A closer look to the timing of orchidopexy in undescended testes and adherence to the AWMF-guideline.

BACKGROUND: To lower the risk of testicular malignancies and subfertility, international guidelines recommend orchidopexy for undescended testis (UDT) before the age of 12-18 months. Previous studies reported low rates of 5-15% of timely surgery. Most of these studies are based on DRG and OPS code-based data from healthcare system institutions that do not distinguish between congenital and acquired UDT. METHODS: In a retrospective study data of all boys who underwent orchidopexy in a university hospital and two outpatient surgical departments from 2009 to 2022 were analyzed. The data differentiates congenital from acquired UDT. RESULTS: Out of 2694 patients, 1843 (68.4%) had congenital and 851 (31.6%) had acquired UDT. In 24.9% of congenital cases surgery was performed before the age of 12 months. The median age at surgery for congenital UDT was 16 months (range 7-202). Over the years there was an increased rate of boys operated on before the age of 2 (40% in 2009, 60% in 2022). The median age fluctuated over the years between 21 and 11 months without a trend to younger ages.. The covid pandemic did not lead to an increase of the median age at surgery. The median time between referral and surgery was 46 days (range 1-1836). Reasons for surgery after 12 months of age were a delayed referral to pediatric surgeries (51.2%), followed by relevant comorbidities (28.2%). CONCLUSION: Compared to recent literature, out data show that a closer look at details enables a more realistic approach. Still, there is no trend towards the recommended age for surgical treatment observable, but the rate of timely operated boys with congenital UDT is significantly higher than stated in literature.

The first European woolly rhinoceros mitogenomes, retrieved from cave hyena coprolites, suggest long-term phylogeographic differentiation.

The woolly rhinoceros (Coelodonta antiquitatis) is an iconic species of the Eurasian Pleistocene megafauna, which was abundant in Eurasia in the Pleistocene until its demise beginning approximately 10 000 years ago. Despite the early recovery of several specimens from well-known European archaeological sites, including its type specimen (Blumenbach 1799), no genomes of European populations were available so far, and all available genomic data originated exclusively from Siberian populations. Using coprolites of cave hyenas (Crocuta crocuta spelea) recovered from Middle Palaeolithic layers of two caves in Germany (Bockstein-Loch and Hohlenstein-Stadel), we isolated and enriched predator and prey DNA to assemble the first European woolly rhinoceros mitogenomes, in addition to cave hyena mitogenomes. Both coprolite samples produced copious sequences assigned to C. crocuta (27% and 59% mitogenome coverage, respectively) and woolly rhinoceros (Coelodonta antiquitatis; 27% and 81% coverage, respectively). The sequences suggested considerable DNA degradation, which may limit the conclusions to be drawn; however, the mitogenomes of European woolly rhinoceros are genetically distinct from the Siberian woolly rhinoceros, and analyses of the more complete mitogenome suggest a split of the populations potentially coinciding with the earliest fossil records of woolly rhinoceros in Europe.

Identifying and ranking novel independent features for cardiovascular disease prediction in people with type 2 diabetes.

Background: CVD prediction models do not perform well in people with diabetes. We therefore aimed to identify novel predictors for six facets of CVD, (including coronary heart disease (CHD), Ischemic stroke, heart failure (HF), and atrial fibrillation (AF)) in people with T2DM. Methods: Analyses were conducted using the UK biobank and were stratified on history of CVD and of T2DM: 459,142 participants without diabetes or a history of CVD, 14,610 with diabetes but without CVD, and 4,432 with diabetes and a history of CVD. Replication was performed using a 20% hold-out set, ranking features on their permuted c-statistic. Results: Out of the 600+ candidate features, we identified a subset of replicated features, ranging between 32 for CHD in people with diabetes to 184 for CVD+HF+AF in people without diabetes. Classical CVD risk factors (e.g. parental or maternal history of heart disease, or blood pressure) were relatively highly ranked for people without diabetes. The top predictors in the people with diabetes without a CVD history included: cystatin C, self-reported health satisfaction, biochemical measures of ill health (e.g. plasma albumin). For people with diabetes and a history of CVD top features were: self-reported ill health, and blood cell counts measurements (e.g. red cell distribution width). We additionally identified risk factors unique to people with diabetes, consisting of information on dietary patterns, mental health and biochemistry measures. Consideration of these novel features improved risk classification, for example per 1000 people with diabetes 133 CVD and 165 HF cases appropriately received a higher risk. Conclusion: Through data-driven feature selection we identified a substantial number of features relevant for prediction of cardiovascular risk in people with diabetes, the majority of which related to non-classical risk factors such as mental health, general illness markers, and kidney disease.

Performance of polygenic risk scores in screening, prediction, and risk stratification: secondary analysis of data in the Polygenic Score Catalog.

Objective: To clarify the performance of polygenic risk scores in population screening, individual risk prediction, and population risk stratification. Design: Secondary analysis of data in the Polygenic Score Catalog. Setting: Polygenic Score Catalog, April 2022. Secondary analysis of 3915 performance metric estimates for 926 polygenic risk scores for 310 diseases to generate estimates of performance in population screening, individual risk, and population risk stratification. Participants: Individuals contributing to the published studies in the Polygenic Score Catalog. Main outcome measures: Detection rate for a 5% false positive rate (DR5) and the population odds of becoming affected given a positive result; individual odds of becoming affected for a person with a particular polygenic score; and odds of becoming affected for groups of individuals in different portions of a polygenic risk score distribution. Coronary artery disease and breast cancer were used as illustrative examples. Results: For performance in population screening, median DR5 for all polygenic risk scores and all diseases studied was 11% (interquartile range 8-18%). Median DR5 was 12% (9-19%) for polygenic risk scores for coronary artery disease and 10% (9-12%) for breast cancer. The population odds of becoming affected given a positive results were 1:8 for coronary artery disease and 1:21 for breast cancer, with background 10 year odds of 1:19 and 1:41, respectively, which are typical for these diseases at age 50. For individual risk prediction, the corresponding 10 year odds of becoming affected for individuals aged 50 with a polygenic risk score at the 2.5th, 25th, 75th, and 97.5th centiles were 1:54, 1:29, 1:15, and 1:8 for coronary artery disease and 1:91, 1:56, 1:34, and 1:21 for breast cancer. In terms of population risk stratification, at age 50, the risk of coronary artery disease was divided into five groups, with 10 year odds of 1:41 and 1:11 for the lowest and highest quintile groups, respectively. The 10 year odds was 1:7 for the upper 2.5% of the polygenic risk score distribution for coronary artery disease, a group that contributed 7% of cases. The corresponding estimates for breast cancer were 1:72 and 1:26 for the lowest and highest quintile groups, and 1:19 for the upper 2.5% of the distribution, which contributed 6% of cases. Conclusion: Polygenic risk scores performed poorly in population screening, individual risk prediction, and population risk stratification. Strong claims about the effect of polygenic risk scores on healthcare seem to be disproportionate to their performance.

DCM-PROGRESS: predicting end-stage heart failure in non-ischemic dilated cardiomyopathy patients.

Aims: Patients with non-ischemic dilated cardiomyopathy (DCM) are at considerable risk for end-stage heart failure (HF), requiring close monitoring to identify early signs of disease. We aimed to develop a model to predict the 5-years risk of end-stage HF, allowing for tailored patient monitoring and management. Methods and results: Derivation data were available from a Dutch cohort of 293 DCM patients, with external validation available from a Czech Republic cohort of 235 DCM patients. Candidate predictors spanned patient and family histories, ECG and echocardiogram measurements, and biochemistry. End-stage HF was defined as a composite of death, heart transplantation, or implantation of a ventricular assist device. Lasso and sigmoid kernel support vector machine (SVM) algorithms were trained using cross-validation. During follow-up 65 (22%) of Dutch DCM patients developed end-stage HF, with 27 (11%) cases in the Czech cohort. Out of the two considered models, the lasso model (retaining NYHA class, heart rate, systolic blood pressure, height, R-axis, and TAPSE as predictors) reached the highest discriminative performance (testing c-statistic of 0.85, 95%CI 0.58; 0.94), which was confirmed in the external validation cohort (c-statistic of 0.75, 95%CI 0.61; 0.82), compared to a c-statistic of 0.69 for the MAGGIC score. Both the MAGGIC score and the DCM-PROGRESS model slightly over-estimated the true risk, but were otherwise appropriately calibrated. Conclusion: We developed a highly discriminative risk-prediction model for end-stage HF in DCM patients. The model was validated in two countries, suggesting the model can meaningfully improve clinical decision-making.

Genetic evidence for serum amyloid P component as a drug target for treatment of neurodegenerative disorders.

The direct causes of neurodegeneration underlying Alzheimer's disease (AD) and many other dementias, are not known. Here we identify serum amyloid P component (SAP), a constitutive plasma protein normally excluded from the brain, as a potential drug target. After meta-analysis of three genome-wide association studies, comprising 44,288 participants, cis-Mendelian randomization showed that genes responsible for higher plasma SAP values are significantly associated with AD, Lewy body dementia and plasma tau concentration. These genetic findings are consistent with experimental evidence of SAP neurotoxicity and the strong, independent association of neocortex SAP content with dementia at death. Depletion of SAP from the blood and from the brain, as is provided by the safe, well tolerated, experimental drug, miridesap, may therefore contribute to treatment of neurodegeneration.

["Rheuma (be-)greifen"- A multimodal teaching concept to improve rheumatology education for medical students]. / "Rheuma (be-)greifen" ­ ein multimodales Lehrkonzept zur Verbesserung der rheumatologischen Lehre für Studierende der Humanmedizin.

BACKGROUND: The German Society for Rheumatology, through its campaign Rheuma2025, aims to improve student teaching in order to ensure patient care for rheumatological patients in the future. OBJECTIVE: To assess whether a combination of traditional and innovative educational methods provide both an improvement in the quality of teaching and an increase in the attractiveness of rheumatology as a discipline. MATERIAL AND METHODS: Establishment of the teaching concept "Rheuma (be-)greifen" consisting of five modules on patient history taking with acting patients, musculoskeletal ultrasound, arthrocentesis, 3D printing of pathological joints and virtual reality applications based on real patient cases in the curricular teaching of medical students. RESULTS: The evaluation of the teaching concept with 93 students of medicine showed a consistently high acceptance of all modules, which were rated as very effective or rather effective. Direct patient-related modules, such as history taking with acting patients, musculoskeletal ultrasound and arthrocentesis, received even higher acceptance than the visualization methods utilizing 3D printing and virtual reality. CONCLUSION: Innovative teaching methods can help to improve the acceptance of teaching in the field of rheumatology, especially when combined with classical teaching contents.

Circulating Acylcarnitines Associated with Hypertrophic Cardiomyopathy Severity: an Exploratory Cross-Sectional Study in MYBPC3 Founder Variant Carriers.

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value.

Sex-specific Mendelian randomisation to assess the causality of sex differences in the effects of risk factors and treatment: spotlight on hypertension.

Hypertension is a key modifiable risk factor for cardiovascular disease. Several observational studies have found a stronger association of blood pressure and cardiovascular disease risk in women compared to men. Since observational studies can be affected by sex-specific residual confounding and reverse causation, it remains unclear whether these differences reflect actual differential effects. Other study designs are needed to uncover the causality of sex differences in the strength of risk factor and treatment effects. Mendelian randomisation (MR) uses genetic variants as instrumental variables to provide evidence about putative causal relations between risk factors and outcomes. By exploiting the random allocation of genes at gamete forming, MR is unaffected by confounding and results in more reliable causal effect estimates. In this review, we discuss why and how sex-specific MR and cis-MR could be used to study sex differences in risk factor and drug target effects. Sex-specific MR can be helpful to strengthen causal inferences in the field of sex differences, where it is often challenging to distinguish nature from nurture. The challenge of sex-specific (drug target) MR lays in leveraging robust genetic instruments from sex-specific GWAS studies which are not commonly available. Knowledge on sex-specific causal effects of hypertension, or other risk factors, could improve clinical practice and health policies by tailoring interventions based on personalised risk. Drug target MR can help to determine the anticipated on-target effects of a drug compound and to identify targets to pursue in drug development.

Evaluation of continuous ampicillin/sulbactam infusion in critically ill patients.

Continuous infusion (CI) of beta-lactam-antibiotics may improve pharmacodynamics in critically ill patients, but resulting concentrations have not been studied. Therapeutic drug monitoring is increasingly used to ensure antibiotic concentration. The aim of this study is to evaluate therapeutic ampicillin/sulbactam concentrations of a continuous infusion regimen. METHODS: Medical records of all patients admitted to ICU between January 2019 and December 2020 were retrospectively reviewed. Each patient received a 2/1 g ampicillin/sulbactam loading dose, followed by a continuous infusion of 8/4 g per 24 h. Ampicillin serum concentrations were measured. Main outcomes were reaching of plasma concentrations breakpoint defined by minimum inhibitory concentration (MIC at 8 mg/l) and 4-fold MIC (MIC at 32 mg/l) during steady state of CI. RESULTS: In 50 patients a total of 60 concentration measurements were performed. The first concentration was measured after a median of 29 h (IQR 21-61 h). Mean ampicillin concentration was 62.6 ± 39.1 mg/l. Furthermore, serum concentrations exceeded the defined MIC breakpoint in all measurements (100 %) and were above the 4-fold MIC in 43 analyses (71.1 %). However, patients suffering from acute kidney injury exhibited significant higher serum concentrations (81.1 ± 37.7 mg/l vs. 38.2 ± 24.8 mg/l; p < 0.001). Also, there was a negative correlation between ampicillin serum concentrations and GFR (r = -0.659; p < 0.001). CONCLUSION: The described dosing regimen for ampicillin/sulbactam is safe with respect to the defined MIC breakpoints for ampicillin, and continuous subtherapeutic concentration is unlikely. However, with impaired renal function drug accumulation occurs, and with increased renal clearance, drug levels can be below the 4-fold MIC breakpoint.

Less risk of conversion to total knee arthroplasty without significant clinical and survivorship difference for opening-wedge high tibial osteotomies in varus knee deformities at 10-year minimum follow-up compared to closing-wedge high tibial osteotomies.

PURPOSE: The purpose of this study was to evaluate the clinical outcomes and survivorship at minimum 10-year follow-up of patients undergoing primary valgisation high tibial osteotomy (HTO) for medial osteoarthritis (OA), treated by Opening-Wedge HTO (OW-HTO) or Closing-Wedge HTO (CW-HTO). METHODS: This was a retrospective cohort study of consecutive patients presenting to a single institution undergoing HTO for isolated medial compartment OA. Two hundred and twenty three HTOs for isolated medial tibio-femoral OA were performed between January 2002 and December 2010. Patients were eligible if they had minimum 10-year follow-up and received either a CW or OW-HTO. Fifteen (6.7%) patients died and twenty-five (11.2%) were lost to follow-up. One hundred and eighty three (82.1%) patients were included in the final analysis and divided into two groups: OW-HTO (96/183; 52.4%) and CW-HTO (87/183; 47.6%). Range of motion, KSS, KOOS scores, and conversion to TKA rate were analyzed between groups. Both groups were comparable regarding age, arthrosis stage, gender, ASA score and BMI at the time of HTO. Survival analysis was conducted with re-intervention for TKA as the end point. RESULTS: At the time of HTO, mean age was 55 years ± 7.9 (27-73.9) with 72.7% of patients being male. The mean follow-up was 13.3 years ± 2.7 (10-19). Sixty-four (34.9%) patients underwent TKA at a mean delay of 9.3 years ± 3 (3-16). The conversion to TKA rate was significantly higher in the CW-HTO group versus the OW-HTO group: 42.5% (37/87) versus 28.1% (27/96) (p = 0.04). The survival at 15-year follow-up was 59.2% in the OW-HTO group versus 54.6% in the CW-HTO group (n.s.). At 13-year follow-up, KSS Function score was significantly better in the OW-HTO (90.9 versus 82.4; p = 0.007). No significant difference was observed between the two groups regarding the KOOS score, KSS Knee Score and complication rate. CONCLUSION: At mean follow-up of 13 years, no significant clinical and survivorship difference was observed between the two groups. The conversion to TKA was significantly lower following OW-HTO. Minor correction was associated with risk of requiring subsequent TKA. LEVEL OF EVIDENCE: Retrospective case series, IV.

Noise-optimized virtual monoenergetic reconstructions of dual-energy CT angiographies improve assessability of the lower leg arterial segments in peripheral arterial occlusive disease.

INTRODUCTION: The aim of this study was to evaluate the influence of a noise optimized virtual monoenergetic reconstruction algorithm (VMI+) on the image quality and assessability of dual energy (DE) computed tomography angiography (CTA) of the lower extremity runoff. METHODS: A total of 118 lower extremity runoff CTA performed on a 3rd generation DE-CT scanner in 109 patients (54 females; 75.6 ± 9.5 years) were included in this retrospective study. Axial image stacks were reconstructed with a standard 120 kV setting and VMI+ of different keV levels. Objective image quality criteria (contrast attenuation, signal-to-noise [SNR] and contrast-to-noise ratio [CNR]) were measured. Two radiologists evaluated subjective image quality regarding intraluminal attenuation and image noise using a 5-point Likert scale. Diagnostic accuracy for significant stenosis (>75%) and vessel occlusion was assessed for 120 kV and 50 keV VMI+ images rated by two radiologists. In all patients, a digital subtraction angiography (DSA) rated by on board-certified radiologist served as the standard of reference. RESULTS: Intraluminal attenuation was highest in 40/50 keV VMI+ while SNR were similar to 120 kV images. In subjective assessment, intraluminal contrast of 50 keV images was deemed superior compared to 120 kV despite higher image noise. Sensitivity, specificity, and accuracy for detection of a vessel occlusion were similar in 50 keV VMI+ compared to 120 kV (70%/92%/84%; 70%/91%/83%; p < 0.001) but 13 of 118 (11%) lower leg runoffs were only assessable with 50 keV VMI+. CONCLUSION: VMI+ reconstructions improve assessability of DE-CTA by increased luminal attenuation with consistent image noise, also allowing the evaluation of lower leg arterial segments inassessable with standard reconstructions. IMPLICATIONS FOR PRACTICE: Providing higher intraluminal attenuation and similar image noise compared with conventional reconstructions, 50 keV VMI+ may be appropriate for routine evaluation of DE-CTA.

Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited Cardiomyopathies in the General Population.

BACKGROUND: Pathogenic and likely pathogenic variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM) are recommended to be reported as secondary findings in genome sequencing studies. This provides opportunities for early diagnosis, but also fuels uncertainty in variant carriers (G+), since disease penetrance is incomplete. We assessed the prevalence and disease expression of G+ in the general population. METHODS: We identified pathogenic and likely pathogenic variants associated with ARVC, DCM and/or HCM in 200 643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analyzed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analyzed early signs of disease expression using available electrocardiography and cardiac magnetic resonance imaging data. RESULTS: We found a prevalence of 1:578, 1:251, and 1:149 for pathogenic and likely pathogenic variants associated with ARVC, DCM and HCM respectively. Compared with controls, cardiovascular mortality was higher in DCM G+ (odds ratio 1.67 [95% CI 1.04; 2.59], P=0.030), but similar in ARVC and HCM G+ (P≥0.100). Cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (odds ratio 3.66 [95% CI 2.24; 5.81], P=4.9×10-7) and HCM G+ (odds ratio 3.03 [95% CI 1.98; 4.56], P=5.8×10-7), but comparable in ARVC G+ (P=0.172). In contrast, ARVC G+ had more ventricular arrhythmias (P=3.3×10-4). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ (P=0.009). CONCLUSIONS: In the general population, pathogenic and likely pathogenic variants associated with ARVC, DCM, or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease penetrance in these carriers from the general population remains low (1.2-3.1%). Follow-up decisions in case of incidental findings should not be based solely on a variant, but on multiple factors, including family history and disease expression.

[Colonic pouch reconstruction after low anterior rectal resection]. / Kolonpouchrekonstruktionen nach tiefer anteriorer Rektumresektion.

For many decades the coloanal anastomosis was traditionally created as an end-to-end anastomosis. Despite successful surgical restoration of the intestinal passage after low rectal resection and total mesorectal excision (TME), physiological continence and evacuation function cannot be achieved in many cases using end-to-end anastomosis. Subsequent complaints, such as fecal incontinence and urge problems, evacuation difficulties and high stool frequency (so-called low anterior resection syndrome, LARS) are the result. The combination of symptoms after TME known as LARS is described in the literature in up to 60% of cases. The increased occurrence of the imperative urge to defecate, frequent bowel movements and problems with fecal incontinence motivated surgeons to look for alternative anastomosis techniques. Side-to-end anastomosis, coloplasty pouch and colonic J­pouch have been shown in various studies to be superior to end-to-end anastomosis in terms of functional results. Current studies could show that the side-to-end anastomosis (even if this is not a pouch in the actual sense) and the two pouch techniques show comparable results in terms of functional outcome and the rate of anastomotic leakage. The alternative to coloanal anastomosis after TME is the abdominoperineal resection. Most, especially younger patients, prefer to try to maintain continence with the risk of the described functional problems. If the patients are well selected, TME can be carried out with the current techniques in such a way that continuity is maintained and a good defecation function is achieved for a large proportion of patients using the pouch-anal anastomosis or the side-to-end techniques.

HIV pre-exposure prophylaxis during the SARS-CoV-2 pandemic: Results from a prospective observational study in Germany.

Aims: Since 2017, HIV pre-exposure prophylaxis (PrEP) care has been provided through an intersectoral collaboration at WIR (Walk-in-Ruhr, Center for Sexual Health and Medicine, Bochum, Germany). The aim of this study was to establish possible impact of COVID-restrictions on the sexual behavior of PrEP users in North Rhine-Westphalia. Methods: The current PrEP study collected data of individuals using PrEP, their sexual behavior and sexually transmitted infections (STIs) before (each quarter of year 2018) and during the COVID-19 pandemic (each quarter of year 2020). Results: During the first lockdown in Germany from mid-March until May 2020, PrEP-care appointments at WIR were postponed or canceled. Almost a third of PrEP users had discontinued their PrEP intake in the 2nd quarter of 2020 due to alteration of their sexual behavior. The number of sexual partners decreased from a median of 14 partners in the previous 6 months in 1st quarter of 2020, to 7 partners in 4th quarter of 2020. Despite such a significant reduction in partner number during the pandemic in comparison to the pre-pandemic period, a steady rate of STIs was observed among PrEP users in 2020. Conclusion: The SARS-CoV-2-pandemic has impacted PrEP-using MSM in North Rhine-Westphalia with respect to their PrEP intake regimen and sexual behavior in 2020. Our study revealed a steady rate of STI among PrEP users even during the pandemic, thus highlighting the importance of ensuring appropriate HIV/STI prevention services in times of crisis.

The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: a Mendelian randomization study.

Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple CVDs, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL) cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the etiology of CVDs and suggest LDL cholesterol as a potential mediating trait between PUFA biosynthesis and CVDs risk.

Low-Density Lipoprotein Cholesterol Attributable Cardiovascular Disease Risk Is Sex Specific.

Background Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sex-specific differential effect of genetically increased low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) and other lipid-associated diseases. Methods and Results This is a 2-sample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80-variant LDL-C weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sex-specific LDL-C effects on lipids, carotid-intima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDL-C effect on CVD events was sex specific: per SD genetically increased LDL-C, female participants had a higher LDL-C increase but an attenuated CVD risk increase compared with male participants (LDL-C: female participants 0.71 mmol/L, 95% CI, 0.70-0.72 and male participants 0.57 mmol/L, 95% CI, 0.56-0.59. P for interaction: 5.03×10-60; CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24-1.40 and male participants: OR, 1.52; 95% CI, 1.46-1.58. P for interaction: 9.88×10-5). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDL-C results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDL-C was also associated with an attenuated carotid-intima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sex-specific weighted genetic scores showed similar results. Conclusions We found that genetically increased LDL-C has a sex-specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDL-C might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDL-C targeted therapies for CVD management than female patients and warranting investigations into the sex-specific relative contribution of risk factors for CVD.

Oncology clinical trial disruption during the COVID-19 pandemic: a COVID-19 and cancer outcomes study.

BACKGROUND: COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct. PATIENTS AND METHODS: This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations. RESULTS: The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded. CONCLUSIONS: Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial.

Metal artefact reduction in low-dose computed tomography: Benefits of tin prefiltration versus postprocessing of dual-energy datasets over conventional CT imaging.

INTRODUCTION: The purpose of this study was to determine the potential for metal artefact reduction in low-dose multidetector CT as these pose a frequent challenge in clinical routine. Investigations focused on whether spectral shaping via tin prefiltration, virtual monoenergetic imaging or virtual blend imaging (VBI) offers superior image quality in comparison with conventional CT imaging. METHODS: Using a third-generation dual-source CT scanner, two cadaveric specimens with different metal implants (dental, cervical spine, hip, knee) were examined with acquisition protocols matched for radiation dose with regards to tube voltage and current. In order to allow for precise comparison, and due to the relatively short scan lengths, automatic tube current modulation was disabled. Specifically, the following scan protocals were examined: conventional CT protocols (100/120 kVp), tin prefiltration (Sn 100/Sn 150 kVp), VBI and virtual monoenergetic imaging (VME 100/120/150 keV). Mean attenuation and image noise were measured in hyperdense and hypodense artefacts, in artefact-impaired and artefact-free soft tissue. Subjective image quality was rated independently by three radiologists. RESULTS: Objectively, Sn 150 kVp allowed for the best reduction of hyperdense streak artefacts (p < 0.001), while VME 150 keV and Sn 150 kVp protocols facilitated equally good reduction of hypodense artefacts (p = 0.173). Artefact-impaired soft tissue attenuation was lowest in Sn 150 kVp protocols (p ≤ 0.011), whereas all VME showed significantly less image noise compared to conventional or tin-filtered protocols (p ≤ 0.001). Subjective assessment favoured Sn 150 kVp regarding hyperdense streak artefacts and delineation of cortical bone (p ≤ 0.005). The intraclass correlation coefficient was 0.776 (95% confidence interval: 0.712-0.831; p < 0.001) indicating good interrater reliability. CONCLUSION: In the presence of metal implants in our cadaveric study, tin prefiltration with 150 kVp offers superior artefact reduction for low-dose CT imaging of osseous tissue compared with virtual monoenergetic images of dual-energy datasets. The delineation of cortical boundaries seems to benefit particularly from spectral shaping. IMPLICATIONS FOR PRACTICE: Low-dose CT imaging of osseous tissue in combination with tin prefiltration allows for superior metal artefact reduction when compared to virtual monoenergetic images of dual-energy datasets. Employing this technique ought to be considered in daily routine when metal implants are present within the scan volume as findings suggest it allows for radiation dose reduction and facilitates diagnosis relevant to further treatment.