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Abstract Nicotinamide N-methyltransferase (NNMT) is a metabolic regulator that catalyzes the methylation of nicotinamide (Nam) using the co-factor S-adenosyl-L-methionine to form 1-methyl-nicotinamide (MNA). Overexpression of NNMT and the presence of the active metabolite MNA is associated with a number of diseases including metabolic disorders. We conducted a high-throughput screening campaign that led to the identification of a tricyclic core as a potential NNMT small molecule inhibitor series. Elaborate medicinal chemistry efforts were undertaken and hundreds of analogs were synthesized to understand the structure activity relationship and structure property relationship of this tricyclic series. A lead molecule, JBSNF-000028, was identified that inhibits human and mouse NNMT activity, reduces MNA levels in mouse plasma, liver and adipose tissue, and drives insulin sensitization, glucose modulation and body weight reduction in a diet-induced obese mouse model of diabetes. The co-crystal structure showed that JBSNF-000028 binds below a hairpin structural motif at the nicotinamide pocket and stacks between Tyr-204 (from Hairpin) and Leu-164 (from central domain). JBSNF-000028 was inactive against a broad panel of targets related to metabolism and safety. Interestingly, the improvement in glucose tolerance upon treatment with JBSNF-000028 was also observed in NNMT knockout mice with diet-induced obesity, pointing towards the glucose-normalizing effect that may go beyond NNMT inhibition. JBSNF-000028 can be a potential therapeutic option for metabolic disorders and developmental studies are warranted.

Abstract Background There is a growing need for genetic testing of women with epithelial ovarian cancer. Mainstream genetic testing provides an alternative care pathway in which non-genetic healthcare professionals offer pre-test counseling themselves. We aimed to explore the impact of mainstream genetic testing on patients’ experiences, turnaround times and adherence of non-genetic healthcare professionals to the mainstream genetic testing protocol. Methods Patients receiving pre-test counseling at the gynecology departments between April 2018 and April 2020 were eligible to participate in our intervention group. Patients receiving pre-test counseling at the genetics department between January 2017 and April 2020 were eligible to participate in our control group. We evaluated patients’ experiences with questionnaires, consisting of questions regarding knowledge, satisfaction and psychosocial outcomes. Patients in the intervention group were sent two questionnaires: one after pre-test counseling and one after receiving their DNA test result. Patients in our control group were sent one questionnaire after receiving their test result. In addition, we collected data regarding turnaround times and adherence of non-genetic healthcare professionals to the mainstream genetic testing protocol. Results Participation was 79% in our intervention group (105 out of 133 patients) and 60% in our control group (91 out of 152 patients). Knowledge regarding genetics, decisional conflict, depression, anxiety, and distress were comparable in the two groups. In the intervention group, the risk of breast cancer in patients carrying a pathogenic germline variant was discussed less often (49% versus 74% in control group, p ≤ 0.05), and the mean score of regret about the decision to have genetic testing was higher than in the control group (mean 12.9 in the intervention group versus 9.7 in the control group, p ≤ 0.05), although below the clinically relevant threshold of 25. A consent form for the DNA test and a checklist to assess family history were present for ≥ 95% of patients in the intervention group. Conclusion Mainstream genetic testing is an acceptable approach to meet the increase in genetic testing among women with epithelial ovarian cancer.

Nina Grotenhuis,1 Miranda C Schreuder,1 Tine WL van den Bos,2 Henk van der Worp,1 Marco H Blanker1 1Department of General Practice and Elderly Care Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 2Foundation Bekkenbodem4All, Tiel, the NetherlandsCorrespondence: Miranda C Schreuder, Department of General Practice and Elderly Care medicine, University Medical Center Groningen, University of Groningen, FA21, PO Box 196, Groningen, 9700AD, the Netherlands, Tel +31 625647144, Email m.c.schreuder@umcg.nlPurpose: We aimed to examine how supply source affects satisfaction with continence products and care among individuals with urinary incontinence (UI). Supply source was compared among pharmacies, national suppliers, and shops. The secondary aim was to compare participant characteristics between the three groups.Patients and Methods: A survey questionnaire was distributed via social media between April and June 2020. This included the international consultation on incontinence questionnaire (ICIQ) UI short form (ICIQ-UI-SF), the ICIQ-PadPROM, and the ICIQ-LUTSqol, together with questions about respondent characteristics and satisfaction with continence products.Results: Of the 1045 respondents, 706 fully completed and 339 partially completed the survey. Among these, 322 (45.6%), 199 (28.1%), and 185 (26.2%) made purchases from shops, national suppliers, and pharmacies, respectively. The mean ICIQ-UI-SF sum scores were comparable for the pharmacy (13.3 ± 3.7) and national supplier (13.8 ± 3.5) groups, but were significantly lower for the shop group (12.0 ± 3.3). Mean sum scores for satisfaction with continence products and satisfaction with continence care were also significantly lower in the shop group (7.9 ± 2.6 and 6.4 ± 2.7, respectively) compared with the pharmacy (9.1 ± 2.7 and 7.9 ± 2.6, respectively) and national supplier (9.3 ± 2.6 and 8.1 ± 3.0, respectively) groups. There were no statistically significant differences in the ICIQ-PadPROM and ICIQ-LUTSqol scores. Respondents’ characteristics were similar, apart from the significantly lower number of males in the shop group.Conclusion: Satisfaction with continence products and continence care is lower for people with UI who purchase materials from a shop than from a pharmacy or national supplier.Keywords: incontinence care, health insurance, incontinence pads, urinary loss

Background: Glycogen storage disease (GSD) Ia is an ultra-rare inherited disorder of carbohydrate metabolism. Patients often present in the first months of life with fasting hypoketotic hypoglycemia and hepatomegaly. The diagnosis of GSD Ia relies on a combination of different biomarkers, mostly routine clinical chemical markers and subsequent genetic confirmation. However, a specific and reliable biomarker is lacking. As GSD Ia patients demonstrate altered lipid metabolism and mitochondrial fatty acid oxidation, we built a machine learning model to identify GSD Ia patients based on plasma acylcarnitine profiles. Methods: We collected plasma acylcarnitine profiles from 3958 patients, of whom 31 have GSD Ia. Synthetic samples were generated to address the problem of class imbalance in the dataset. We built several machine learning models based on gradient-boosted trees. Our approach included hyperparameter tuning and feature selection and generalization was checked using both nested cross-validation and a held-out test set. Results: The binary classifier was able to correctly identify 5/6 GSD Ia patients in a held-out test set without generating significant amounts of false positive results. The best model showed excellent performance with a mean received operator curve (ROC) AUC of 0.955 and precision-recall (PR) curve AUC of 0.674 in nested CV. Conclusions: This study demonstrates an innovative approach to applying machine learning to ultra-rare diseases by accurately identifying GSD Ia patients based on plasma free carnitine and acylcarnitine concentrations, leveraging subtle acylcarnitine abnormalities. Acylcarnitine features that were strong predictors for GSD Ia include C16-carnitine, C14OH-carnitine, total carnitine and acetylcarnitine. The model demonstrated high sensitivity and specificity, with selected parameters that were not only robust but also highly interpretable. Our approach offers potential prospect for the inclusion of GSD Ia in newborn screening. Rare diseases are underrepresented in machine learning studies and this work highlights the potential for these techniques, even in ultra-rare diseases such as GSD Ia. [ABSTRACT FROM AUTHOR]

Background: Nurse staffing remains an ongoing issue in healthcare worldwide. However, a Dutch urology ward has hardly any staffing difficulties. Nevertheless, it remains challenging to grasp what exactly is the success formula of the ward. Investigating a practical example of a successful ward will facilitate a deeper understanding of the application of current knowledge. Furthermore, novel concepts offer potential solutions to current problems. There is a need of putting the knowledge into practice. Objective: The objective is to identify the factors that contribute to the success of the urology ward in engaging, binding, and retaining nurses, to provide practical insights and opportunities for other wards. Methods: The Dutch Model for Excellent Care forms the basis of a prospective, qualitative research study with focus groups. Twelve nurses were divided into three focus groups, based on work experience. They were asked about why they love working on the ward. Analysis was performed using Braun and Clarke's method for thematic analysis. Emerged themes were presented, substantiated by quotes. Results: Four themes and twelve subthemes became apparent: (a) Supportive structures: nursing governance, professional development, and quality of leadership. (b) Optimal work environment: working with skilled nurses, a professional relationship with physicians and professional autonomy. (c) Team culture: feeling seen, good ambiance, and equality. (d) Specialty of urology: variation in work, workload, and the type of patient. Conclusions: Nurses are uniquely positioned to provide invaluable insight into their needs. They illuminated the crucial importance of fostering a work environment that prioritizes both professional as well as personal needs. [ABSTRACT FROM AUTHOR]

Determining egg freshness is critical for ensuring food safety and security and as such, different methods have been evaluated and implemented to accurately measure and predict it. In this study, a portable near-infrared (NIR) instrument combined with chemometrics was used to monitor and predict the storage time of eggs under two storage conditions—room temperature (RT) and cold (CT) storage—from two production systems: cage and free-range. A total of 700 egg samples were analyzed, using principal component analysis (PCA) and partial least squares (PLS) regression to analyze the NIR spectra. The PCA score plot did not show any clear separation between egg samples from the two production systems; however, some egg samples were grouped according to storage conditions. The cross-validation statistics for predicting storage time were as follows: for cage and RT eggs, the coefficient of determination in cross validation (R2CV) was 0.67, with a standard error in cross-validation (SECV) of 7.64 days and residual predictive deviation (RPD) of 1.8; for CT cage eggs, R2CV of 0.84, SECV of 5.38 days and RPD of 3.2; for CT free-range eggs, R2CV of 0.83, SECV of 5.52 days and RPD of 3.2; and for RT free-range eggs, R2CV of 0.82, SECV of 5.61 days, and RPD of 3.0. This study demonstrated that NIR spectroscopy can predict storage time non-destructively in intact egg samples. Even though the results of the present study are promising, further research is still needed to further extend these results to other production systems, as well as to explore the potential of this technique to predict other egg quality parameters associated with freshness.

Author(s): Marloes A. H. M. Michels [sup.1] , Kioa L. Wijnsma [sup.1] , Roel A. J. Kurvers [sup.2] , Dineke Westra [sup.1] , Michiel F. Schreuder [sup.1] , Joanna A. [...], Background C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G. Methods Twenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood. Results DDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m.sup.2 at last follow-up. Conclusions We extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics. Graphical abstract

The purpose of this metasynthesis is to present a structured review of the literature on lesbian, gay, bisexual, transgender, and queer (LGBTQ) language usage. Much of the rhetoric surrounding individuals who identify as LGBTQ focuses on their victimization and oppression. To problematize this limited perspective, this metasynthesis of literature suggests that LGBTQ youth are actively working against marginalization, oppression, and silencing through language practices that employ critical literacy and elicit the disruption of hegemonic ideology. Drawing on Darvin and Norton's (2015, Identity and a model of investment in applied linguistics. Annual Review of Applied Linguistics, 35, 36-56) key concepts from the model of investment and queer theory, I explore three uses of LGBTQ language: the creation of safe spaces, agency, and resistance. My findings reveal the need for safety within classrooms in order for LGBTQ students to participate successfully in critical literacy practices.

Abstract Background In bipolar disorder treatment, accurate episode prediction is paramount but remains difficult. A novel idiographic approach to prediction is to monitor generic early warning signals (EWS), which may manifest in symptom dynamics. EWS could thus form personalized alerts in clinical care. The present study investigated whether EWS can anticipate manic and depressive transitions in individual patients with bipolar disorder. Methods Twenty bipolar type I/II patients (with ≥ 2 episodes in the previous year) participated in ecological momentary assessment (EMA), completing five questionnaires a day for four months (Mean = 491 observations per person). Transitions were determined by weekly completed questionnaires on depressive (Quick Inventory for Depressive Symptomatology Self-Report) and manic (Altman Self-Rating Mania Scale) symptoms. EWS (rises in autocorrelation at lag-1 and standard deviation) were calculated in moving windows over 17 affective and symptomatic EMA states. Positive and negative predictive values were calculated to determine clinical utility. Results Eleven patients reported 1–2 transitions. The presence of EWS increased the probability of impending depressive and manic transitions from 32-36% to 46–48% (autocorrelation) and 29–41% (standard deviation). However, the absence of EWS could not be taken as a sign that no transition would occur in the near future. The momentary states that indicated nearby transitions most accurately (predictive values: 65–100%) were full of ideas, worry, and agitation. Large individual differences in the utility of EWS were found. Conclusions EWS show theoretical promise in anticipating manic and depressive transitions in bipolar disorder, but the level of false positives and negatives, as well as the heterogeneity within and between individuals and preprocessing methods currently limit clinical utility.

Computer-aided diagnosis systems (CADx) can improve colorectal polyp (CRP) optical diagnosis. For integration into clinical practice, better understanding of artificial intelligence (AI) by endoscopists is needed. We aimed to develop an explainable AI CADx capable of automatically generating textual descriptions of CRPs. For training and testing of this CADx, textual descriptions of CRP size and features according to the Blue Light Imaging (BLI) Adenoma Serrated International Classification (BASIC) were used, describing CRP surface, pit pattern, and vessels. CADx was tested using BLI images of 55 CRPs. Reference descriptions with agreement by at least five out of six expert endoscopists were used as gold standard. CADx performance was analyzed by calculating agreement between the CADx generated descriptions and reference descriptions. CADx development for automatic textual description of CRP features succeeded. Gwet’s AC1 values comparing the reference and generated descriptions per CRP feature were: size 0.496, surface-mucus 0.930, surface-regularity 0.926, surface-depression 0.940, pits-features 0.921, pits-type 0.957, pits-distribution 0.167, and vessels 0.778. CADx performance differed per CRP feature and was particularly high for surface descriptors while size and pits-distribution description need improvement. Explainable AI can help comprehend reasoning behind CADx diagnoses and therefore facilitate integration into clinical practice and increase trust in AI.

IntroductionPosterior urethral valves (PUV) is a congenital disorder causing an obstruction of the lower urinary tract that affects approximately 1 in 4,000 male live births. PUV is considered a multifactorial disorder, meaning that both genetic and environmental factors are involved in its development. We investigated maternal risk factors for PUV.MethodsWe included 407 PUV patients and 814 controls matched on year of birth from the AGORA data- and biobank and three participating hospitals. Information on potential risk factors (family history of congenital anomalies of the kidney and urinary tract (CAKUT), season of conception, gravidity, subfertility, and conception using assisted reproductive techniques (ART), plus maternal age, body mass index, diabetes, hypertension, smoking, and use of alcohol and folic acid) was derived from maternal questionnaires. After multiple imputation, adjusted odds ratios (aORs) were estimated using conditional logistic regression corrected for minimally sufficient sets of confounders determined using directed acyclic graphs.ResultsA positive family history and low maternal age (35 years) was associated with a lower risk (aOR: 0.7 95% CI: 0.4–1.0). Maternal preexisting hypertension seemed to increase PUV risk (aOR: 2.1 95% CI: 0.9–5.1), while gestational hypertension seemed to decrease this risk (aOR: 0.6 95% CI: 0.3–1.0). Concerning use of ART, the aORs for the different techniques were all above one, but with very wide 95% CIs including one. None of the other factors studied were associated with PUV development.ConclusionOur study showed that family history of CAKUT, low maternal age, and potentially preexisting hypertension were associated with PUV development, whereas higher maternal age and gestational hypertension seemed to be associated with a lower risk. Maternal age and hypertension as well as the possible role of ART in the development of PUV require further research.

BackgroundPerihematomal edema (PHE) after spontaneous intracerebral hemorrhage (sICH) is associated with clinical deterioration, but the etiology of PHE development is only partly understood.AimsWe aimed to investigate the association between systemic blood pressure (BP) variability (BPV) and formation of PHE.MethodsFrom a multicenter prospective observational study, we selected patients with sICH who underwent 3T brain MRI within 21 days after sICH, and had at least 5 BP measurements available in the first week after sICH. Primary outcome was the association between coefficient of variation (CV) of systolic BP (SBP) and edema extension distance (EED) using multivariable linear regression, adjusting for age, sex, ICH volume and timing of the MRI. In addition, we investigated the associations of mean SBP, mean arterial pressure (MAP), their CVs with EED and absolute and relative PHE volume.ResultsWe included 92 patients (mean age 64 years; 74% men; median ICH volume 16.8 mL (IQR 6.6–36.0), median PHE volume 22.5 mL (IQR 10.2–41.4). Median time between symptom onset and MRI was 6 days (IQR 4–11), median number of BP measurements was 25 (IQR 18–30). Log-transformed CV of SBP was not associated with EED (B = 0.050, 95%-CI −0.186 to 0.286, p = 0.673). Furthermore, we found no association between mean SBP, mean and CV of MAP and EED, nor between mean SBP, mean MAP or their CVs and absolute or relative PHE.DiscussionOur results do not support a contributing role for BPV on PHE, suggesting mechanisms other than hydrostatic pressure such as inflammatory processes, may play a more important role.

Background: The incidence of cardiovascular disease (CVD) among women is lower before the menopause, which may be due to the atheroprotective effects of female sex hormones, including estrogens. This study explored whether women experienced acute coronary syndrome (ACS) more often during menstruation, when the levels of female sex hormones are low. Methods: All premenopausal women referred to the local cardiac rehabilitation program after ACS between August 2010 and September 2018 were contacted by telephone to gather information about their menstrual cycle, contraceptive use and whether ACS occurred during menstruation. Information on cardiovascular risk factors was collected using the clinical electronic health record. Results: Of the 22 women fulfilling the inclusion criteria and having a regular menstrual cycle, 22.7% reported that they were diagnosed with ACS at the time of menstruation. Conclusions: The percentage of women who were menstruating whilst having their cardiovascular event is higher than the percentage expected if the event was unrelated to the menstrual cycle. To gain more insight into the effect of female sex hormones on ACS, it is suggested that information on the menstrual cycle is routinely collected from women admitted to hospital with the condition.