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Background: Although patients with gastroesophageal reflux are often instructed to change their lifestyle, population-based data on the risk factors for reflux in the United States are lacking.Methods: We performed a cross-sectional study in an age- and gender-stratified random sample of the population of Olmsted County, Minnesota. Residents aged 25 to 74 years were mailed a valid self-report questionnaire that measured reflux symptoms and potential risk factors. Logistic regression was used to estimate the odds ratios (OR) with 95% confidence intervals (CI) for reflux symptoms (heartburn or acid regurgitation) associated with potential risk factors.Results: Overall, 1,524 (72%) of 2,118 eligible subjects responded. A body mass index >30 kg/m2 (OR = 2.8; CI, 1.7 to 4.5), reporting an immediate family member with heartburn or disease of the esophagus or stomach (OR = 2.6; CI, 1.8 to 3.7), a past history of smoking (OR = 1.6; CI, 1.1 to 2.3), consuming more than seven drinks per week (OR = 1.9; Cl, 1.1 to 3.3), and a higher psychosomatic symptom checklist score (OR per 5 units = 1.4; CI, 1.3 to 1.6) were independently associated with frequent (at least weekly) reflux symptoms.Conclusion: Obesity is a strong risk factor for gastroesophageal reflux, although the value of weight reduction remains to be proven. That family history was also a risk factor suggests that there may be a genetic component to the disorder. [ABSTRACT FROM AUTHOR]

Background: Although the number of places at medical schools and physicians in Germany has increased continuously over the past 25 years, there is a threat of a shortage of physicians. Based on data from the Bavarian Medical Association (BLÄK) and the Association of Statutory Health Insurance Physicians of Bavaria (KVB), an analysis of the number of physicians in Bavaria over a longer period of time was carried out in order to understand current developments and possible starting points for the future organization of medical care. The figures were analyzed with regard to the distribution of physicians by outpatient and inpatient sector as well as with regard to the development of the number of employees, the scope of employment and the gender distribution in the outpatient sector., Methods: Data were taken from the annually published and systematically compiled numbers of physicians from the BLÄK (2000 to 2022) as well as the outpatient billing data of practicing and employed physicians in Bavaria (2010 to 2022), processed by the KVB. Descriptive analyses were performed., Results: Since 2000, the number of physicians in Bavaria has risen by 83% in the inpatient setting and by 35% in the outpatient setting. As a result, more physicians have been working in hospitals than in outpatient care since 2010. In the outpatient setting the trend is moving away from establishing one's own practice and full-time work towards salaried and part-time employment. Employed physicians have lower average working hours than self-employed physicians. The proportion of women among physicians has steadily increased, with female physicians more likely to be employed and working part-time compared with male physicians. Nevertheless, part-time employment is also prominent among male physicians in some specialties today., Conclusion: The trend towards practicing in salaried and part-time positions continues unabated and is represented across all specialties, suggesting that more physicians are needed to maintain the number of working hours over time. In addition to incentives and subsidies, this reality must be taken into account when planning care. At the same time, it is questionable whether increasing medical school places without managing them according to need is the right way to address the shortage of physicians in outpatient care when an ever-increasing proportion of physicians is working in inpatient care., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental diagnoses. Although incompletely understood, structural and functional network alterations are increasingly recognized to be at the core of the condition. We utilized multimodal imaging and connectivity modeling to study structure-function coupling in ASD and probed mono- and polysynaptic mechanisms on structurally-governed network function. We examined multimodal magnetic resonance imaging data in 80 ASD and 61 neurotypical controls from the Autism Brain Imaging Data Exchange (ABIDE) II initiative. We predicted intrinsic functional connectivity from structural connectivity data in each participant using a Riemannian optimization procedure that varies the times that simulated signals can unfold along tractography-derived personalized connectomes. In both ASD and neurotypical controls, we observed improved structure-function prediction at longer diffusion time scales, indicating better modeling of brain function when polysynaptic mechanisms are accounted for. Prediction accuracy differences (∆prediction accuracy) were marked in transmodal association systems, such as the default mode network, in both neurotypical controls and ASD. Differences were, however, lower in ASD in a polysynaptic regime at higher simulated diffusion times. We compared regional differences in ∆prediction accuracy between both groups to assess the impact of polysynaptic communication on structure-function coupling. This analysis revealed that between-group differences in ∆prediction accuracy followed a sensory-to-transmodal cortical hierarchy, with an increased gap between controls and ASD in transmodal compared to sensory/motor systems. Multivariate associative techniques revealed that structure-function differences reflected inter-individual differences in autistic symptoms and verbal as well as non-verbal intelligence. Our network modeling approach sheds light on atypical structure-function coupling in autism, and suggests that polysynaptic network mechanisms are implicated in the condition and that these can help explain its wide range of associated symptoms., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

NLRP3 inflammasome activation is a highly regulated process for controlling secretion of the potent inflammatory cytokines IL-1β and IL-18 that are essential during bacterial infection, sterile inflammation, and disease, including colitis, diabetes, Alzheimer's disease, and atherosclerosis. Diverse stimuli activate the NLRP3 inflammasome, and unifying upstream signals has been challenging to identify. Here, we report that a common upstream step in NLRP3 inflammasome activation is the dissociation of the glycolytic enzyme hexokinase 2 from the voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria. Hexokinase 2 dissociation from VDAC triggers activation of inositol triphosphate receptors, leading to release of calcium from the ER, which is taken up by mitochondria. This influx of calcium into mitochondria leads to oligomerization of VDAC, which is known to form a macromolecule-sized pore in the outer membranes of mitochondria that allows proteins and mitochondrial DNA (mtDNA), often associated with apoptosis and inflammation, respectively, to exit the mitochondria. We observe that VDAC oligomers aggregate with NLRP3 during initial assembly of the multiprotein oligomeric NLRP3 inflammasome complex. We also find that mtDNA is necessary for NLRP3 association with VDAC oligomers. These data, together with other recent work, help to paint a more complete picture of the pathway leading to NLRP3 inflammasome activation.

Background: Although the human papillomavirus (HPV) vaccine has been recommended in Germany for girls since 2007, no organised vaccination programme was introduced and HPV vaccine coverage remains low. We investigated the HPV vaccination rates from 2008 to 2018 and the effects of HPV vaccination on anogenital warts and precancerous lesions in young women in Bavaria, Germany, a state with low vaccination rates., Methods: Retrospective analyses of claims data from the Bavarian Association of Statutory Health Insurance Physicians (KVB) on females born between 1990 and 2009 (9 to 28 years old in 2018) were conducted to calculate vaccination rates by birth cohort, proportion of vaccine types administered and incidence of anogenital warts and precancerous lesions of the cervix uteri. 942 841 Bavarian females 9 to 28 years old with available information on HPV vaccination were included to calculate vaccination rates. For the outcome analyses, data from 433 346 females 19 to 28 years old were analysed. Hazard ratios (HR) were computed from univariable and multivariable Cox regression models comparing vaccinated and unvaccinated women, considering type of vaccine used and contraceptive prescription., Results: 40·9% of 18-year-olds and only 13·3% of 12-year-olds were fully vaccinated in 2018 in Bavaria. Gardasil® and Gardasil9® were most commonly administered. Vaccinated compared to unvaccinated women had a lower incidence of anogenital warts and cervical lesions, however only small differences were detected between fully and partially vaccinated women. Fully vaccinated women had a 63% (HR 0·37 (95% confidence interval (CI) 0·34 to 0·40) and 23% (HR 0·77, 95%CI 0·71 to 0·84) lower risk of anogenital warts and cervical lesions, respectively. Women who were prescribed contraceptives prior to vaccination had a 49% higher risk of developing anogenital warts (HR 1·49, 95%CI 1·25 to 1·79) or cervical lesions (HR 1·49, 95%CI 1·27 to 1·75) compared to vaccinated women without contraceptive prescription., Conclusions: The evaluation of the effects of HPV vaccination in Bavaria showed a promising decline of anogenital warts and precancerous lesions in vaccinated young women. However, an increase in vaccination rates is necessary to achieve a greater population impact in preventing HPV-related diseases., (© 2022. The Author(s).)

Background and Aims: Indirect fluorescent antibody assays are still the gold standard for the detection of Epstein-Barr-virus-specific antibodies; however, this technique requires several manual steps and an experienced technician. This retrospective study investigated the performance of the new VIDAS(®) enzyme-linked fluorescent assays for automated qualitative detection of EBV VCA IgM, VCA/EA IgG, and EBNA IgG antibodies in routine diagnostics., Methods: 174 serum samples were tested first with the gold standard. In context with the clinical status, 60 samples IFA IgG/IgM positive and with clinical symptoms compatible with infectious mononucleosis, 26 samples IFA IgG/IgM negative and missing any clinical symptoms and 88 samples with varying IFA status and without any clinical information were defined. In a second step all samples were retested with the new assays., Results: In the overall agreement between VIDAS(®) and IFA for evaluable results, almost perfect agreement was observed (kappa = 0.91; 95% confidence interval (CI), 0.86-0.97). Estimating all indeterminate VIDAS(®) results as discordant or concordant the observed kappa values were 0.71 (CI 0.63-0.79) and 0.93 (CI 0.88-0.98), respectively. With the new assays 45, 22, and 70 identical results were obtained, respectively. Western blot analysis of the discrepant samples showed a quasi similar performance of both assays., Conclusions: The new VIDAS(®) assays can be an alternative to IFA testing especially in high-throughput laboratories. Full automation of EBV serological diagnostis by the new VIDAS assays is of major importance for routine diagnostic laboratories.

Objectives: Perception of sensations arising from the gastrointestinal tract may be diminished in obese subjects and thus facilitate overeating. Alternatively, excess food intake may cause gastrointestinal (GI) symptoms in obese patients. We evaluated the relationship between body mass index (BMI) and specific GI symptoms in the community., Methods: Residents of Olmsted County, MN were selected at random to receive by mail one of two validated questionnaires. The association of reported GI symptoms with BMI (kg/m(2)) was assessed using a logistic regression analysis adjusting for age, gender, psychosomatic symptom score, and alcohol and tobacco use., Results: Response rate was 74% (1,963 of 2,660). The prevalence of obesity (BMI > or = 30 kg/m(2)) was 23%. There was a positive relationship between BMI and frequent vomiting (p= 0.02), upper abdominal pain (p= 0.03), bloating (p= 0.002), and diarrhea (p= 0.01). The prevalence of frequent lower abdominal pain, nausea, and constipation was increased among obese (BMI > or = 30 kg/m(2)) compared to normal weight participants, however, no significant association was found between BMI and these symptoms., Conclusions: In the community, increasing BMI is associated with increased upper GI symptoms, bloating, and diarrhea. Clarification of the cause-and-effect relationships and the mechanisms of these associations require further investigation.

Objective: The aim of this study was to estimate the prevalence of irritable bowel syndrome using different standard definitions (Rome and Manning criteria) and to determine the degree of agreement between these definitions., Methods: A population-based, cross-sectional survey study was conducted by mailing a valid, reliable questionnaire to an age- and gender-stratified random sample of residents of Olmsted County, MN, aged 30-69 yr. The threshold for a positive diagnosis of irritable bowel was varied from two to four of the six Manning criteria and from two to three of the five defecation disorders in the Rome criteria. Unadjusted as well as age- and gender-adjusted prevalence rates were calculated for each of the five definitions of IBS. Percent agreement and kappa statistics were calculated to assess agreement between the definitions., Results: Questionnaires were returned by 643 of 892 eligible subjects (72% response rate). The age- and gender-adjusted prevalence of IBS varied from 20.4% using a threshold of two symptoms in the Manning criteria to 8.5% using a threshold of three defecation disorders in the Rome criteria. The percent agreement for each comparison of Manning and Rome definitions was always >90%. The kappa values ranged from 0.55 to 0.78, with the best agreement occurring between a threshold of three symptoms of Manning and two defecation disorders in Rome., Conclusions: The prevalence of IBS varied substantially depending on the specific definition of IBS used. The range of prevalence estimates in Olmsted County was similar to other published figures when IBS definition was accounted for. These findings are useful in interpreting epidemiological and clinical studies of IBS.

Objective: To evaluate the association between functional gastrointestinal (GI) symptoms and a family history of abdominal pain or bowel problems., Subjects and Methods: A valid self-report questionnaire that records GI symptoms and spouse's and first-degree relatives' history of abdominal pain or bowel troubles and includes the psychosomatic symptom checklist (a measure of somatization) was mailed to an age- and sex-stratified random sample of Olmsted County, Minnesota, residents aged 30 to 64 years. A logistic regression model that adjusted for age, sex, and somatic symptom score was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of a positive family history for each functional GI disorder., Results: Six hundred forty-three (72%) of 892 eligible subjects returned the survey. Reporting a first-degree relative with abdominal pain or bowel problems was significantly associated with reporting of irritable bowel syndrome (OR, 2.3; 95% CI, 1.3-3.9) and dyspepsia (OR, 1.8; 95% CI, 1.05-3.0) but not constipation, diarrhea, or gastroesophageal reflux. The reporting of a spouse with abdominal pain or bowel problems was not associated with any of these disorders., Conclusions: A history of abdominal pain or bowel troubles in first-degree relatives was significantly associated with irritable bowel syndrome and dyspepsia. Whether the familial associations represent similar exposures in a shared environment, heightened familial awareness of GI symptoms (reporting bias), or genetic factors remains to be determined.

Objective: Symptoms of irritable bowel syndrome (IBS) are reported by 10% of the general population; however, evaluation of traditional risk factors has not provided any insight into the pathogenesis of this condition. The objective of this study was to identify additional risk factors for irritable bowel syndrome., Methods: A valid self-report questionnaire that records the gastrointestinal (GI) symptoms required for a diagnosis of IBS, self-reported measures of potential risk factors, and a psychosomatic symptom checklist was mailed to an age-and gender-stratified random sample of Olmsted County, Minnesota residents aged 30-64 yr. A logistic regression model that adjusted for age, gender, and psychosomatic symptom score was used to identify factors significantly associated with IBS., Results: A total of 643 (72%) of 892 eligible subjects returned the survey. IBS symptoms were reported by 12% of the respondents. IBS was significantly associated with use of analgesics (acetaminophen, aspirin, or nonaspirin nonsteroidal antiinflammatory drugs) for reasons other than IBS, reporting a food allergy or sensitivity, and ratings of somatic symptoms. No association was detected for age, gender, body mass index, smoking history, alcohol use, educational level, exposure to pets in the household, or water supply. Among subjects reporting the use of just one type of analgesic, IBS was associated with acetaminophen but not aspirin or nonaspirin nonsteroidal antiinflammatory drugs used alone. The odds of having IBS were higher among subjects reporting more reasons for taking analgesics and intolerance to a higher number of foods., Conclusions: IBS is significantly associated with analgesic use. However, this is confounded by other somatic pain complaints. IBS symptoms are associated with the reporting of many food allergies or sensitivities. The role of food-induced symptoms in IBS requires further investigation.

Background: During the 1980s, mortality from coronary artery disease (CAD) decreased markedly in the United States. This raises the question of whether a parallel decrease occurred in excess mortality due to CAD in patients undergoing surgical correction of valvular regurgitation., Methods and Results: Survival of 752 patients (age, 64 +/- 13 years) with isolated left-sided valvular regurgitation operated on from 1980 to 1991 was analyzed. Of 242 patients with CAD (stenosis > or = 70%), 208 had coronary artery bypass grafting. Multivariate analysis identified CAD as an independent predictor of operative mortality (odds ratio [OR] = 2.35, P = 0.012), overall (hazard ratio [HR] = 1.65, P < 0.0001) and late mortality (HR = 1.57, P = 0.0006), and postoperative congestive heart failure (HR = 2.35, P = 0.0001). Comparison of patients operated on in 1980 to 1985 with those operated on in 1986 to 1991, excess of operative, overall, and late mortality and postoperative congestive heart failure (adjusted for age and gender) related to associated CAD did not decrease significantly (P = 0.23, P = 0.64, P = 0.90, and P = 0.61, respectively). Overall survival was better for patients receiving an internal mammary artery graft than those receiving vein grafts only (HR = 0.57, P = 0.011)., Conclusions: In contrast to the secular trend for decreased mortality from CAD, excess mortality related to associated CAD after surgery for valvular regurgitation has not decreased. Internal mammary artery grafts were associated with improved outcome. In patients with valvular regurgitations, these results support continued active search of associated CAD, wide use of internal mammary artery graft, and vigorous efforts for secondary prevention of complications of CAD.

Objectives: We sought to determine the reliability of the proximal isovelocity surface area (PISA) method for calculation of effective regurgitant orifice (ERO) of aortic regurgitation (AR)., Background: The ERO area can be calculated by the PISA method, but this method has not been validated in AR., Methods: ERO calculation by the PISA method was undertaken prospectively in 71 consecutive patients with isolated AR and achieved in 64 and compared with two simultaneous reference methods (quantitative Doppler and quantitative two-dimensional echocardiography). In addition, this method was compared with angiography in 12 patients, with surgical assessment in 18 patients and with ventricular volumes in all patients., Results: Good correlations between PISA and reference methods were obtained (both r=0.90, both p < 0.0001), but a trend toward underestimation of the ERO by the PISA method was noted (24+/-19 vs. 26+/-22 mm2 and 27+/-23 mm2, respectively, both p=0.04). However, this trend was confined to five patients with an obtuse flow convergence angle (>220 degrees), and on multivariate analysis this variable was the only independent determinant of underestimation of the ERO. In contrast, in 59 patients with a flat flow convergence (< or =220 degrees ), the PISA method, in comparison with reference methods, showed excellent correlations, with a narrow standard error of the estimate (r=0.95, SEE 5.4 mm2, and r=0.95, SEE 5.8 mm2; all p < 0.0001) and no trend toward underestimation (22+/-18 vs. 23+/-16 mm2, p=0.44, and vs. 23+/-18 mm2, p=0.34)., Conclusions: In patients with AR, the PISA method can be used to measure the ERO with reasonable feasibility. Underestimation of the ERO by PISA may occur in patients with an obtuse flow convergence angle. However, in most patients with appropriate flow convergence, PISA provides reliable measurement of the ERO of AR.

Background & Aims: Gastroesophageal reflux is considered a common condition, but detailed population-based data on reflux in the United States are lacking. The aim of this study was to determine the prevalence and clinical spectrum of gastroesophageal reflux in Olmsted County, Minnesota., Methods: A reliable and valid self-report questionnaire was mailed to an age- and sex-stratified random sample of 2200 Olmsted County residents aged 25-74 years., Results: The prevalence per 100 of heartburn and/or acid regurgitation experienced at least weekly was 19.8 (95% confidence interval [95% CI], 17.7-21.9). Heartburn and acid regurgitation were associated with noncardiac chest pain (odds ratio [OR], 4.2; 95% CI, 2.9-6.0), dysphagia (OR, 4.7; 95% CI, 2.9-7.4), dyspepsia (OR, 3.1; 95% CI, 1.9-5.0), and globus sensation (OR, 1.9; 95% CI, 1.0-3.6) but not with asthma, hoarseness, bronchitis, or a history of pneumonia. Among subjects with reflux symptoms, 1.0% reported an episode of hematemesis and 1.3% had a past esophageal dilatation., Conclusions: Symptoms of reflux are common among white men and women who are 25-74 years of age. Heartburn and acid regurgitation are significantly associated with chest pain, dysphagia, dyspepsia, and globus sensation. The percentage of patients reporting complications is low, but the absolute number is probably considerable given the high prevalence of the condition in the community.

Effects of the nonbenzamide 5-hydroxytryptamine4 agonist SDZ HTF 919 on gastrointestinal motility are unclear. Our aim was to assess the in vivo effects on gastrointestinal and colonic transit of radiolabeled residue and on colonic phasic contractility. In six female dogs, transit was measured over a period of 2 days by radioscintigraphy and colonic motility was measured by pneumohydraulic perfusion manometry of the proximal and distal colon. SDZ HTF 919 was administered initially by bolus i.v. infusion, followed by s.c. injection 8 and 16 hr later. Doses tested were 0.03, 0.1 and 0.3 mg/kg, and isotonic saline and vehicle served as controls in each dog. Stomach and small bowel transit was not significantly altered by SDZ HTF 919. Overall, i.v. SDZ HTF 919 accelerated colonic transit during the first 1 hr, compared with controls. These effects were significant even with the lowest dose of SDZ HTF 919. Responses to higher infusion doses were more variable. SDZ HTF 919 did not cause significant changes in quantitative pressure indices, such as amplitude or motor index, in the small bowel or colon. Prolonged postprandial colonic contractions, each lasting >30 sec, were noted after each i.v. agent and were significantly more frequent with the 0.03 mg/kg dose than with control (vehicle) treatment. Thus, SDZ HTF 919 accelerates canine colonic transit in vivo during the first 1 hr after i.v. administration. SDZ HTF 919 appears to be a promising agent for stimulation of mammalian colonic transit.

Objective: A link between functional bowel disease and sexual, physical, emotional, or verbal abuse remains controversial. We aimed to determine whether abuse is associated with functional bowel disease in outpatients., Methods: A consecutive sample of outpatients completed a validated questionnaire; 997 responded. Using standard criteria, we obtained data on symptoms, psychosocial factors, and abuse (sexual, physical, and emotional or verbal). Logistic regression analysis was used to determine whether abuse was associated with functional bowel disease (versus organic disease) and with irritable bowel syndrome (IBS)-type symptoms defined by the Manning criteria. Adjustments were made for age, gender, marital status, education level, psychological distress, and social support., Results: Of those with a physician-based diagnosis of functional bowel disease (n = 440), 22% reported some form of abuse (13% sexual and/or physical abuse), compared with those with organic disease (n = 557), 16% of whom reported some form of abuse; this difference was not significant. However, abused patients were significantly more likely to report IBS-type symptoms than those who did not report a history of abuse (odds ratio = 1.7, 95% confidence interval = 1.2, 2.5)., Conclusion: Outpatients who report abuse are more likely to have IBS-type symptoms.

Background/aims: A link between abuse and irritable bowel syndrome (IBS) has been reported in outpatients but remains controversial. No population-based studies have investigated this issue. The aim of this study was to determine the prevalence of abuse and its association with symptoms in a representative community sample., Methods: An age- and sex-stratified random sample of residents of Olmsted County, Minnesota ranging in age from 30 to 49 years was mailed a valid self-report symptom questionnaire. Abuse was assessed by standard published criteria., Results: Of the 919 responders (74%), the age-adjusted prevalence of any abuse was 41% in women and 11% in men, resulting in an age- and sex-adjusted prevalence of 26%. Symptoms of IBS, dyspepsia, and frequent heartburn were reported by 14%, 23%, and 12%, respectively. There was a significant association between IBS and sexual abuse, emotional or verbal abuse, and abuse in childhood and adulthood. Similarly, dyspepsia and heartburn were both significantly associated with abuse. In the population, 31% had visited a physician for gastrointestinal symptoms; the odds of visiting a physician were highest in those reporting abuse in adulthood and childhood., Conclusions: Self-reported abuse is common in middle-aged subjects; those who report abuse are more likely to have symptoms consistent with IBS, dyspepsia, or heartburn and to visit a physician for bowel symptoms.