Identification and characterization of the novel colonization factor CS30 based on whole genome sequencing in enterotoxigenic Escherichia coli (ETEC).

The ability to colonize the small intestine is essential for enterotoxigenic Escherichia coli (ETEC) to cause diarrhea. Although 22 antigenically different colonization factors (CFs) have been identified and characterized in ETEC at least 30% of clinical ETEC isolates lack known CFs. Ninety-four whole genome sequenced "CF negative" isolates were searched for novel CFs using a reverse genetics approach followed by phenotypic analyses. We identified a novel CF, CS30, encoded by a set of seven genes, csmA-G, related to the human CF operon CS18 and the porcine CF operon 987P (F6). CS30 was shown to be thermo-regulated, expressed at 37 °C, but not at 20 °C, by SDS-page and mass spectrometry analyses as well as electron microscopy imaging. Bacteria expressing CS30 were also shown to bind to differentiated human intestinal Caco-2 cells. The genes encoding CS30 were located on a plasmid (E873p3) together with the genes encoding LT and STp. PCR screening of ETEC isolates revealed that 8.6% (n = 13) of "CF negative" (n = 152) and 19.4% (n = 13) of "CF negative" LT + STp (n = 67) expressing isolates analyzed harbored CS30. Hence, we conclude that CS30 is common among "CF negative" LT + STp isolates and is associated with ETEC that cause diarrhea

Publisher Correction: Identification and characterization of the novel colonization factor CS30 based on whole genome sequencing in enterotoxigenic Escherichia coli (ETEC).

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Biochemical Recurrence and Risk of Mortality Following Radiotherapy or Radical Prostatectomy

Importance: Stratifying patients with biochemical recurrence (BCR) after primary treatment for prostate cancer based on the risk of prostate cancer-specific mortality (PCSM) is essential for determining the need for further testing and treatments. Objective: To evaluate the association of BCR after radical prostatectomy or radiotherapy and its current risk stratification with PCSM. Design, Setting, and Participants: This population-based cohort study included a total of 16 311 male patients with 10 364 (64%) undergoing radical prostatectomy and 5947 (36%) undergoing radiotherapy with curative intent (cT1-3, cM0) and PSA follow-up in Stockholm, Sweden, between 2003 and 2019. Follow-up for all patients was until death, emigration, or end of the study (ie, December 31, 2018). Data were analyzed between September 2022 and March 2023. Main Outcomes and Measures: Primary outcomes of the study were the cumulative incidence of BCR and PCSM. Patients with BCR were stratified in low- and high-risk according to European Association of Urology (EAU) criteria. Exposures: Radical prostatectomy or radiotherapy. Results: A total of 16 311 patients were included. Median (IQR) age was 64 (59-68) years in the radical prostatectomy cohort (10 364 patients) and 69 (64-73) years in the radiotherapy cohort (5947 patients). Median (IQR) follow-up for survivors was 88 (55-138) months and 89 (53-134) months, respectively. Following radical prostatectomy, the 15-year cumulative incidences of BCR were 16% (95% CI, 15%-18%) for the 4024 patients in the low D'Amico risk group, 30% (95% CI, 27%-32%) for the 5239 patients in the intermediate D'Amico risk group, and 46% (95% CI, 42%-51%) for 1101 patients in the high D'Amico risk group. Following radiotherapy, the 15-year cumulative incidences of BCR were 18% (95% CI, 15%-21%) for the 1230 patients in the low-risk group, 24% (95% CI, 21%-26%) for the 2355 patients in the intermediate-risk group, and 36% (95% CI, 33%-39%) for the 2362 patients in the high-risk group. The 10-year cumulative incidences of PCSM after radical prostatectomy were 4% (95% CI, 2%-6%) for the 1101 patients who developed low-risk EAU-BCR and 9% (95% CI, 5%-13%) for 649 patients who developed high-risk EAU-BCR. After radiotherapy, the 10-year PCSM cumulative incidences were 24% (95% CI, 19%-29%) for the 591 patients in the low-risk EAU-BCR category and 46% (95% CI, 40%-51%) for the 600 patients in the high-risk EAU-BCR category. Conclusions and Relevance: These findings suggest the validity of EAU-BCR stratification system. However, while the risk of dying from prostate cancer in low-risk EAU-BCR after radical prostatectomy was very low, patients who developed low-risk EAU-BCR after radiotherapy had a nonnegligible risk of prostate cancer mortality. Improving risk stratification of patients with BCR is pivotal to guide salvage treatment decisions, reduce overtreatment, and limit the number of staging tests in the event of PSA elevations after primary treatment.</p

The Mount Sinai Prebiopsy Risk Calculator for Predicting any Prostate Cancer and Clinically Significant Prostate Cancer: Development of a Risk Predictive Tool and Validation with Advanced Neural Networking, Prostate Magnetic Resonance Imaging Outcome Database, and European Randomized Study of Screening for Prostate Cancer Risk Calculator

Background: The European Association of Urology guidelines recommend the use of imaging, biomarkers, and risk calculators in men at risk of prostate cancer. Risk predictive calculators that combine multiparametric magnetic resonance imaging with prebiopsy variables aid as an individualized decision-making tool for patients at risk of prostate cancer, and advanced neural networking increases reliability of these tools.Objective: To develop a comprehensive risk predictive online web-based tool using magnetic resonance imaging (MRI) and clinical data, to predict the risk of any prostate cancer (PCa) and clinically significant PCa (csPCa) applicable to biopsy-naive men, men with a prior negative biopsy, men with prior positive low-grade cancer, and men with negative MRI.Design, setting, and participants: Institutional review board-approved prospective data of 1902 men undergoing biopsy from October 2013 to September 2021 at Mount Sinai were collected.Outcome measurements and statistical analysis: Univariable and multivariable analyses were used to evaluate clinical variables such as age, race, digital rectal examination, family history, prostate-specific antigen (PSA), biopsy status, Prostate Imaging Reporting and Data System score, and prostate volume, which emerged as predictors for any PCa and csPCa. Binary logistic regression was performed to study the probability. Validation was performed with advanced neural networking (ANN), multi-institutional European cohort (Prostate MRI Outcome Database [PROMOD]), and European Randomized Study of Screening for Prostate Cancer Risk Calculator (ERSPC RC) 3/4.Results and limitations: Overall, 2363 biopsies had complete clinical information, with 57.98% any cancer and 31.40% csPCa. The prediction model was significantly associated with both any PCa and csPCa having an area under the curve (AUC) of 81.9% including clinical data. The AUC for external validation was calculated in PROMOD, ERSPC RC, and ANN for any PCa (0.82 vs 0.70 vs 0.90) and csPCa (0.82 vs 0.78 vs 0.92), respectively. This study is limited by its retrospective design and over-estimation of csPCa in the PROMOD cohort.Conclusions: The Mount Sinai Prebiopsy Risk Calculator combines PSA, imaging and clinical data to predict the risk of any PCa and csPCa for all patient settings. With accurate validation results in a large European cohort, ERSPC RC, and ANN, it exhibits its efficiency and applicability in a more generalized population. This calculator is available online in the form of a free web-based tool that can aid clinicians in better patients counseling and treatment decision-making.Patient summary: We developed the Mount Sinai Prebiopsy Risk Calculator (MSP-RC) to assess the likelihood of any prostate cancer and clinically significant disease based on a combination of clinical and imaging characteristics. MSP-RC is applicable to all patient settings and accessible online. Crown Copyright (C) 2022 Published by Elsevier B.V. on behalf of European Association of Urology.</p

Entrepreneurs’ mental health and well-being:A review and research agenda

Interest in entrepreneurs’ mental health and well-being (MWB) is growing in recognition of the role of MWB in entrepreneurs’ decision making, motivation, and action. Yet relevant knowledge is dispersed across disciplines, which makes what we currently understand about entrepreneurs’ MWB unclear. In this systematic review I integrate insights from 144 empirical studies. These studies show that research is focused on three research questions: (1) Do different types of entrepreneurs differ in their MWB? What are the (2) antecedents and (3) consequences of entrepreneurs’ MWB? The review systematizes evidence on known antecedents and consequences of entrepreneurs’ MWB but also reveals overlooked and undertheorized sources and outcomes of entrepreneurs’ MWB. The review provides a mapping and framework that advance research on entrepreneurs’ MWB and help to position entrepreneurs’ MWB more centrally in management and entrepreneurship research. It calls for researchers to go beyond applying models developed for employees to understand entrepreneurs. Instead, the findings point the way to developing a dedicated theory of entrepreneurial work and MWB that is dynamic, socialized, and open to considering context and acknowledges variability and fluidity across entrepreneurs’ life domains, as well as the centrality of work for entrepreneurs’ identity

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Insomnia Symptoms in Chronic Pain : Clinical presentation, risk and treatment

In recent years, chronic and recurrent pain have gained interest as distinct conditions interacting both with peripheral and central parts of the nervous system as well as with the immune system. The risk of getting affected by abnormal pain modulation i.e., chronic pain is not equally distributed in the population and the search for risk factors is therefore of interest. One potential risk factor for chronic pain is insomnia symptoms i.e., difficulties falling asleep or maintaining sleep. In turn, insomnia symptoms are overrepresented in persons with chronic pain. Common current pain treatments lead to limited improvement of insomnia symptoms calling for treatments specifically directed to improve sleep. The overall aim of this thesis is therefore to investigate the distribution of insomnia severity in patients seeking specialized care for chronic pain, to investigate the role of insomnia severity as a risk factor for spreading of pre-existing pain, and to evaluate potential treatments for insomnia symptoms comorbid to chronic pain. Study I highlighted the high prevalence rates of insomnia symptoms in patients with chronic pain conditions. Roughly, insomnia was six times more common in our sample compared to the general population. We also showed that there were weak connections between insomnia symptoms and other variables (primarily psychological symptoms and pain intensity). In Study II physical exercise was more efficacious than Acceptance and Commitment Therapy-based stress management and the active control group in reducing insomnia symptoms and pain intensity short term. Improvements in physical exercise were largely maintained after twelve months but pain intensity had then also declined in the control group. No improvements in the Acceptance and Commitment Therapy-based stress management remain significant when an intention to treat principles were applied. In Study III, a dose-dependent increase in risk for spreading of pain was confirmed in subjects reporting moderate and severe insomnia symptoms. Though, there was no increase in the risk of pain spreading in subjects reporting sub-threshold insomnia symptoms (according to Insomnia Severity Index). In Study IV patients in the Internet-delivered Cognitive Behavioural Therapy for insomnia group, showed a more rapid improvement in insomnia symptoms than patients in the internet-delivered applied relaxation. The effect of Cognitive Behavioural Therapy for insomnia had declined slightly after six months and the Applied Relaxation group had continued to improve, leading to a comparable outcome on the Insomnia Severity Index at six-month follow-up. In conclusion, insomnia symptoms are common in patients seeking specialized pain care. High levels of insomnia symptoms increase the risk of spreading of pre-existing pain and this in a dose-dependent manner. Physical exercise has significant, but not clinically meaningful effects on pain intensity and insomnia symptoms. Internet-delivered Cognitive Behavioral Therapy for insomnia leads to a more rapid reduction of insomnia symptoms compared to applied relaxation, although long-term effects are uncertain Under senare år har kronisk och återkommande smärta uppmärksammats som egna tillstånd som interagerar med både perifera och centrala delar av nervsystemet samt immunsystemet. Risken för att bli påverkad av avvikande smärtmodulering dvs långvarig/kronisk smärta är inte jämnt fördelad i befolkningen och forskningen om riskfaktorer är därför av stor vikt. En potentiell riskfaktor för kronisk smärta är insomnisymptom, det vill säga svårigheter att somna på kvällen, eller att upprätthålla sömnen under natten. Insomnisymptom är i sin tur överrepresenterade hos personer med kronisk smärta. Sedvanliga smärtbehandlingar leder endast till begränsade förbättringar av sömnen viket understryker behovet av behandlingar som är inriktade på att förbättra sömnen. Det övergripande syftet med denna avhandling är därför att undersöka fördelningen av insomnisymptom hos patienter som söker specialiserad vård för kronisk smärta, att undersöka insomnisymptom som riskfaktor för spridning av befintliga smärttillstånd och att utvärdera potentiella behandlingar för sömnproblem hos patienter med kronisk smärta.  Studie I lyfte fram den höga förekomsten av insomnisymptom hos patienter med kroniska smärta. Insomnisymptom var ungefär sex gånger vanligare i vårt stickprov jämfört med befolkningen i stort. Vi visade också att det fanns relativt svaga samband mellan insomnisymptom och andra variabler (främst psykologiska symtom och smärtintensitet). I studie II var fysisk träning mer effektiv än acceptansbaserad stresshantering och den aktiva kontrollgruppen för att minska insomnisymptom och smärtintensitet på kort sikt. Förbättringarna av fysisk träning kvarstod i stor utsträckning efter tolv månader, men smärtintensiteten hade då också minskat i kontrollgruppen. Inga effekter av den acceptansbaserade stresshanteringen var signifikanta när data från samtliga deltagare togs med i analyserna. I studie III bekräftades ett dos-responsförhållande mellan insomnisymptom och risk för smärtspridning hos personer som skattade måttliga till svåra insomnisymtom. Däremot förelåg det ingen ökad risk för smärtspridning hos patienter som skattade lätt förhöjda nivåer av insomnisymptom. I studie IV uppvisade patienter som fått internetadministrerad kognitiv beteendeterapi för insomni en snabbare förbättring av insomnisymptom jämfört med patienter som fick internetlevererad tillämpad avslappning. Effekten av kognitiv beteendeterapi för insomni hade minskat något efter sex månader och avslappningsgruppen hade fortsatt att förbättras, vilket ledde till likvärdiga resultat vid sexmånadersuppföljningen.  Sammanfattningsvis är insomnisymptom vanliga hos patienter som söker specialiserad smärtvård. Höga nivåer av insomnisymptom ökar risken för spridning av befintlig smärta och detta på ett dosberoende sätt. Fysisk träning har signifikanta, men inte kliniskt betydelsefulla, effekter på smärtintensitet och insomnisymptom. Internetadministrerad kognitiv beteendeterapi för insomni leder till en snabbare minskning av insomnisymptom jämfört med tillämpad avslappning, även om långtidseffekterna är oklara.