The Role of Surgical Expertise and Surgical Access in Retroperitoneal Sarcoma Resection - A Retrospective Study.

Background Retroperitoneal sarcoma (RPS) is a rare disease often requiring multi-visceral and wide margin resections for which a resection in a sarcoma center is advised. Midline incision seems to be the access of choice. However, up to now there is no evidence for the best surgical access. This study aimed to analyze the oncological outcome according to the surgical expertise and also the incision used for the resection. Methods All patients treated for RPS between 2007 and 2018 at the Department of Visceral Surgery and Medicine of the University Hospital Bern and receiving a RPS resection in curative intent were included. Patient- and treatment specific factors as well as local recurrence-free, disease-free and overall survival were analyzed in correlation to the hospital type where the resection occurred. Results Thirty-five patients were treated for RPS at our center. The majority received their primary RPS resection at a sarcoma center (SC = 23) the rest of the resection were performed in a non-sarcoma center (non-SC = 12). Median tumor size was 24 cm. Resections were performed via a midline laparotomy (ML = 31) or flank incision (FI = 4). All patients with a primary FI (n = 4) were operated in a non-SC (p = 0.003). No patient operated at a non-SC received a multivisceral resection (p = 0.004). Incomplete resection (R2) was observed more often when resection was done in a non-SC (p = 0.013). Resection at a non-SC was significantly associated with worse recurrence-free survival and disease-free survival after R0/1 resection (2 vs 17 months; Log Rank p-value = 0.02 respectively 2 vs 15 months; Log Rank p-value < 0.001). Conclusions Resection at a non-SC is associated with more incomplete resection and worse outcome in RPS surgery. Inadequate access, such as FI, may prevent complete resection and multivisceral resection if indicated and demonstrates the importance of surgical expertise in the outcome of RPS resection

Association of smoking and nicotine dependence with pre-diabetes in young and healthy adults.

INTRODUCTION: Several studies have shown an increased risk of type 2 diabetes among smokers. Therefore, the aim of this analysis was to assess the relationship between smoking, cumulative smoking exposure and nicotine dependence with pre-diabetes. METHODS: We performed a cross-sectional analysis of healthy adults aged 25-41 in the Principality of Liechtenstein. Individuals with known diabetes, Body Mass Index (BMI) &gt;35 kg/m² and prevalent cardiovascular disease were excluded. Smoking behaviour was assessed by self-report. Pre-diabetes was defined as glycosylated haemoglobin between 5.7% and 6.4%. Multivariable logistic regression models were done. RESULTS: Of the 2142 participants (median age 37 years), 499 (23.3%) had pre-diabetes. There were 1,168 (55%) never smokers, 503 (23%) past smokers and 471 (22%) current smokers, with a prevalence of pre-diabetes of 21.2%, 20.9% and 31.2%, respectively (p &lt;0.0001). In multivariable regression models, current smokers had an odds ratio (OR) of pre-diabetes of 1.82 (95% confidential interval (CI) 1.39; 2.38, p &lt;0.0001). Individuals with a smoking exposure of &lt;5, 5-10 and &gt;10 pack-years had an OR (95% CI) for pre-diabetes of 1.34 (0.90; 2.00), 1.80 (1.07; 3.01) and 2.51 (1.80; 3.59) (p linear trend &lt;0.0001) compared with never smokers. A Fagerström score of 2, 3-5 and &gt;5 among current smokers was associated with an OR (95% CI) for pre-diabetes of 1.27 (0.89; 1.82), 2.15 (1.48; 3.13) and 3.35 (1.73; 6.48) (p linear trend &lt;0.0001). DISCUSSION: Smoking is strongly associated with pre-diabetes in young adults with a low burden of smoking exposure. Nicotine dependence could be a potential mechanism of this relationship

Prospective Assessment of Sex-Related Differences in Symptom Status and Health Perception Among Patients With Atrial Fibrillation.

We prospectively assessed sex-specific differences in health perception, overall symptom status, and specific symptoms in a large cohort of patients with atrial fibrillation. We performed a prospective multicenter observational cohort study of 1553 patients with atrial fibrillation. Patients completed questionnaires about personal characteristics, comorbidities, and symptoms on a yearly basis. Mean age was 70±11 years among women and 67±12 years among men. Health perception on a visual analogue scale ranging from 0 to 100 (with higher scores indicating better health perception) was significantly lower in women than in men (70 [interquartile range: 50-80] versus 75 [interquartile range: 60-85]; javax.xml.bind.JAXBElement@29592a5d &lt;0.0001). More women than men had any symptoms (85.0% versus 68.3%; javax.xml.bind.JAXBElement@7ac0b4e4 &lt;0.0001), palpitations (65.2% versus 44.4%; javax.xml.bind.JAXBElement@41229466 &lt;0.0001), dizziness (25.6% versus 13.5%; javax.xml.bind.JAXBElement@61871784 &lt;0.0001), dyspnea (35.7% versus 21.8%; javax.xml.bind.JAXBElement@16cc22b &lt;0.0001), and fatigue (25.3% versus 19.1%; javax.xml.bind.JAXBElement@7ef43176 =0.006). At 1-year follow-up, symptoms decreased in both sexes but remained more frequent in women (49.1% versus 32.6%, javax.xml.bind.JAXBElement@2b200b6a &lt;0.0001). In multivariable adjusted longitudinal regression models, female sex remained an independent predictor for lower health perception (ß=-4.8; 95% CI, -6.5 to -3.1; javax.xml.bind.JAXBElement@72c212bd &lt;0.0001), any symptoms (odds ratio [OR]: 2.6; 95% CI, 2.1-3.4; javax.xml.bind.JAXBElement@15d8fb54 &lt;0.0001), palpitations (OR: 2.6; 95% CI, 2.1-3.2; javax.xml.bind.JAXBElement@4af80718 &lt;0.0001), dizziness (OR: 2.9; 95% CI, 2.1-3.9; javax.xml.bind.JAXBElement@61282e76 &lt;0.0001), dyspnea (OR: 2.1; 95% CI, 1.6-2.8; javax.xml.bind.JAXBElement@31d9f14 &lt;0.0001), fatigue (OR: 1.6; 95% CI, 1.2-2.2; javax.xml.bind.JAXBElement@51cdd678 =0.0008), and chest pain (OR: 1.8; 95% CI, 1.3-2.6; javax.xml.bind.JAXBElement@5b87db9e =0.001). Women with atrial fibrillation have a substantially higher symptom burden and lower health perception than men. These relationships persisted after multivariable adjustment and during prospective follow-up

Relationship between QRS duration and incident atrial fibrillation

Background: QRS duration (QRSd), a measure of ventricular conduction, has been associated with adverse cardiovascular outcomes, but its relationship with incident atrial fibrillation (AF) is poorly understood. Methods and results: This study included 15,314 participants from the Atherosclerosis Risk in Communities (ARIC) study who were free of AF at baseline. QRSd was automatically measured from resting 12-lead electrocardiograms (ECGs) at baseline. Incident AF cases were systematically ascertained using ECGs, hospital discharge diagnoses and death certificates. Multivariable adjusted Cox regression analyses were performed to investigate the relationship between QRSd and incident AF. Mean age of our population was 54 ± 6 years (55% females). During a median follow-up of 21.2 years, 2041 confirmed incident AF cases occurred. In multivariable adjusted Cox models, a 1-SD increase in QRSd was associated with a hazard ratio (HR) (95% CI) for AF of 1.05 (1.01; 1.10), p = 0.01. This relationship was significant among women (HR per 1-SD increase in QRSd (95% CI) 1.13 (1.06; 1.20), p < 0.001), but not among men (1.00 (0.95; 1.06), p = 0.97) (p for interaction 0.005). Compared to individuals with a QRSd <100 ms, the HRs for incident AF in individuals with a QRSd of 100–119 and ≥120 ms were 1.13 (1.02; 1.26) and 1.35 (1.08; 1.68), respectively (p for trend 0.002). Again, this relationship was significant among women (p for trend <0.001) but not among men (p for trend 0.23). Conclusion: In this large population-based study, QRSd was an independent predictor of incident AF among women, but not in men. Further studies are needed to better understand the underlying mechanisms

Long-term risk of adverse outcomes according to atrial fibrillation type.

Sustained forms of atrial fibrillation (AF) may be associated with a higher risk of adverse outcomes, but few if any long-term studies took into account changes of AF type and co-morbidities over time. We prospectively followed 3843 AF patients and collected information on AF type and co-morbidities during yearly follow-ups. The primary outcome was a composite of stroke or systemic embolism (SE). Secondary outcomes included myocardial infarction, hospitalization for congestive heart failure (CHF), bleeding and all-cause mortality. Multivariable adjusted Cox proportional hazards models with time-varying covariates were used to compare hazard ratios (HR) according to AF type. At baseline 1895 (49%), 1046 (27%) and 902 (24%) patients had paroxysmal, persistent and permanent AF and 3234 (84%) were anticoagulated. After a median (IQR) follow-up of 3.0 (1.9; 4.2) years, the incidence of stroke/SE was 1.0 per 100 patient-years. The incidence of myocardial infarction, CHF, bleeding and all-cause mortality was 0.7, 3.0, 2.9 and 2.7 per 100 patient-years, respectively. The multivariable adjusted (a) HRs (95% confidence interval) for stroke/SE were 1.13 (0.69; 1.85) and 1.27 (0.83; 1.95) for time-updated persistent and permanent AF, respectively. The corresponding aHRs were 1.23 (0.89, 1.69) and 1.45 (1.12; 1.87) for all-cause mortality, 1.34 (1.00; 1.80) and 1.30 (1.01; 1.67) for CHF, 0.91 (0.48; 1.72) and 0.95 (0.56; 1.59) for myocardial infarction, and 0.89 (0.70; 1.14) and 1.00 (0.81; 1.24) for bleeding. In this large prospective cohort of AF patients, time-updated AF type was not associated with incident stroke/SE

Novel bleeding risk score for patients with atrial fibrillation on oral anticoagulants, including direct oral anticoagulants

Objective: Balancing bleeding risk and stroke risk in patients with atrial fibrillation (AF) is a common challenge. Though several bleeding risk scores exist, most have not included patients on direct oral anticoagulants (DOACs). We aimed at developing a novel bleeding risk score for patients with AF on oral anticoagulants (OAC) including both vitamin K antagonists (VKA) and DOACs. Methods: We included patients with AF on OACs from a prospective multicenter cohort study in Switzerland (SWISS-AF). The outcome was time to first bleeding. Bleeding events were defined as major or clinically relevant non-major bleeding. We used backward elimination to identify bleeding risk variables. We derived the score using a point score system based on the β-coefficients from the multivariable model. We used the Brier score for model calibration (&lt;0.25 indicating good calibration), and Harrel's c-statistics for model discrimination. Results: We included 2147 patients with AF on OAC (72.5% male, mean age 73.4&nbsp;±&nbsp;8.2&nbsp;years), of whom 1209 (56.3%) took DOACs. After a follow-up of 4.4&nbsp;years, a total of 255 (11.9%) bleeding events occurred. After backward elimination, age&nbsp;&gt;&nbsp;75&nbsp;years, history of cancer, prior major hemorrhage, and arterial hypertension remained in the final prediction model. The Brier score was 0.23 (95% confidence interval [CI] 0.19–0.27), the c-statistic at 12&nbsp;months was 0.71 (95% CI 0.63–0.80). Conclusion: In this prospective cohort study of AF patients and predominantly DOAC users, we successfully derived a bleeding risk prediction model with good calibration and discrimination

Amount of Information Needed for Model Choice in Approximate Bayesian Computation

Approximate Bayesian Computation (ABC) has become a popular technique in evolutionary genetics for elucidating population structure and history due to its flexibility. The statistical inference framework has benefited from significant progress in recent years. In population genetics, however, its outcome depends heavily on the amount of information in the dataset, whether that be the level of genetic variation or the number of samples and loci. Here we look at the power to reject a simple constant population size coalescent model in favor of a bottleneck model in datasets of varying quality. Not only is this power dependent on the number of samples and loci, but it also depends strongly on the level of nucleotide diversity in the observed dataset. Whilst overall model choice in an ABC setting is fairly powerful and quite conservative with regard to false positives, detecting weaker bottlenecks is problematic in smaller or less genetically diverse datasets and limits the inferences possible in non-model organism where the amount of information regarding the two models is often limited. Our results show it is important to consider these limitations when performing an ABC analysis and that studies should perform simulations based on the size and nature of the dataset in order to fully assess the power of the study

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin

Background Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. Methods We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. Results Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. Conclusions Common variants in KRT40,WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function