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Abstract Objective To characterize the experience of people with epilepsy and aligned healthcare workers (HCWs) during the first 18 months of the COVID‐19 pandemic and compare experiences in high‐income countries (HICs) with non‐HICs. Methods Separate surveys for people with epilepsy and HCWs were distributed online in April 2020. Responses were collected to September 2021. Data were collected for COVID‐19 infections, the effect of COVID‐related restrictions, access to specialist help for epilepsy (people with epilepsy), and the impact of the pandemic on work productivity (HCWs). The frequency of responses for non‐HICs and HICs were compared using non‐parametric Chi‐square tests. Results Two thousand one hundred and five individuals with epilepsy from 53 countries and 392 HCWs from 26 countries provided data. The same proportion of people with epilepsy in non‐HICs and HICs reported COVID‐19 infection (7%). Those in HICs were more likely to report that COVID‐19 measures had affected their health (32% vs. 23%; p

Stuck or sluggish malolactic fermentation (MLF) can be problematic in stressful wine conditions, particularly white and sparkling base musts/wines. In these cases, knowledge of yeast-bacteria strain compatibility and the amount of sulfur dioxide (SO2) a yeast strain produces are important considerations for successful MLF. Here, laboratory- and pilot-scale co-fermentations in Chardonnay were used to investigate the effect of yeast-derived SO2 on Oenococcus oeni survival. Although yeast-derived SO2 is generally inhibitory, we show that SO2 production (to approximately 65 mg/L) can be uncoupled from O. oeni survival in the early stages of co-fermentation. Bacterial survival in the presence of specific SO2-producing yeast strains was correlated with the early, transient formation of high acetaldehyde concentrations. Oenococcus oeni survival coincided with molecular SO2 concentrations remaining below an extremely low threshold of inhibition, which exponentially increased from approximately 3–6 µg/L in the first three days of co-fermentation. Strain-dependent sensitivity of O. oeni to bound SO2 remains a possibility, although the extent and mechanism of such inhibition by the SO2 adduct during co-fermentation remain unclear. The choice of co-inoculation yeast strain also influenced wine diacetyl concentration, which was only detected in wines co-inoculated with high SO2-producing S. cerevisiae strains. The wines with high diacetyl concentrations were found to be distinct by a sensory panel, with comparatively high citation frequency for a buttery sensory attribute. Both the SO2- and acetaldehyde production capacity of yeasts are, therefore, seen as meaningful co-inoculation selection criteria. The range of yeast strains suitable for MLF induction by co-inoculation could be widened to include SO2-producing strains that transiently produce an early, high concentration of acetaldehyde. The effects of low, equilibrium concentrations of molecular SO2 should also be considered in conjunction with total SO2 as a measure of SO2 toxicity towards O. oeni following co-inoculation.

Background: The term local recurrence in prostate cancer is considered to mean persistent local disease in the prostatic bed, most commonly at the site of the vesicourethral anastomosis (VUA). Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging for assessment of early biochemical recurrence (BCR), we have found histologically confirmed prostate cancer in the prostatic vascular pedicle (PVP). If a significant proportion of local recurrences are distant to the VUA, it may be possible to alter adjuvant and salvage radiation fields in order to reduce the potential morbidity of radiation in selected patients. Objective: To describe PVP local recurrence and to map the anatomic pattern of prostate bed recurrence on PSMA PET/CT. Design, setting, and participants: This was a retrospective multicentre study of 185 patients imaged with PSMA PET/CT following radical prostatectomy (RP) between January 2016 and November 2018. All patient data and clinical outcomes were prospectively collected. Recurrences were documented according to anatomic location. For patients presenting with local recurrence, the precise location of the recurrence within the prostate bed was documented. Intervention: PSMA PET/CT for BCR following RP. Results and limitations: A total of 43 local recurrences in 41/185 patients (22%) were identified. Tumour recurrence at the PVP was found in 26 (63%), VUA in 15 (37%), and within a retained seminal vesicle and along the anterior rectal wall in the region of the neurovascular bundle in one (2.4%) each. Histological and surgical evidence of PVP recurrence was acquired in two patients. The study is limited by its retrospective nature with inherent selection bias. This is an observational study reporting on the anatomy of local recurrence and does not include follow-up for patient outcomes. Conclusions: Our study showed that prostate cancer can recur in the PVP and is distant to the VUA more commonly than previously thought. This may have implications for RP technique and for the treatment of selected patients in the local recurrence setting. Patient summary: We investigated more precise identification of the location of tumour recurrence after removal of the prostate for prostate cancer. We describe a new definition of local recurrence in an area called the prostatic vascular pedicle. This new concept may alter the treatment recommended for recurrent disease.

Introduction Type 2 diabetes mellitus (T2DM) is a powerful risk factor for cardiovascular disease (CVD), conferring a greater relative risk in women than men. We sought to examine sex differences in cardiometabolic risk factors and management in the contemporary cohort represented by the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).Research design and methods GRADE enrolled 5047 participants (1837 women, 3210 men) with T2DM on metformin monotherapy at baseline. The current report is a cross-sectional analysis of baseline data collected July 2013 to August 2017.Results Compared with men, women had a higher mean body mass index (BMI), greater prevalence of severe obesity (BMI≥40 kg/m2), higher mean LDL cholesterol, greater prevalence of low HDL cholesterol, and were less likely to receive statin treatment and achieve target LDL, with a generally greater prevalence of these risk factors in younger women. Women with hypertension were equally likely to achieve blood pressure targets as men; however, women were less likely to receive ACE inhibitors or angiotensin receptor blockers. Women were more likely to be divorced, separated or widowed, and had fewer years of education and lower incomes.Conclusions This contemporary cohort demonstrates that women with T2DM continue to have a greater burden of cardiometabolic and socioeconomic risk factors than men, particularly younger women. Attention to these persisting disparities is needed to reduce the burden of CVD in women.Trial registration number ClinicalTrials.gov (NCT01794143)

Anthropogenic climate change is increasingly threatening biodiversity on a global scale. Rich spots of biodiversity, regions with exceptionally high endemism and/or number of species, are a top priority for nature conservation. Terrestrial studies have hypothesized that rich spots occur in places where long-term climate change was dampened relative to other regions. Here we tested whether biodiversity rich spots are likely to provide refugia for organisms during anthropogenic climate change. We assessed the spatial distribution of both historic (absolute temperature change and climate change velocities) and projected climate change in terrestrial, freshwater, and marine rich spots. Our analyses confirm the general consensus that global warming will impact almost all rich spots of all three realms and suggest that their characteristic biota is expected to witness similar forcing to other areas, including range shifts and elevated risk of extinction. Marine rich spots seem to be particularly sensitive to global warming: they have warmed more, have higher climate velocities, and are projected to experience higher future warming than non-rich-spot areas. However, our results also suggest that terrestrial and freshwater rich spots will be somewhat less affected than other areas. These findings emphasize the urgency of protecting a comprehensive and representative network of biodiversity-rich areas that accommodate species range shifts under climate change.

Abstract Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r g ) among rater-specific assessment of AGG ranged from r g = 0.46 between self- and teacher-assessment to r g = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong r g s with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r g = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

Abstract Background Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. Results In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. Conclusions This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.

Abstract Objective To evaluate local clinical outcomes of sliding clip renorrhaphy, from inception to current utilization for open, laparoscopic, and robotically assisted partial nephrectomy. Methods We reviewed prospectively maintained databases of three surgeons performing partial nephrectomies with the sliding‐clip technique at teaching hospitals between 2005 and 2019. Baseline characteristics, operative parameters, including surgical approach, RENAL Nephrometry Score, and post‐operative outcomes, including Clavien‐Dindo classification of complications, were recorded for 76 consecutive cases. We compared perioperative and 90‐day events with patient and tumor characteristics, stratified by operative approach and case complexity, using Wilcoxon rank‐sum test for continuous variables and the Chi‐squared or Fisher's exact test, for binary and categorical variables, respectively. Results Open surgery (n = 15) reduced ischemia time and operative time, but increased hospital admission time. Pre‐ and post‐operative estimated glomerular filtration rates did not change significantly by operative approach. Older patients (P = .007) and open surgery (P = .003) were associated with a higher rate of complications (any‐grade). Six grade ≥3 complications occurred: these were associated with higher RENAL Nephrometry Score (P = .016) and higher pathological tumor stage (P = .045). Limits include smaller case volumes which incorporate the learning curve cases; therefore, these data are most applicable to lower volume teaching hospitals. Conclusion The sliding‐clip technique for partial nephrectomy was first described by Agarwal et al and has low complication rates, acceptable operative time, and preserves renal function across open and minimally invasive surgeries. This series encompasses the initial learning curve with developing the technique through to present‐day emergence as a routine standard of practice.

Introduction The COVID-19 pandemic caused changes to how healthcare services are utilised and delivered. Objectives We examine the impact of COVID-19 on the pattern of emergency patient presentations referred on to the community mental health team and the impact of utilising telemedicine on time to follow-up. Methods We retrospectively reviewed all clinical records of patients currently attending our service. We identified presentations to the emergency department (N=119) who were subsequently referred on for mental health follow-up. Results Patients being referred to our team from emergency departments were significantly younger during, mean age 33.1 years (SD=12.3) compared to before the pandemic, mean age 40.0 years (SD=14.5), p=0.006 and a higher proportion were new patients during, 55.8%, compared to pre-pandemic period 33.3%, p=0.015. There was also a higher proportion of patients presenting with suicidal ideation and lower proportions of affective, psychosis and suicidal/self-injurious acts during the pandemic period compared to before, p=0.006. The ratio of female to male patients on the other hand were similar during both periods, p=0.853. There appeared to be no difference in median time to follow-up pre and during the pandemic (6.0 vs 5.5 days, p=0.995). Further analysis also found no significant impact on time to follow-up upon implementing telemedicine consultations, with median days to initial follow-up of 6 days pre-pandemic, 4.5 days during pandemic + prior to telemedicine and 6.5 days during pandemic + telemedicine, p=0.602. Conclusions This study provides preliminary data on the impact of COVID-19 on mental health emergency presentations and utilization of telemedicine on time to follow-up by CMHTs. Disclosure No significant relationships.

Abstract Background DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. Methods We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. Results Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2–4.8, p = 0.014). Conclusions CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.

Summary: Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for PC, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9 × 10−7 and GAB2, p = 2.0 × 10−6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% confidence interval [CI] = 0.94–1.36); whereas decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04–1.50). These results suggest that germline genetics may help inform and individualize the decision of AS—or the intensity of monitoring on AS—versus treatment for the initial management of patients with low-risk PC.

ABSTRACT To successfully complete malolactic fermentation (MLF), Oenococcus oeni must overcome wine stress conditions of low pH, high ethanol, and the presence of SO2. Failure to complete MLF may result in detrimental effects to the quality and stability of the resulting wines. Research efforts to date have focused on elucidating the mechanisms and genetic features that confer the ability to withstand low pH and high ethanol concentrations on O. oeni; however, the responses to SO2 stress are less well defined. This study focused on characterizing the transcriptional response of O. oeni to SO2 challenge during cultivation in a continuous system at wine-like pH (3.5). This experimental design allowed the precise discrimination of transcriptional changes linked to SO2 stress from responses associated with growth stage and cultivation parameters. Differential gene expression analysis revealed major transcriptional changes following SO2 exposure and suggested that this compound primarily interacts with intracellular proteins, DNA, and the cell envelope of O. oeni. The molecular chaperone hsp20, which has a demonstrated function in the heat, ethanol, and acid stress response, was highly upregulated, confirming its additional role in the response of this species to SO2 stress. This work also reports the first nanopore-based complete genome assemblies for O. oeni. IMPORTANCE Malolactic fermentation is an indispensable step in the elaboration of most wines and is generally performed by Oenococcus oeni, a Gram-positive heterofermentative lactic acid bacterium species. While O. oeni is tolerant to many of the wine stresses, including low pH and high ethanol concentrations, it has high sensitivity to SO2, an antiseptic and antioxidant compound regularly used in winemaking. Understanding the physiological changes induced in O. oeni by SO2 stress is essential for the development of more robust starter cultures and methods for their use. This study describes the main transcriptional changes induced by SO2 stress in the wine bacterium O. oeni and provides foundational understanding on how this compound interacts with the cellular components and the induced protective mechanisms of this species.

Introduction The shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects β-cell function in populations without diabetes but has not been as well studied in those with diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone.Research design and methods This is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed