a wide range of assumed confounders) that incorporated volume in three different ways (80th percentile and higher vs. below, median and higher vs. below, continuous [quintiles]). Effect sizes were presented as hazard ratios (95% confidence interval). Results: We identified 7426 patients who were diagnosed with T1 BC and followed for 4.8 years. A third of all patients (n=1895, 25.5%) received surgery by a high-volume surgeon (80th percentile and higher). Higher T1 case volume was associated with improved survival both in unadjusted (80th percentile: 0.93 [0.86–0.99]; median: 0.93 [0.87–0.99]; continuous: 0.97 [0.94–0.99]) and adjusted analysis (80th percentile: 0.94 [0.88–1.01]; median: 0.93 [0.87–0.99]; continuous: 0.97 [0.95–0.99]). Conclusions: This province-wide cohort study could demonstrate a volume-outcome relationship in T1 BC and raises questions regarding the regionalization of care in high-risk non-muscle-invasive BC. The generalizability of our findings, however, is limited by the fact that the performance of the initial resection by a high-volume surgeon does not necessarily translate into downstream care by the same surgeon.

Introduction: Our previous study in British Columbia (BC) indicated that pharmacists have a poor perception of their working conditions. The objective of this study is to assess pharmacists’ perceptions of their working conditions in 4 other Canadian provinces. Methods: This was a cross-sectional study across Alberta, New Brunswick, Prince Edward Island and Newfoundland and Labrador, using a survey adapted from the Oregon Board of Pharmacy. Data collected previously from BC were also included in the analyses. The survey was emailed to all pharmacist registrants. Respondents were provided with 6 statements and asked to rate their agreement with them, using a 5-point Likert scale. Statements were framed such that agreement with them indicated good perception of working conditions. Logistic regression analyses were used to study the relationship between workplace factors on perception of working conditions. Results: Pharmacists perceived their working conditions to be poor. Pharmacists indicated that they do not have time for break/lunch (48.3% of respondents), work in environments that are not conducive to safe and effective primary care (26.5%), are not satisfied with the amount of time they have to do their job (44.0%) and face shortage of staff (shortage of pharmacists: 33.7%, technicians: 36.4%, clerk staff: 30.3%). Significant factors associated with poor perception were workplace-imposed quotas, high prescription volume, working in chain pharmacies and long prescription wait times. Conclusion: A high percentage of Canadian pharmacists perceived their working conditions to be poor. Considering the patient-related consequences of pharmacists’ poor working conditions and the system-related reasons identified behind it, we call for collaborative efforts to tackle this issue.

SARS-CoV-2, the causative agent of COVID-19, emerged in Wuhan, China in December 2019 and spread rapidly throughout the world. Understanding the introductions of this new coronavirus in different settings may assist control efforts and the establishment of frameworks to support rapid response in future infectious disease outbreaks.We investigated the first four weeks of emergence of the SARS-CoV-2 virus in Scotland after the first case reported on the 1st March 2020. We obtained full genome sequences from 452 individuals with a laboratory-confirmed diagnosis of COVID-19, representing 20% of all cases until 1st April 2020 (n=2310). This permitted a genomic epidemiology approach to study the introductions and spread of the SARS-2 virus in Scotland.From combined phylogenetic and epidemiological analysis, we estimated at least 113 introductions of SARS-CoV-2 into Scotland during this period. Clusters containing multiple sequences suggestive of onward transmission occurred in 48/86 (56%). 42/86 (51%) clusters had no known international travel history indicating undetected introductions.The majority of viral sequences were most closely related to those circulating in other European countries, including Italy, Austria and Spain. Travel-associated introductions of SARS-CoV-2 into Scotland predated travel restrictions in the UK and other European countries. The first local transmission occurred three days after the first case. A shift from travel-associated to sustained community transmission was apparent after only 11 days. Undetected introductions occurred prior to the first known case of COVID-19. Earlier travel restrictions and quarantine measures might have resulted in fewer introductions into Scotland, thereby reducing the number of cases and the subsequent burden on health services. The high number of introductions and transmission rates were likely to have impacted on national contact tracing efforts. Our results also demonstrate that local real-time genomic epidemiology can be used to monitor transmission clusters and facilitate control efforts to restrict the spread of COVID-19.FundingMRC (MC UU 1201412), UKRI/Wellcome (COG-UK), Wellcome Trust Collaborator Award (206298/Z/17/Z – ARTIC Network; TCW Wellcome Trust Award 204802/Z/16/ZResearch in contextEvidence before this studyCoronavirus disease-2019 (COVID-19) was first diagnosed in Scotland on the 1st of March 2020 following the emergence of the causative severe acute respiratory system coronavirus 2 (SARS-CoV-2) virus in China in December 2019. During the first month of the outbreak in Scotland, 2310 positive cases of COVID-19 were detected, associated with 1832 hospital admissions, 207 intensive care admissions and 126 deaths. The number of introductions into Scotland and the source of those introductions was not known prior to this study.Added value of this studyUsing a combined phylogenetic and epidemiological approach following real-time next generation sequencing of 452 SARS-CoV-2 samples, it was estimated that the virus was introduced to Scotland on at least 113 occasions, mostly from other European countries, including Italy, Austria and Spain. Localised outbreaks occurred in the community across multiple Scottish health boards, within healthcare facilities and an international conference and community transmission was established rapidly, before local and international lockdown measures were introduced.

CACNA1E is a gene encoding the ion-conducting α1 subunit of R-type voltage-dependent calcium channels, whose roles in tumorigenesis remain to be determined. We previously showed that CACNA1E was significantly mutated in patients with non-small cell lung cancer (NSCLC) who were long-term exposed to household air pollution, with a mutation rate of 19% (15 of 79 cases). Here we showed that CACNA1E was also mutated in 207 (12.8%) of the 1616 patients with NSCLC in The Cancer Genome Atlas (TCGA) datasets. At mRNA and protein levels, CACNA1E was elevated in tumor tissues compared to counterpart non-tumoral lung tissues in NSCLCs of the public datasets and our settings, and its expression level was inversely associated with clinical outcome of the patients. Overexpression of wild type (WT) or A275S or R249G mutant CACNA1E transcripts promoted NSCLC cell proliferation with activation of epidermal growth factor receptor (EGFR) signaling pathway, whereas knockdown of this gene exerted inhibitory effects on NSCLC cells in vitro and in vivo. CACNA1E increased current density and Ca

Previous studies have suggested that interstitial lung disease (ILD) progresses most rapidly early in the course of systemic sclerosis-associated (SSc)-ILD, and that SSc-ILD is often more stable or even "burned out" after the first 4 years following diagnosis.Our objectives were to determine whether an apparent plateau in pulmonary function decline is due to survival bias and to identify distinct prognostic phenotypes of ILD progression.Consecutive patients with SSc-ILD from a single center were included. Pulmonary function measurements were typically performed every 6 months. Study participants were categorized into long-term survivors (8 yr survival from diagnosis), and those with medium-term and short-term mortality (4-8 and4 yr survival, respectively). We excluded those censored with less than 8 years of follow-up. Subject-specific slopes for change in forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DlThe cohort included 171 study participants with SSc-ILD. A plateau in the progression of FVC was apparent in the full cohort analysis but disappeared with stratification into prognostic subgroups to account for survival bias. Those with short-term mortality had a higher annual rate of decline in FVC (-4.10 [95% confidence interval (CI), -7.92 to -0.28] vs. -2.14 [95% CI, -3.31 to -0.97] and -0.94 [-1.46 to -0.42]; P = 0.003) and DlAdults with SSc-ILD have distinct patterns of physiological progression that remain relatively consistent during long-term follow-up; however, recent change in FVC cannot be used to predict future change in FVC within shorter follow-up intervals. The findings of this study provide important information on the course of disease in SSc-ILD and identify specific phenotypes of progression that may improve clinical decision-making and design of future therapeutic trials.

Activity-dependent transcription factors critically coordinate the gene expression program underlying memory formation. The tumor suppressor gene, MEN1, encodes a ubiquitously expressed transcription regulator required for synaptogenesis and synaptic plasticity in invertebrate and vertebrate central neurons. In this study, we investigated the role of MEN1 in long-term memory (LTM) formation in an aversive operant conditioning paradigm in the freshwater pond snail Lymnaea stagnalis (L. stagnalis). We demonstrated that LTM formation is associated with an increased expression of MEN1 coinciding with an up-regulation of creb1 gene expression. In vivo knockdown of MEN1 prevented LTM formation and conditioning-induced changes in neuronal activity in the identified pacemaker neuron RPeD1. Our findings suggest the involvement of a new pathway in LTM consolidation that requires MEN1-mediated gene regulation.

Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents.

The aim of this study was to comprehensively measure work productivity losses of employees enrolled in a pharmacist-led wellness program and assess associated risk factors.The study sample was employees at least 18 years old with a Framingham Risk Score (FRS) at least 10% or 1+ medication-modifiable cardiovascular risk factor (196 participants at baseline and 166 at 12-month endpoint). Total work hour losses (WHL) were measured using the Valuation of Lost Productivity questionnaire. The factors anticipated to be associated with WHL included work habits, FRS, body mass index (BMI), physical activity, and health-related quality of life (HRQoL).Sedentary work habits, higher BMI, and lower HRQoL were significantly associated with more WHL for males. Among females, only a lower HRQoL was significantly associated with more WHL.Our findings help identify employees at greater risk for WHL and provide insights on how workplace wellness programs can be modified.

Background Gonorrhea and chlamydia testing is poor among Chinese MSM with HIV risk. Furthermore, gonorrhea and chlamydia testing programs are poorly funded and unlinked to HIV testing services. Pay-it-forward offers an individual a gift (e.g. an STD test) and then asks whether they would like to give a gift to another person. This study assesses the effectiveness of a pay-it-forward program in increasing gonorrhea/chlamydia testing among MSM compared to standard of care. Methods We conducted a cluster randomized controlled trial at three HIV testing sites run by MSM community-based organizations in Beijing and Guangzhou (NCT03741725). We included MSM aged 16 or older who had met indications for testing based on US CDC guidelines. Twenty clusters of 10 men each were randomized into pay-it-forward and standard of care arms. In pay-it-forward, men were offered free testing and then given the option to donate money toward future participants’ tests; in standard of care, testing was offered at the standard price of 150RMB (US$22). The primary outcome was dual gonorrhea/chlamydia test uptake ascertained by administrative record. Generalized estimating equations were used to assess the population-averaged effect of the pay-it-forward intervention. This analysis focuses on the primary comparison between pay-it-forward and standard of care. Results Overall, 201 participants were recruited. Most participants were younger than 30 years old (67.5%, 127/188) and had college or above education (85.1%, 165/194). 43.1% (69/160) reported condomless anal sex in the last three months. Gonorrhea/chlamydia testing rates were 56.4% (57/101) in pay-it-forward and 18.0% (18/100) in standard of care. Gonorrhea/chlamydia testing rates were three times higher in pay-it-forward compared to standard of care (RR:3.14, p Conclusion Findings suggest that pay-it-forward increases gonorrhea/chlamydia testing and may inform the integration of STD and HIV testing services among MSM. Disclosure No significant relationships.

There is inconsistent evidence on the efficacy of agriculture programmes at improving women and children's anaemia and nutritional status. The primary aim of this study was to evaluate the impact of a nutrition‐sensitive enhanced homestead food production (EHFP) programme on anaemia in women (18–45 years) and children (6–59 months) in rural Cambodia. Secondary outcomes were women's micronutrient status and women and children's anthropometry. In this cluster‐randomized controlled trial, 900 households from 90 villages (clusters) were randomized to either (a) home gardens and behaviour change communication (BCC) on nutrition, hygiene, women's empowerment, and marketing (EHFP); (b) home gardens plus fishponds and BCC (EHFP + F); or (c) control (no intervention). Haemoglobin concentration and anthropometry were measured in women and children at baseline and at 22 months. Venous blood samples were collected in a subset of women (n = 450) at baseline and at 22 months. Generalized linear mixed effect models with repeated measures were used to evaluate the difference across groups and the change from baseline to end of study. Ninety clusters, 552 women, and 754 children completed the trial. Compared with control, we found a statistically significant impact on anaemia prevalence in children (−14.0 percentage points; P = 0.02) and retinol binding protein concentrations in women (difference in difference: 0.34; P = 0.02) randomized to EHFP and EHFP + F groups, respectively. No other statistically significant effects on anaemia, nutritional biomarker concentrations, or anthropometry were observed. Future research is needed to examine longer term impacts of EHFP on anthropometry in women and children and into the nutritional causes of anaemia among children in Cambodia.