Gut cytokines modulate olfaction through metabolic reprogramming of glia.

Infection-induced aversion against enteropathogens is a conserved sickness behaviour that can promote host survival1,2. The aetiology of this behaviour remains poorly understood, but studies in Drosophila have linked olfactory and gustatory perception to avoidance behaviours against toxic microorganisms3-5. Whether and how enteric infections directly influence sensory perception to induce or modulate such behaviours remains unknown. Here we show that enteropathogen infection in Drosophila can modulate olfaction through metabolic reprogramming of ensheathing glia of the antennal lobe. Infection-induced unpaired cytokine expression in the intestine activates JAK-STAT signalling in ensheathing glia, inducing the expression of glial monocarboxylate transporters and the apolipoprotein glial lazarillo (GLaz), and affecting metabolic coupling of glia and neurons at the antennal lobe. This modulates olfactory discrimination, promotes the avoidance of bacteria-laced food and increases fly survival. Although transient in young flies, gut-induced metabolic reprogramming of ensheathing glia becomes constitutive in old flies owing to age-related intestinal inflammation, which contributes to an age-related decline in olfactory discrimination. Our findings identify adaptive glial metabolic reprogramming by gut-derived cytokines as a mechanism that causes lasting changes in a sensory system in ageing flies.

High incidence of imperforate vagina in ADGRA3-deficient mice.

BACKGROUND: Ten percent of the female population suffers from congenital abnormalities of the vagina, uterus, or oviducts, with severe consequences for reproductive and psychological health. Yet, the underlying causes of most of these malformations remain largely unknown. ADGRA3 (GPR125) is involved in WNT signaling and planar cell polarity, mechanisms vital to female reproductive tract development. Although ADGRA3 is a well-established spermatogonial stem cell marker, its role within the female urogenital system remains unclear. RESULTS: In this study, we found Adgra3 to be expressed throughout the murine female urogenital system, with higher expression pre-puberty than after sexual maturation. We generated a global Adgra3-/- mouse line and observed imperforate vagina in 44% of Adgra3-/- females, resulting in distension of the reproductive tract and infertility. Ovarian morphology, plasma estradiol, ovarian Cyp19a1, and vaginal estrogen receptor α (Esr1) expression were unaffected. However, compared to controls, a significantly lower bone mineral density was found in Adgra3-/- mice. Whereas vaginal opening in mice is an estrogen-dependent process, 17ß-estradiol treatment failed to induce vaginal canalization in Adgra3-/- mice. Furthermore, a marked reduction in vaginal and ovarian progesterone receptor expression was observed concomitant with an upregulation of apoptotic regulators Bcl2, Bid, and Bmf in adult Adgra3-/- females with a closed vagina. CONCLUSIONS: Our collective results shed new insights into the complex mechanisms by which the adhesion receptor ADGRA3 regulates distal vaginal tissue remodeling during vaginal canalization via altered sex hormone responsiveness and balance in apoptotic regulators. This highlights the potential of ADGRA3 as a target in diagnostic screening and/or therapy for obstructive vaginal malformations in humans.

Net Clinical Benefit of Oral Anticoagulation Among Frail Patients With Atrial Fibrillation: Nationwide Cohort Study.

BACKGROUND: Frail people with atrial fibrillation are often undertreated with oral anticoagulants (OACs), and evidence for the net clinical benefit (NCB) of OAC is sparse. We, therefore, examined the risk of thromboembolic events, major bleeding, and NCB of anticoagulation treatment. METHODS: This was a nationwide cohort study including frail patients aged with incident atrial fibrillation between 2013 and 2018. Patients were categorized according to OAC treatment exposure. One-year risks of thromboembolic events and major bleeding were ascertained where death was treated as a competing risk. The NCB of anticoagulation was assessed by a bivariate trade-off between thromboembolism and bleeding. RESULTS: We identified 36 223 frail patients with atrial fibrillation (median age, 79 years; 50.5% female), of whom 61.8% started OAC therapy, while 38.2% were untreated despite indication for stroke prevention. At 1 year, the risk of thromboembolic events was 2.1% (95% CI, 1.8%-2.3%) among patients not receiving OAC versus 1.5% (95% CI, 1.4%-1.7%) in patients with OAC. The bleeding risk was 3.2% (95% CI, 2.9%-3.5%) among patients without OAC versus 3.5% (95% CI, 3.2%-3.8%) among anticoagulated patients. The NCB was 0.70% (95% CI, 0.32%-1.08%), suggesting a benefit of OAC treatment; however, the NCB declined with age and increasing frailty and was lowest among patients >75 years of age or with high frailty level. CONCLUSIONS: Frail patients with atrial fibrillation are often untreated with OAC in routine clinical care despite an indication for stroke prevention. The NCB balancing thromboembolic events and major bleeding was in favor of anticoagulation but decreased with advancing age and increasing frailty.

High-dose vitamin D3 supplementation shows no beneficial effects on white blood cell counts, acute phase reactants, or frequency of respiratory infections.

BACKGROUND: Vitamin D has been suggested to influence the immune system, and vitamin D metabolites and the vitamin D receptor (VDR) are generated and expressed in white blood cells (WBC). Moreover, vitamin D status has been associated with incidence and prognosis of some respiratory tract infections (RTI). Therefore, we investigated the effect of vitamin D3 supplementation on WBC, acute phase reactants (APR), and the risk of developing RTIs. METHODS: A double-blinded, randomized, placebo-controlled clinical trial of 307 infertile men with multiple secondary immunological endpoints. The vitamin D3 group (n = 151) initially received 300,000 IU (7,500 µg) cholecalciferol once - followed by 1,400 IU (35 µg) daily for 150 days. The placebo group (n = 156) did not receive active ingredients. RESULTS: At baseline, stratification into clinically relevant groups of vitamin D status (< 25; 25-50; 50-75; >75 nmol/L), showed an inverse association with total leucocyte concentrations (7.0 vs. 6.0 vs. 6.0 vs. 5.5 (109/L); p = 0.007), lymphocytes (2.4 vs. 2.1 vs. 2.0 vs. 2.0 (109/L); p = 0.048), CRP (2.0 vs. 1.7 vs. 1.2 vs. 1.2 (mg/L); p = 0.037), and orosomucoid (0.82 vs. 0.77 vs. 0.76 vs. 0.70 (g/L); p = 0.015). After 150 days, no differences were detected in WBC counts or APRs between the vitamin D3 and the placebo group. However, vitamin D3 treated men had a higher prevalence of self-reported RTIs compared with the placebo group (55% vs. 39%; p = 0.005). CONCLUSIONS: High-dose vitamin D3 supplementation did not alter WBCs or APRs, but a higher prevalence of respiratory infections was observed in the vitamin D3 group. Serum 25(OH)D3 was negatively correlated with most WBCs, indicating that vitamin D status may be linked with inflammation and WBC turnover, but not an important determinant of developing RTIs. TRIAL REGISTRATION: NCT01304927 (ClinicalTrials.gov). Registered February 20, 2011.

Loss of Adgra3 causes obstructive azoospermia with high penetrance in male mice.

The adhesion receptor ADGRA3 (GPR125) is a known spermatogonial stem cell marker, but its impact on male reproduction and fertility has not been examined. Using a mouse model lacking Adgra3 (Adgra3-/- ), we show that 55% of the male mice are infertile from puberty despite having normal spermatogenesis and epididymal sperm count. Instead, male mice lacking Adgra3 exhibited decreased estrogen receptor alpha expression and transient dilation of the epididymis. Combined with an increased estradiol production, this indicates a post-pubertal hormonal imbalance and fluid retention. Dye injection revealed a blockage between the ejaculatory duct and the urethra, which is rare in mice suffering from infertility, thereby mimicking the etiologies of obstructive azoospermia found in human male infertility. To summarize, male reproductive tract development is dependent on ADGRA3 function that in concert with estrogen signaling may influence fluid handling during sperm maturation and storage.

Salmonella infections in Denmark from 2013-2022 with focus on serotype distribution, invasiveness, age, sex, and travel exposition.

PURPOSE: To analyze the nationwide incidence of Salmonella infections in Denmark from 2013 to 2022. METHODS: Confirmed cases of Salmonella enterica subsp. enterica were examined using the National Register of Enteric Pathogens during 2013-2022. Proportions, incidence rates (IR), relative risk (RR), and 95% confidence intervals (CI) were calculated to assess differences in serotypes, invasiveness, age, sex, and travel exposure. RESULTS: We identified 9,944 Danish Salmonella enterica subsp. enterica cases, with an average annual incidence rate of 16.9 per 100,000 inhabitants, declining during the COVID-19 pandemic. Typhoidal cases totaled 206, with an average annual IR of 0.35 per 100,000 inhabitants. Enteric fever patients had a median age of 24 years (IQR:17-36). Leading non-typhoid Salmonella (NTS) serotypes were S. Enteritidis (26.4%), monophasic S. Typhimurium (16.5%), and S. Typhimurium (13.5%). Median age for NTS cases was 42 (IQR: 18-62), with even sex distribution, and a third reported travel prior to onset of disease. The overall percentage of invasive NTS (iNTS) infection was 8.1% (CI: 7.6-8.7). Eleven serotypes were associated with higher invasiveness, with S. Dublin and S. Panama having the highest invasiveness with age and sex-adjusted RR of 7.31 (CI: 6.35-8.43) and 5.42 (CI: 3.42-8.60), respectively, compared to all other NTS serotypes. Increased age was associated with higher RR for iNTS infection. CONCLUSION: During the decade, there was a limited number of typhoidal cases. The dominant NTS serotypes were S. Enteritidis and monophasic S. Typhimurium, whereas S. Dublin and S. Panama exhibited the highest invasive potential.

High-dose cholecalciferol supplementation to obese infertile men is sufficient to reach adequate vitamin D status.

Obesity is associated with low vitamin D status, and the optimal supplement and dosage of cholecalciferol (vitamin D3) or calcidiol (25OHD) for individuals with obesity have been debated. We aimed to determine the effect of high-dose vitamin D3 supplementation on achieving adequate vitamin D levels among infertile men with normal weight v. obesity. Here, we present secondary end points from a single-centre, double-blinded, randomised clinical trial, comprising 307 infertile men randomised to active or placebo treatment for 150 days. Men in the active group initially received an oral bolus of 300 000 mg of vitamin D3, followed by daily supplementation with 1400 mg of vitamin D3 and 500 mg of calcium. Baseline BMI was listed as a predefined subgroup. At baseline, serum 25OHD was significantly higher in men with normal weight (BMI < 25 kg/m2) compared with men with overweight (BMI 25-30 kg/m2) and obesity (BMI > 30 kg/m2) (48 nmol/l v. 45 nmol/l and 39 nmol/l, respectively; P = 0·024). After the intervention, men with normal weight, overweight and obesity treated with vitamin D3 had a significantly higher serum 25OHD compared with corresponding placebo-treated men (BMI < 25 kg/m2: 92 nmol/l v. 53 nmol/l, BMI = 25-30 kg/m2: 87 nmol/l v. 49 nmol/l and BMI > 30 kg/m2: 85 nmol/l v. 48 nmol/l; P < 0·001 for all, respectively). In conclusion, we show that high-dose vitamin D3 supplementation to infertile men with obesity and low vitamin D status is sufficient to achieve adequate serum 25OHD levels.

The association between sleep, mental health, and health behaviours: a Danish population-based cross-sectional study.

AIMS: Sleep problems constitute a significant public health problem due to their high prevalence and impact on mental health and health behaviours, with major consequences for individuals and society. Therefore, the aim of this study was to investigate the association between sleep problems (duration and quality), mental health and health behaviours. METHODS: Cross-sectional data was derived from the 2021 health survey 'How are you?' from the Central Denmark Region. The study population was a stratified random sample of 33,925 respondents aged 16 years or older. We used logistic regression models to analyse the associations between sleep problems and indicators of mental health and health behaviour. The models were adjusted for sex, age, educational attainment, labour market attachment, cohabitation, and indicators of mental health and health behaviour. RESULTS: A prevalence of around 10% for both short- and long sleep duration and poor sleep quality was found. All were associated with poor mental health-related quality of life, depression, stress, perceived stressors and obesity. In addition, short sleep duration was associated with daily smoking, and long sleep duration was associated with physical inactivity and daily smoking. CONCLUSIONS: Our findings revealed a stronger association between sleep problems and mental health indicators in comparison to health behaviours. We found that sleep duration and sleep quality in broad terms were associated with similar variables within mental health and health behaviour. These findings underline the importance of adopting a comprehensive approach to addressing sleep problems in the context of health promotion, disease prevention, treatment and rehabilitation.

Exploring general practice staff perspectives on a teaching concept based on instruction videos for diabetic retinopathy screening - an interview study.

OBJECTIVE: The aim of this study is to explore general practice staff perspectives regarding a teaching concept based on instructional videos for conducting DR screenings. Furthermore, this study aims to investigate the competencies acquired by the staff through this teaching concept. DESIGN AND SETTING: Qualitative cross-sectional study conducted in general practice clinics in the North Denmark Region. METHOD: A teaching concept was developed based on instruction videos to teach general practice staff to conduct diabetic retinopathy screenings with automated grading through artificial intelligence. Semi-structured interviews were performed with 16 staff members to investigate their perspectives on the concept and acquired competencies. RESULTS: This study found no substantial resistance to the teaching concept from staff; however, participants' satisfaction with the methods employed in the instruction session, the progression of learning curves, screening competencies, and their acceptance of a known knowledge gap during screenings varied slightly among the participants. CONCLUSION: This study showed that the teaching concept can be used to teach general practice staff to conduct diabetic retinopathy screenings. Staffs' perspectives on the teaching concept and acquired competencies varied, and this study suggest few adjustments to the concept to accommodate staff's preferences and establish more consistent competencies.

Low serum anti-Müllerian hormone is associated with semen quality in infertile men and not influenced by vitamin D supplementation.

BACKGROUND: Anti-Müllerian hormone (AMH) is released by testicular Sertoli cells and of great importance during fetal male sexual development, but less is known about the role of circulating AMH during adulthood. In vitro studies have shown that vitamin D may induce AMH transcription, but a controlled trial investigating the possible effect of vitamin D on serum AMH has not been conducted in men. METHODS: A single-center, double-blinded, randomized placebo-controlled clinical trial (NCT01304927) conducted in Copenhagen, Denmark. A total of 307 infertile men were included and randomly assigned (1:1) to a single dose of 300,000 IU cholecalciferol followed by 1400 IU cholecalciferol + 500 mg of calcium daily (n = 151) or placebo (n = 156) for 150 days. Difference in serum AMH was a predefined secondary endpoint. Explorative outcomes were associations between serum AMH and gonadal function in infertile men. The primary endpoint was difference in semen quality and has previously been published. RESULTS: Infertile men in the lowest AMH tertile had significantly lower sperm concentration (∆T3-1 16 mill/mL (228%); P < 0.001), sperm count (∆T3-1 55 million (262%); P < 0.001), motile sperm count (∆T3-1 28 million (255%); P < 0.001), progressive motile sperm count (∆T3-1 18 million (300%); P < 0.001), testis size (∆T3-1 2.7 mL (16%); P < 0.001), serum inhibin B (∆T3-1 72 pg/mL (59%); P < 0.001), inhibin B/FSH ratio (∆T3-1 48 (145%); P < 0.001), and higher FSH (∆T3-1 2.6 (38%); P < 0.001) than the tertile of infertile men with highest serum AMH. Vitamin D supplementation had no effect on serum AMH compared with placebo treatment. CONCLUSIONS: In infertile men, low serum AMH is associated with severely impaired gonadal function illustrated by poor semen quality and lower testosterone/LH ratio. Serum AMH in infertile men was not influenced by vitamin D supplementation.

Use of primary health care and radiological imaging preceding a diagnosis of rheumatoid arthritis: a nationwide cohort study in Denmark.

OBJECTIVE: To explore health-care use in the 12 months preceding a diagnosis of RA in Denmark. METHODS: We conducted a population-based cohort study using data from national registries. Every patient diagnosed with RA in 2014-18 was matched to 10 reference individuals without RA from the Danish background population. Health-care use was defined as contacts to general practitioners, contacts to private practicing physiotherapists, and X-rays of hands and/or feet performed in primary or secondary care. We estimated the monthly contact rates for patients and references in the 12 months preceding the diagnosis, and we compared incidence rates for health-care use in each month between the two groups while adjusting for sociodemographic characteristics and comorbidity. RESULTS: We included 7427 patients with RA and 74 270 references. Patients with RA had increasing contact rates with general practitioners and physiotherapists from 6 to 8 months before the diagnosis. Compared with references, women with RA had statistically significantly more contacts to general practitioners and physiotherapists during all 12 months. A similar contact pattern was seen in men, albeit less distinct. The number of X-rays increased slightly from 8 months before the diagnosis, with a steep increase in the last 3 months. CONCLUSION: Increased contacts to general practitioners and physiotherapists were seen in all 12 months preceding the RA diagnosis, intensifying in the last 6 to 8 months. Imaging increased from 3 months before the diagnosis. This indicates an opportunity to expedite referral to specialist care and ensure earlier diagnosis of RA.

In-vitro screening of compatible synbiotics and (introducing) "prophybiotics" as a tool to improve gut health.

Synbiotics have been intensively studied recently to improve gut health of humans and animals. The success of synergistic synbiotics depends on the compatibility of the prebiotic and probiotic components. Certain plant extracts possess both antimicrobial and prebiotic properties representing a potential use in combination with probiotics to improve the gut health. Here, we coined the term "prophybiotics" to describe this combined bioactivity. The current study aimed to select prebiotics that are preferred as an energy source and antimicrobial plant extracts which do not inhibit the growth, of six strains of lactic acid bacteria (LAB namely; Lactiplantibacillus plantarum, Lacticaseibacillus casei, Limosilactobacillus reuteri, Lacticaseibacillus rhamnosus, Leuconostoc mesenteroides, and Pediococcus pentosaceus) in-vitro to identify compatible combinations for potential synbiotic/prophybiotic use, respectively. Their growth kinetics were profiled in the presence of prebiotics: Inulin, Raffinose, and Saccharicterpenin with glucose, as the control, using carbohydrate free MRS broth media. Similarly, their growth kinetics in MRS broth supplemented with turmeric, green tea, and garlic extracts at varying concentrations were profiled. The results revealed the most compatible pairs of prebiotics and LAB. Turmeric and garlic had very little inhibitory effect on the growth of the LAB while green tea inhibited the growth of all LAB in a dose-dependent manner. Therefore, we conclude that turmeric and garlic have broad potential for use in prophybiotics, while the prebiotics studied here have limited use in synbiotics, with these LAB.

Patient perspectives on data sharing regarding implementing and using artificial intelligence in general practice - a qualitative study.

BACKGROUND: Due to more elderly and patients with complex illnesses, there is an increasing pressure on the healthcare system. General practice especially feels this pressure as being the first point of contact for the patients. Developments in digitalization have undergone fast progress and data-driven artificial intelligence (AI) has shown great potential for use in general practice. To develop AI as a support tool for general practitioners (GPs), access to patients' health data is needed, but patients have concerns regarding data sharing. Furthermore, studies show that trust is important regarding the patient-GP relationship, data sharing, and AI. The aim of this paper is to uncover patient perspectives on trust regarding the patient-GP relationship, data sharing and AI in general practice. METHOD: This study investigated 10 patients' perspectives through qualitative interviews and written vignettes were chosen to elicit the patients (interviewees) perspectives on topics that they were not familiar with prior to the interviews. The study specifically investigated perspectives on 1) The patient-GP relationship, 2) data sharing regarding developing AI for general practice, and 3) implementation and use of AI in general practice using thematic analysis. The study took place in the North Denmark Region and the interviewees included had to be registered in general practice and be above 18 years in age. We included four men between 25 to 74 years in age and six women between 27 to 46 years in age. RESULTS: The interviewees expressed a high level of trust towards their GP and were willing to share their health data with their GP. The interviewees believed that AI could be a great help to GPs if used as a support tool in general practice. However, it was important for the interviewees that the GP would still be the primary decision maker. CONCLUSION: Patients may be willing to share health data to help implement and use AI in general practice. If AI is implemented in a way that preserves the patient-GP relationship and used as a support tool for the GP, our results indicate that patients may be positive towards the use of AI in general practice.

Does a corticosteroid injection plus exercise or exercise alone add to the effect of patient advice and a heel cup for patients with plantar fasciopathy? A randomised clinical trial.

OBJECTIVE: To compare the effectiveness of patient advice plus heel cup alone (PA) versus PA and lower limb exercise (PAX) versus PAX plus corticosteroid injection (PAXI) to improve self-reported pain in patients with plantar fasciopathy. METHODS: We recruited 180 adults with plantar fasciopathy confirmed by ultrasonography for this prospectively registered three-armed, randomised, single-blinded superiority trial. Patients were randomly allocated to PA (n=62), PA plus self-dosed lower limb heavy-slow resistance training consisting of heel raises (PAX) (n=59), or PAX plus an ultrasound-guided injection of 1 mL triamcinolone 20 mg/mL (PAXI) (n=59). The primary outcome was changed in the pain domain of the Foot Health Status Questionnaire (ranging from 0 'worst' to 100 'best') from baseline to the 12-week follow-up. The minimal important difference in the pain domain is 14.1 points. The outcome was collected at baseline and at 4, 12, 26, and 52 weeks. RESULTS: The primary analysis found a statistically significant difference between PA and PAXI after 12 weeks favouring PAXI (adjusted mean difference: -9.1 (95% CI -16.8 to -1.3; p=0.023)) and over 52 weeks (adjusted mean difference: -5.2 (95% CI -10.4 to -0.1; p=0.045)). At no follow-up did the mean difference between groups exceed the pre-specified minimal important difference. No statistically significant difference was found between PAX and PAXI or between PA and PAX at any time. CONCLUSION: No clinically relevant between-group differences were found after 12 weeks. The results indicate that combining a corticosteroid injection with exercise is not superior to exercise or no exercise. TRIAL REGISTRATION NUMBER: NCT03804008.

Risk of Cerebrovascular Events in Intracerebral Hemorrhage Survivors With Atrial Fibrillation: A Nationwide Cohort Study.

BACKGROUND: In patients with intracerebral hemorrhage (ICH) and prevalent atrial fibrillation (AF), the optimal stroke prevention strategy is unclear. We sought to estimate the risk of cerebrovascular events among ICH survivors with AF. METHODS: We used the Danish Stroke Registry to identify patients with incident ICH and prevalent AF between 2003 and 2018. Key inclusion/exclusion criteria of the PRESTIGE-AF (Prevention of Stroke in Intracerebral hemorrhage Survivors With Atrial Fibrillation) trial were applied. Cumulative incidence of recurrent ICH, cerebrovascular ischemic event, and all-cause death were investigated after one year. RESULTS: A total of 1885 patients (median age 80.0 years; 47.6% females) were included in the study. We observed 191 cerebrovascular events and 650 all-cause deaths, and more cerebrovascular ischemic events (N=63) than recurrent ICH events (N=40). Risks of recurrent ICH, cerebrovascular ischemic event, and all-cause death were 1.5%, 3.2%, and 30.3%, respectively, among patients not exposed to OAC during follow-up. The cumulative incidences were 2.8% for recurrent ICH, 3.2% for cerebrovascular ischemic events, and 22.0% for all-cause death among patients initiating/resuming OAC during follow-up. CONCLUSIONS: We observed a high risk of cerebrovascular ischemic events and a very high risk of all-cause death at one year after the incident ICH. The results of ongoing clinical trials are warranted to determine optimal stroke prevention treatment among ICH survivors with concomitant AF.

RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma.

BACKGROUND: Testicular germ cell tumours (TGCTs) have a high sensitivity to chemotherapy and a high cure rate, although with serious adverse effects. In the search for tumour suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis, came up as a candidate since RANKL signalling was recently identified in the testis. METHODS: Expression of RANKL, RANK and OPG, and the effects of RANKL inhibition were investigated in human TGCTs, TGCT-derived cell-lines, and TGCT-xenograft models. Serum RANKL was measured in TGCT-patients. RESULTS: RANKL, RANK, and OPG were expressed in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL-inhibition reduced proliferation of seminoma-derived TCam-2 cells, but had no effect on embryonal carcinoma-derived NTera2 cells. Pretreatment with Denosumab did not augment the effect of cisplatin in vitro. However, inhibition of RANKL in vivo reduced tumour growth exclusively in the TCam-2-xenograft model and Denosumab-treatment decreased proliferation in human GCNIS cultures. In TGCT-patients serum RANKL had no prognostic value. CONCLUSIONS: This study shows that the RANKL signalling system is expressed in GCNIS and seminoma where RANKL inhibition suppresses tumour growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation or transition from GCNIS to invasive tumours.

Disparities in oral anticoagulation initiation in patients with schizophrenia and atrial fibrillation: A nationwide cohort study.

AIMS: Schizophrenia is associated with poor anticoagulation control and clinical prognosis in patients with atrial fibrillation (AF). Little is known about initiation of oral anticoagulation therapy (OAC) in this patient population. METHODS: In the nationwide Danish health registries, we identified all patients with incident AF and schizophrenia with indication for OAC treatment. Patients with schizophrenia (n = 673) were matched 1:5 on sex, age, stroke risk score, and calendar-period to incident AF patients without schizophrenia. We calculated absolute risk and risk difference (RD) of OAC initiation, adjusting for stroke and bleeding risk factors. Analyses were stratified by calendar period (2000-2011 and 2012-2018) to account for changes after the introduction of non-vitamin K OACs (NOAC). RESULTS: Among patients with schizophrenia (mean age 69.5 years, 50.3% females), 33.7% initiated OAC within the first year after AF diagnosis, compared with 54.4% of patients without schizophrenia, corresponding to an adjusted RD of -20.7 (95% confidence interval [CI]: -24.7 to -16.7). OAC initiation increased over time regardless of schizophrenia status. During 2000-2011, 18.3% of patients with schizophrenia and 42.9% without schizophrenia initiated OAC (adjusted RD -23.6%, 95% CI -28.8 to -18.6). During 2012-2018, this was 48.5% and 65.7%, respectively (adjusted RD -14.4%, 95% CI -20.4 to -8.4). CONCLUSION: Initiation of OAC was substantially lower among patients with AF and schizophrenia compared with matched AF peers. These findings accentuate the importance of close attention to disparities in initiation of OAC treatment, and potential missed opportunities for prevention of disabling strokes in AF patients with schizophrenia.

General Practitioners' Perspectives on Appropriate Use of Ultrasonography in Primary Care in Denmark: A Multistage Mixed Methods Study.

PURPOSE: Researchers aimed to describe general practitioners' understanding of appropriate ultrasound use, to record actual scanning practices of early adopters in general practice, and to identify differences between attitudes and actual practice via a mixed methods analysis. METHODS: This study was part of a larger multistage mixed methods research framework exploring the use of ultrasound in general practice in Denmark. We used an exploratory sequential approach in the data collection with initial qualitative findings from an interview study applied to building a quantitative questionnaire utilized in a cohort study. In addition, we merged the qualitative and quantitative data using joint display analysis to compare and contrast the results from the 2 stages of the study. RESULTS: In the interviews, general practitioners described appropriate ultrasound use as point-of-care examinations with a clear purpose and limited to predefined specific conditions within delimited anatomic areas. They stated that general practitioners should receive formalized ultrasound training and be skilled in the examinations they perform. In the cohort study, general practitioners performed ultrasound examinations of anatomic areas with or without a defined clinical suspicion. Some performed ultrasound examinations for which they had no previous training or skills. CONCLUSIONS: We found a difference between the ideas about the appropriate uses for ultrasound in general practice and the actual use by early adopters in clinical practice. Our findings suggest a need for evidence-based guidelines to support general practitioners in choosing which examinations to perform and strategies for developing and maintaining scanning competency.

Risk of complications in the late vs early days of the 42nd week of pregnancy: A nationwide cohort study.

INTRODUCTION: Uncertainty remains about the most appropriate timing of induction of labor in late-term pregnancies. To address this issue, this study aimed to compare the risk of neonatal morbidity and pregnancy- and birth-related complications between gestational age (GA) 41+4 -42+0 and GA 41+0 -41+3  weeks. MATERIAL AND METHODS: This nationwide registry-based cohort study included singleton births without major congenital malformations, with registered GA, and with intended vaginal delivery at GA 41+0 - 42+0  weeks between 2009 and 2018 in Denmark. Logistic regression models were used to estimate the crude risk ratio and adjusted risk ratio (RRA ) of neonatal and obstetric adverse outcomes in births at GA 41+4 - 42+0  weeks compared with GA 41+0 - 41+3  weeks. The results were adjusted for relevant confounders, including induction of labor. RESULTS: A higher incidence of neonatal morbidity and birth complications was observed in births at GA 41+4 -42+0  weeks than in births at GA 41+0 -41+3  weeks. Neonatal morbidities included an increased risk of low Apgar score (Apgar 0-6 after 5 min; RRA 1.17, 95% confidence interval [CI] 1.01-1.34), meconium aspiration (RRA 1.25, 95% CI 1.06-1.48), need for respiratory support (continuous positive airway pressure; RRA 1.09, 95% CI 1.03-1.15), and a composite outcome of need for comprehensive treatment at a neonatal department or neonatal death (RRA 1.65, 95% CI 1.29-2.11). Birth complications included emergency cesarean section (RRA 1.17, 95% CI 1.14-1.21), severe lacerations (RRA 1.11, 95% Cl 1.04-1.17), and increased blood loss after birth (RRA 1.13, 95% CI 1.06-1.21). CONCLUSIONS: Births at GA 41+4 -42+0  weeks were associated with an increased risk of neonatal morbidity and birth complications compared with births at GA 41+0 -41+3  weeks. The results of this study may aid clinicians in deciding when to recommend induction of labor in late-term pregnancies.

A cost-minimisation analysis of performing point-of-care ultrasonography on patients with vaginal bleeding in early pregnancy in general practice: a decision analytical model.

BACKGROUND: Spotting and light vaginal bleeding are common and usually harmless symptoms in early pregnancy. Still, vaginal bleeding may be the first sign of an abortion and often causes distress to pregnant women and leads to an expectation of an ultrasonography examination of the uterus. As point-of-care ultrasonography (POCUS) is increasingly being integrated into general practice, these patients may be clinically evaluated and managed by general practitioners (GPs). This can potentially reduce referrals of patients from the primary to the secondary healthcare sector resulting in societal cost-savings. The primary purpose of this study was to investigate whether the accessibility of POCUS in general practice for patients with vaginal bleeding in early pregnancy is cost-saving compared to usual practice where GPs do not have access to POCUS. A secondary purpose of this study was to estimate a remuneration for GPs performing POCUS on these patients in general practice. METHODS: A cost-minimisation analysis was based on a decision tree model reflecting the two alternatives: general practice with and without GPs having access to POCUS. The robustness of the model results was investigated using probabilistic sensitivity analysis and the following deterministic sensitivity analyses: one-way analyses for the model input parameters and a scenario analysis with a change from a societal to a healthcare sector perspective. An expected remuneration reflecting the add-on cost of Danish GPs performing POCUS was estimated based on the related costs: cost of an ultrasonography scanner, GP's time consumption, ultrasonography training, and utensils per scanning. RESULTS: The difference in average cost between the two alternatives from a societal perspective was estimated to be €110, in favour of general practice with GPs using POCUS. The deterministic sensitivity analyses demonstrated robustness of the results to plausible changes in the input parameters. The expected remuneration for performing POCUS in this specific setting was estimated to be €32 per examination. CONCLUSION: Having GPs perform POCUS on patients with vaginal bleeding in early pregnancy is cost-saving compared to usual practice. The results should be taken with caution as this study was based on early modelling with uncertainties associated with the input parameters in the model.