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PURPOSE Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia ( P ≤ .001); febrile neutropenia ( P = .002); and alopecia ( P < .001) were significantly lower, whereas grade 3 or 4 nausea ( P = .004) was more common. CONCLUSION In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Tenosynovitis of the extensor pollicis longus (EPL) is rarely reported in patients without rheumatoid arthritis but may lead to thumb snapping as a consequence of EPL stenosing tenosynovitis.This case presents painful thumb snapping that developed after a wrist trauma and repetitive loading. Ultrasound and MRI were used as diagnostic tools, before surgical release of the EPL in the third extensor compartment was performed. Neither EPL tenosynovitis nor thumb snapping were found at follow-up.

OBJECTIVE Globus pallidus (GP) lesioning improves motor symptoms of Parkinson’s disease (PD) and is occasionally associated with nonmotor side effects. Although these variable clinical effects were shown to be site-specific within the GP, the motor and nonmotor subregions have not been distinguished radiologically in patients with PD. The GP was recently found to have a distinct radiological signature on diffusion MRI (dMRI), potentially related to its unique cellular content and organization (or tissue architecture). In this study, the authors hypothesize that the magnitude of water diffusivity, a surrogate for tissue architecture, will radiologically distinguish motor from nonmotor GP subregions in patients with PD. They also hypothesize that the therapeutic focused ultrasound pallidotomy lesions will preferentially overlap the motor subregion. METHODS Diffusion MRI from healthy subjects (n = 45, test-retest S1200 cohort) and PD patients (n = 33) was parcellated based on the magnitude of water diffusivity in the GP, as measured orientation distribution function (ODF). A clustering algorithm was used to identify GP parcels with distinct ODF magnitude. The individual parcels were used as seeds for tractography to distinguish motor from nonmotor subregions. The locations of focused ultrasound lesions relative to the GP parcels were also analyzed in 11 patients with PD. RESULTS Radiologically, three distinct parcels were identified within the GP in healthy controls and PD patients: posterior, central, and anterior. The posterior and central parcels comprised the motor subregion and the anterior parcel was classified as a nonmotor subregion based on their tractography connections. The focused ultrasound lesions preferentially overlapped with the motor subregion (posterior more than central). The hotspots for motor improvement were localized in the posterior GP parcel. CONCLUSIONS Using a data-driven approach of ODF-based parcellation, the authors radiologically distinguished GP motor subregions in patients with PD. This method can aid stereotactic targeting in patients with PD undergoing surgical treatments, especially focused ultrasound ablation.

Background Few robust longitudinal data on long-term coronavirus disease 2019 (COVID-19) symptoms are available. We evaluated symptom onset, severity and recovery across the full spectrum of disease severity, up to one year after illness onset. Methods The RECoVERED Study is a prospective cohort study based in Amsterdam, the Netherlands. Participants aged ≥18 years were enrolled following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnosis via the local public health service and from hospitals. Standardized symptom questionnaires were completed at enrollment, 1 week and month later, and monthly thereafter. Clinical severity was defined according to World Health Organization (WHO) criteria. Kaplan-Meier methods were used to compare time from illness onset to symptom recovery, by clinical severity. We examined determinants of time to recovery using multivariable Cox proportional hazards models. Results Between 11 May 2020 and 1 May 2021, 342 COVID-19 patients (192 [56%] male) were enrolled, of whom 99/342 (29%) had mild, 145/342 (42%) moderate, 56/342 (16%) severe, and 42/342 (12%) critical disease. The proportion of participants who reported at least 1 persistent symptom at 12 weeks after illness onset was greater in those with severe/critical disease (86.7% [95% confidence interval {CI} = 76.5–92.7%]) compared to those with mild or moderate disease (30.7% [95% CI = 21.1–40.9%] and 63.8% [95% CI = 54.8–71.5%], respectively). At 12 months after illness onset, two-fifths of participants (40.7% [95% CI = 34.2–7.1]) continued to report ≥1 symptom. Recovery was slower in female compared to male participants (adjusted hazard ratio [aHR] 0.65 [95% CI = .47–.92]) and those with a body mass index [BMI] ≥30kg/m2 compared to BMI Conclusions COVID-19 symptoms persisted for one year after illness onset, even in some individuals with mild disease. Female sex and obesity were the most important determinants of speed of recovery from symptoms.

BACKGROUND A causal treatment effect of complete mesocolic excision for right-sided colon cancer on the risk of recurrence has been shown, but it is still unclear whether this is caused solely by a risk reduction of local recurrence. OBJECTIVE To assess to what extent complete mesocolic excision attributes to the risk of local recurrence. DESIGN Post-hoc analyses of data from a population-based cohort. Inverse probability of treatment weighting and competing risk analyses were used to estimate the possible causal effects of complete mesocolic excision. SETTING Data from the four public colorectal cancer centers in the Capital Region of Denmark. PATIENTS Patients undergoing elective colon resections for right-sided colon cancer without distant metastases during the period 2010-2013. One center performed complete mesocolic excision, the remainder conventional resections. MAIN OUTCOME MEASURES The primary outcome was the cumulative incidence of solely local recurrence 5.2 years after surgery. Secondary outcomes were solely distant recurrence and both local and distant recurrence diagnosed within 180 days. RESULTS A total of 807 patients were included with 186 undergoing complete mesocolic excision and 621 conventional resections. The 5.2-year cumulative incidence of a solely local recurrence was 3.7% (95% CI: 0.5-6.1) after complete mesocolic excision compared with 7.0% (5.0-8.9) in the control group, and the absolute risk reduction of complete mesocolic excision was 3.7% (2.5-7.1; p=0.035). The absolute risk reduction on local and distant recurrence was 3.4% (1.3-5.6; p=0.0019) and on solely distant recurrence 3.1% (0.0-6.2; p=0.0516). LIMITATIONS The recurrence risk after conventional resection might under estimated by the use of inappropriate modalities to diagnose local recurrence for some patients and the shorter duration in this group. CONCLUSION This study shows a causal treatment effect of complete mesocolic excision on the risk of a solely local recurrence and of distant recurrence with or without local recurrence. See Video Abstract at http://links.lww.com/DCR/B832 .

Aims/hypothesis Galectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects. Methods Participants (n = 4022; 58.6% women) in the Malmö Diet and Cancer Study–Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 ± 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 ± 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 × 10−11). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort. Results Galectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 × 10−89) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 × 10−3). Conclusions/interpretation Galectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement. Graphical abstract

AIMS: This study aimed to investigate the association between the 'Shrunken pore syndrome' (SPS) and risk of death, 30 day rehospitalization, and health-related quality of life (QoL) in heart failure (HF) patients. SPS is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFRcystatin C /eGFRcreatinine ratio.METHODS AND RESULTS: A total of 373 patients hospitalized for HF [mean age 74.8 (±12.1) years; 118 (31.6%) women] were retrieved from the HeARt and brain failure inVESTigation trial (HARVEST-Malmo). Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were used for estimation of glomerular filtration rate (eGFR). Presence of SPS was defined as eGFRcystatin C ≤ 60% of eGFRcreatinine . In Cox regression multivariate models, associations between SPS, risk of death (median follow-up time 1.8 years), and risk of 30 day rehospitalization were studied. Associations between SPS and impaired QoL were studied using multivariate logistic regressions. In multivariate models, SPS was associated with all-cause mortality [124 events; hazard ratio (HR) 1.99; 95% confidence interval (95% CI) 1.23-3.21; P = 0.005] and with 30 day rehospitalization (70 events; HR 1.82; CI 95% 1.04-3.18; P = 0.036). Analyses of QoL, based on a Kansas City Cardiomyopathy Questionnaire overall score < 50, revealed that SPS was associated with higher risk of low health-related QoL (odds ratios 2.15; CI 95% 1.03-4.49; P = 0.042).CONCLUSIONS: The results of this observational study show for the first time an association between SPS and poor prognosis in HF. Further studies are needed to confirm the results in HF cohorts and experimental settings to identify pathophysiological mechanisms. (Less)

BACKGROUND Acute kidney injury (AKI) is a well-known complication after cardiac surgery and cardiopulmonary bypass (CPB). In the present secondary analysis of a blinded randomized controlled trial, we evaluated the effects of a colloid-based versus a conventional crystalloid-based prime on tubular injury and postoperative renal function in patients undergoing cardiac surgery with CPB. METHODS Eighty-four adult patients undergoing cardiac surgery with CPB were randomized to receive either a crystalloid- or colloid- (dextran 40) based CPB priming solution. The crystalloid solution was based on Ringer-Acetate plus mannitol. The tubular injury biomarker, N-acetyl-b-D-glucosaminidase (NAG), serum creatinine and diuresis were measured before, during and after CPB. The incidence of AKI was assessed according to the KDIGO criteria. RESULTS The urinary-NAG/urinary-creatinine ratio rose in both groups during and after CPB, with a more pronounced increase in the crystalloid group (p = .038). One hour after CPB, the urinary-NAG/urinary-creatinine ratio was 88% higher in the crystalloid group (4.7 ± 6.3 vs. 2.5 ± 2.7, p = .045). Patients that received the dextran 40-based priming solution had a significantly lower intraoperative diuresis (p

Background Gleason grading is the standard diagnostic method for prostate cancer and is essential for determining prognosis and treatment. The dearth of expert pathologists, the inter- and intraobserver variability, as well as the labour intensity of Gleason grading all necessitate the development of a user-friendly tool for robust standardisation. Objective To develop an artificial intelligence (AI) algorithm, based on machine learning and convolutional neural networks, as a tool for improved standardisation in Gleason grading in prostate cancer biopsies. Design, setting, and participants A total of 698 prostate biopsy sections from 174 patients were used for training. The training sections were annotated by two senior consultant pathologists. The final algorithm was tested on 37 biopsy sections from 21 patients, with digitised slide images from two different scanners. Outcome measurements and statistical analysis Correlation, sensitivity, and specificity parameters were calculated. Results and limitations The algorithm shows high accuracy in detecting cancer areas (sensitivity: 100%, specificity: 68%). Compared with the pathologists, the algorithm also performed well in detecting cancer areas (intraclass correlation coefficient [ICC]: 0.99) and assigning the Gleason patterns correctly: Gleason patterns 3 and 4 (ICC: 0.96 and 0.94, respectively), and to a lesser extent, Gleason pattern 5 (ICC: 0.82). Similar results were obtained using two different scanners. Conclusions Our AI-based algorithm can reliably detect prostate cancer and quantify the Gleason patterns in core needle biopsies, with similar accuracy as pathologists. The results are reproducible on images from different scanners with a proven low level of intraobserver variability. We believe that this AI tool could be regarded as an efficient and interactive tool for pathologists. Patient summary We developed a sensitive artificial intelligence tool for prostate biopsies, which detects and grades cancer with similar accuracy to pathologists. This tool holds promise to improve the diagnosis of prostate cancer.

Background: For care planning and support, under-detection and late diagnosis of Alzheimer’s disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer’s Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation. Objective: To make a cost-consequence analysis of MOPEAD. Methods: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the cost per true-positive case (TP) of AD from the screened population. Results: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was €3,115 with the web-approach, €2,722 with the Open-House, €1,530 in primary care, and €1,190 by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists. There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP. Conclusion: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications.

BACKGROUND: Acute kidney injury (AKI) has been associated with cardiovascular disease, but this is sparsely studied in non-selected populations and with little attention to the effect in age and renal function. Using nationwide administrative data, we investigated the hypothesis of increased one-year risk of cardiovascular event or death associated with AKI.METHODS: In a cohort study, we identified all admissions in Denmark between 2008 and 2018. AKI was defined as ≥1.5 times increase from baseline to peak creatinine during admission, or dialysis. We excluded patients with age RESULTS: Among 565,056 hospital admissions, 39,569 (7.0%) cases of AKI were present. In total, 18,642 patients sustained a cardiovascular outcome. AKI was significantly associated with cardiovascular outcome with an adjusted OR [CI] of 1.33 [1.16-1.53], 1.43 [1.33-1.54], 1.23 [1.14-1.34], 1.38 [1.18-1.62] for eGFR ≥90, 60-89, 30-59 and 15-29ml/min/1.73m 2, respectively. When omitting the outcome heart failure, these results were 1.24 [1.06-1.45], 1.22 [1.11-1.33], 1.05 [0.95-1.16], 1.25 [1.02-1.54]. Results did not change substantially in strata of age groups, in AKI stages and in the subcohort adjusted for proteinuria. CONCLUSION: Non-selected patients aged 50 years or above with AKI during admission had significantly higher one-year risk of cardiovascular event or death, especially, but not only due to heart failure, independent of age and eGFR.

Background For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy. Objective To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy. Design, setting, and participants Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation. Outcome measurements and statistical analysis Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes. Results and limitations Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11–0.79) and UroC tumors (HR 0.37, 95% CI: 0.14–0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response. Conclusions Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC. Patient summary This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

Introduction: This trial assessed safety and effectiveness of an advanced hybrid closed-loop (AHCL) system with automated basal (Auto Basal) and automated bolus correction (Auto Correction) in adol...

Background The efficacy and safety of ursodeoxycholic acid (UDCA) for the treatment of liver disease associated with cystic fibrosis (CF) are under discussion, and clinical practice varies among centers. The study aimed at evaluating if the incidence of severe liver disease differs between CF centers routinely prescribing or not prescribing UDCA. Methods We carried out a retrospective multicenter cohort study including 1591 CF patients (1192 patients from UDCA-prescribing centers and 399 from non-prescribing centers) born between 1990 and 2007 and followed from birth up to 31 December 2016. We computed the crude cumulative incidence (CCI) of portal hypertension (PH) at the age of 20 years in the two groups and estimated the subdistribution hazard ratio (HR) through a Fine and Gray model. Results Over the observation period, 114 patients developed PH: 90 (7.6%) patients followed-up in UDCA prescribing centers and 24 (6.0%) in non-prescribing centers. The CCI of PH at 20 years was 10.1% (95% CI: 7.9-12.3) in UDCA-prescribing and 7.7% (95% CI: 4.6-10.7) in non-prescribing centers. The HR among patients followed in prescribing centers indicated no significant difference in the rate of PH either in the unadjusted model (HR: 1.21, 95% CI: 0.69-2.11) or in the model adjusted for pancreatic insufficiency (HR: 1.28, 95% CI: 0.77-2.12). Conclusions CF patients followed-up in UDCA prescribing centers did not show a lower incidence of PH as compared to those followed in centers not prescribing UDCA. These results question the utility of UDCA in reducing the occurrence of severe liver disease in CF.

Key Points Question Are alcohol-induced loss of consciousness and heavy weekly alcohol consumption associated with increased risk of future dementia? Findings In this multicohort study of 131 415 adults, a 1.2-fold excess risk of dementia was associated with heavy vs moderate alcohol consumption. Those who reported having lost consciousness due to alcohol consumption, regardless of their overall weekly consumption, had a 2-fold increased risk of dementia compared with people who had not lost consciousness and were moderate drinkers. Meaning The findings of this study suggest that alcohol-induced loss of consciousness is a long-term risk factor for dementia among both heavy and moderate drinkers., Importance Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131 415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results Of the 131 415 participants (mean [SD] age, 43.0 [10.4] years; 80 344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96 591 participants with data on loss of consciousness, 10 004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (, This cohort study examines the association of overall consumption of alcohol and resultant loss of consciousness with risk for dementia.

BackgroundSex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren’s syndrome (LS) and non-Löfgren’s syndrome (non-LS).MethodsA meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by an SNP lookup in the UK Biobank (UKB, n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex.ResultsWe identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and ANXA11. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified.ConclusionOur findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis.

BackgroundClarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems.MethodsThe study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse (‘baseline’) and the longitudinal Vietnam Era Twin Study of Aging (‘follow-up’). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)].ResultsTotal depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07–1.57), erectile dysfunction (OR 1.32, 95% CI 1.10–1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04–1.53), and sleep apnea (OR 1.40, 95% CI 1.13–1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09–1.60).ConclusionsA history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.

Purpose: To assess potential differences between central and eccentric cones in the aberrometric corneal profile and in visual and keratometric outcomes 6 months after intracorneal ring segment (ICRS) implantation for keratoconus. Methods: This study compared two groups consisting of 12 patients each, with central or eccentric keratoconus who were treated with femtosecond laser-assisted Keraring implantation. Uncorrected (UDVA) and corrected (CDVA) distance visual acuity, keratometric readings and higher order aberrations (HOAs) including high order aberrations root mean square (HOARMS), coma, spherical aberration and trefoil were measured preoperatively and 6 months after ICRS implantation. Results: Trefoil and spherical aberration were significantly reduced after ICRS implantation compared to preoperative values in eccentric keratoconus (Trefoil, p = 0.0049; Spherical aberration, p < 0.0001). In central keratoconus spherical aberration was reduced not significantly after ICRS implantation compared to preoperative values ( p = 0.087). Coma showed a significant reduction in central ( p = 0.0001) and in eccentric keratoconus ( p = 0.0001). The reduction of spherical aberration in central keratoconus was significantly positively correlated to improvement in UDVA (Pearson’s correlation coefficient, r = −0.66; p = 0.02). In eccentric keratoconus there was a significant positive correlation between reduction of trefoil and improvement in UDVA (Spearmans R, r = −0.69; p = 0.01). Conclusion: Patients both with central and eccentric keratoconus benefit from ICRS implantation. Specifically, our data provide a slightly higher gain in visual performance for eccentric cones 6 month after ICRS implantation, which is accentuated by a greater reduction in spherical aberration and trefoil. Improvements in UDVA are positively correlated with reductions in HOAs.

Aim The aim was to investigate whether the previously reported causal treatment effect of complete mesocolic excision on the risk of recurrence was biased by inclusion of patients with potentially undiagnosed disseminated disease at the time of surgery, by non-specialist surgery, or caused by mesocolic plane dissection. Method A population of 1069 patients, 813 undergoing conventional resection and 256 complete mesocolic excision for colon cancer during the period 2008-2013, was stepwise reduced in the following order by excluding patients with recurrence diagnosed within 6 months of the resection, having surgery performed by a non-specialist without supervision, and specimens assessed as not being mesocolic plane dissection. The primary outcome measure was risk of recurrence after 5.2 years using competing risk analyses. Results The absolute risk reduction of complete mesocolic excision was 6.0% (95% CI 1.8-10.2; P = 0.0049) after excluding patients with recurrence within 6 months of resection, 6.1% (95% CI 1.9-10.4; P = 0.0045) after excluding non-specialist surgery, and 7.5% (95% CI 2.9-12.0; P = 0.0013) after the exclusion of patients whose specimens were assessed as dissections not being performed in the mesocolic plane. Conclusion The absolute risk reduction of recurrence after complete mesocolic excision for right-sided colon cancer in our previous study was not biased by potentially undiagnosed disseminated disease at the time of surgery or non-specialist surgery, and was not solely caused by dissection in the mesocolic plane. Central vascular dissection with central lymphadenectomy seems a major factor for better oncological results.

Background Allergic contact dermatitis (ACD) is classically described as a delayed-type hypersensitivity reaction. However, patients often experience flare-ups characterized by itching erythema, edema, and often vesicles occurring within hours after re-exposure of previously sensitized skin to the specific contact allergen. Recent studies have indicated that skin-resident memory T (TRM ) cells play a central role in ACD. However, the pathogenic role of TRM cells in allergen-induced flare-ups is not known. Methods By the use of various mouse models and cell depletion protocols, we investigated the role of epidermal TRM cells in flare-up reactions to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene. The inflammatory response was measured by changes in ear thickness, and the cellular composition in epidermis was determined by flow cytometry and confocal microscopy. Finally, adaptive transfer and inhibitors were used to determine the role of TRM cells, neutrophils, and CXCL1/CXCL2 in the response. Results We show that CD8+ TRM cells initiate massive infiltration of neutrophils in the epidermis within 12 h after re-exposure to the contact allergen. Depletion of neutrophils before re-exposure to the allergen abrogated the flare-up reactions. Furthermore, we demonstrate that CD8+ TRM cells mediate neutrophil recruitment by inducing CXCL1 and CXCL2 production in the skin, and that blockage of the C-X-C chemokine receptor type 1 and 2 inhibits flare-up reactions and neutrophil infiltration. Conclusion As the first, we show that epidermal CD8+ TRM cells cause ACD flare-ups by rapid recruitment of neutrophils to the epidermis.

Ibrutinib is used continuously in CLL. This phase 1b/2 study interim analysis explored on-off-repeat dosing to reduce toxicity. After 12 months, 16/22 patients (73%) remained in first off-phase irrespective if initial CR/PR or

Summary Objectives To compare treatment time, patients’ perceptions during orthodontic treatment, dental fear and side effects, between open and closed surgical exposures in patients with palatally displaced canines (PDCs). Trial design Multicentre, randomized controlled trial, with random 1:1 allocation of two parallel groups. Materials and methods One hundred and twenty patients from three different orthodontic centres were randomized into one of the two intervention arms, open or closed surgical exposure. Both techniques had mucoperiosteal flaps raised and bone removed above the PDCs. In open exposure, tissue was removed above the canine, and glass ionomer – reaching above soft tissue – was built on the crown. The canine was then left to erupt spontaneously, prior to orthodontic alignment. At closed exposure, a chain was bonded to the canine and orthodontic traction was applied under the mucosa until eruption. Orthodontic alignment of the canines was undertaken after eruption into the oral cavity, with fixed appliances in both groups. All participants were treated according to intention to treat (ITT). Blinding Due to the nature of this trial, only outcome assessors could be blinded to the intervention group. Results One hundred and seventeen patients completed the trial. All PDCs were successfully aligned. Total treatment time was equal in the two techniques, mean difference −0.1 months (95% CI −3.2 to 2.9, P = 0.93). The closed group experienced more pain and discomfort during the active orthodontic traction. Dental fear, root resorption and periodontal status did not show any clinically significant differences between the groups. Generalizability Results of this randomized controlled trial (RCT) can be generalized only to a similar population aged 9–16 years, if exclusion criteria are met. Conclusion The closed exposure group experienced more pain and discomfort mostly during active orthodontic traction. All other studied outcomes were similar between the two exposure groups. Clinical Trial registration ClinicalTrials.gov, ID: NCT02186548 and Researchweb.org, ID: 127201.

© 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Background Atrial fibrillation (AF) is common after coronary artery bypass graft (CABG) surgery. Objective To evaluate the incidence and recurrence rate of AF during 1 year after CABG surgery. We also aimed at calculating the AF burden and compare long-term intermittent vs continuous electrocardiogram (ECG) monitoring. Methods Forty patients scheduled for CABG surgery were equipped with an implantable loop recorder (ILR). After discharge, they carried out handheld ECG 3 times daily during the first 30 postoperative days and during 2 weeks at 3 and 12 months. During hospital stay they were monitored with telemetry. Results Altogether 27 of 40 (68%) patients were diagnosed with AF, 24 during the first month (21 in-hospital and 3 after discharge) and 3 during months 2–12. Three patients progressed into persistent AF. In addition, 17 patients had AF recurrence, 9 of them after the first 30 days. In patients with paroxysmal AF, the AF burden was low, 0.1% (interquartile range [IQR] 0.02%–0.3%). Patients with AF had higher CHA2DS2-VASc scores than non-AF patients: median 4 (IQR 3–4) and 3 (IQR 2–3.5), respectively, P = .006. The handheld ECG identified 45% (9/20) of the patients with AF episodes identified with continuous ECG monitoring with the ILR after discharge from hospital, P = .001. Conclusions Patients with AF during the postoperative hospitalization showed a high likelihood of recurrent AF, usually within 30 days. Continuous ECG monitoring with an ILR was superior to the handheld ECG for detecting patients with AF. The AF burden was low., Graphical abstract

Objective: To identify causal pathophysiological mechanisms for atherosclerosis and incident cardiovascular events using protein measurements. Approach and Results: Carotid artery atherosclerosis was assessed by ultrasound, and 86 cardiovascular-related proteins were measured using the Olink CVD-I panel in 7 Swedish prospective studies (11 754 individuals). The proteins were analyzed in relation to intima-media thickness in the common carotid artery (IMT-CCA), plaque occurrence, and incident cardiovascular events (composite end point of myocardial infarction or ischemic stroke) using a discovery/replication approach in different studies. After adjustments for traditional cardiovascular risk factors, 11 proteins remained significantly associated with IMT-CCA in the replication stage, whereas 9 proteins were replicated for plaque occurrence and 17 proteins for incident cardiovascular events. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and MMP (matrix metalloproteinase)-12 were associated with both IMT-CCA and incident events, but the overlap was considerably larger between plaque occurrence and incident events, including MMP-12, TIM-1 (T-cell immunoglobulin and mucin domain 1), GDF (growth/differentiation factor)-15, IL (interleukin)-6, U-PAR (urokinase plasminogen activator surface receptor), LOX-1 (lectin-like oxidized LDL [low-density lipoprotein] receptor 1), and TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2). Only MMP-12 was associated with IMT-CCA, plaque, and incident events with a positive and concordant direction of effect. However, a 2-sample Mendelian randomization analysis suggested that increased MMP-12 may be protective against ischemic stroke ( P =5.5×10 −7 ), which is in the opposite direction of the observational analyses. Conclusions: The present meta-analysis discovered several proteins related to carotid atherosclerosis that partly differed in their association with IMT-CCA, plaque, and incident atherosclerotic disease. Mendelian randomization analysis for the top finding, MMP-12, suggests that the increased levels of MMP-12 could be a consequence of atherosclerotic burden rather than the opposite chain of events.

Background Understanding temporal patterns of organ dysfunction (OD) may aid early recognition of complications after trauma and assist timing and modality of treatment strategies. Our aim was to analyse and characterise temporal patterns of OD in intensive care unit-admitted trauma patients. Methods We used group-based trajectory modelling to identify temporal trajectories of OD after trauma. Modelling was based on the joint development of all six subdomains comprising the sequential organ failure assessment score measured daily during the first two weeks post trauma. Further, the time for trajectories to stabilise and transition to final group assignments were evaluated. Results Six-hundred and sixty patients were included in the final model. Median age was 40 years, and median ISS was 26 (IQR 17–38). We identified five distinct trajectories of OD. Group 1, mild OD (n = 300), median ISS of 20 (IQR 14–27), had an early resolution of OD and a low mortality. Group 2, moderate OD (n = 135), and group 3, severe OD (n = 87), were fairly similar in admission characteristics and initial OD but differed in subsequent OD trajectories, the latter experiencing an extended course and higher mortality. In group 3, 56% of the patients developed sepsis as compared with 19% in group 2. Group 4, extreme OD (n = 40), received most blood transfusions, had the highest proportion of shock at admission and a median ISS of 41 (IQR 29–50). They experienced significant and sustained OD affecting all organ systems and a 28-day mortality of 30%. Group 5, traumatic brain injury with OD (n = 98), had the highest mortality of 35% and the shortest time to death for non-survivors, median 3.5 (IQR 2.4–4.8) days. Groups 1 and 5 reached their final group assignment early, > 80% of the patients within 48 h. In contrast, groups 2 and 3 had a prolonged time to final group assignment. Conclusions We identified five distinct trajectories of OD after severe trauma during the first two weeks post-trauma. Our findings underline the heterogeneous course after trauma and describe some potentially important clinical insights that are suggested by the groupings and temporal trajectories.

Introduction New-onset atrial fibrillation (NOAF) is frequently observed in critically ill patients and may be associated with prolonged hospital stay and increased mortality. Considerable variation exists in the reported frequencies of NOAF due to the lack of a standardised definition and detection method. Importantly, there are limited data on NOAF in the intensive care unit (ICU). Thus, we aim to provide contemporary epidemiological data on NOAF in the ICU.Methods and Analysis We have designed an international inception cohort study including at least 1,000 consecutive adult patients acutely admitted to the ICU without prior history of persistent or permanent AF. We will present data on the incidence, risk factors, used management strategies and outcomes of NOAF. We will register data daily during stay in the ICU for a maximum of 90 days after admission. The incidence of NOAF and management strategies used will be presented descriptively, and we will use Cox regression analyses including competing risk analyses to assess risk factors for NOAF and any association with 90-day mortality.Conclusion The outlined international AFIB-ICU inception cohort study will provide contemporary data on the incidence, risk factors, used management strategies and outcomes of NOAF in adult ICU patients.Ethics and dissemination This observational study poses no risk to the included patients. All participating sites will obtain relevant approvals according to national laws before patient enrollment. Funding sources will have no influence on data handling, analyses or writing of the manuscript. The study report(s) will be submitted to an international peer-reviewed journal.

Intracranial arterial stiffening is a potential early marker of emerging cerebrovascular dysfunction and could be mechanistically involved in disease processes detrimental to brain function via several pathways. A prominent consequence of arterial wall stiffening is the increased velocity at which the systolic pressure pulse wave propagates through the vasculature. Previous non-invasive measurements of the pulse wave propagation have been performed on the aorta or extracranial arteries with results linking increased pulse wave velocity to brain pathology. However, there is a lack of intracranial “target-organ” measurements. Here we present a 4D flow MRI method to estimate pulse wave velocity in the intracranial vascular tree. The method utilizes the full detectable branching structure of the cerebral vascular tree in an optimization framework that exploits small temporal shifts that exists between waveforms sampled at varying depths in the vasculature. The method is shown to be stable in an internal consistency test, and of sufficient sensitivity to robustly detect age-related increases in intracranial pulse wave velocity.

Background: The aim of this study was to examine the incidence, risk factors, and outcomes of patients with acute kidney injury (AKI) after surgery for acute type A aortic dissection (ATAAD) using the Nordic Consortium for Acute Type A Aortic Dissection registry. Methods: Patients who underwent ATAAD surgery at 8 Nordic centers from 2005 to 2014 were analyzed for AKI according to the RIFLE criteria. Patients who died intraoperatively, those who had missing baseline or postoperative serum creatinine, and patients on preoperative renal replacement therapy were excluded. Results: AKI occurred in 382 of 941 patients (40.6%), and postoperative dialysis was required for 105 patients (11.0%). Renal malperfusion was present preoperatively in 42 patients (5.1%), of whom 69.0% developed postoperative AKI. In multivariable analysis patient-related predictors of AKI included age (per 10 years; odds ratio [OR], 1.30; 95% confidence interval [CI], 1.15-1.48), body mass index >30 kg/m 2 (OR, 2.16; 95% CI, 1.51-3.09), renal malperfusion (OR, 4.39; 95% CI, 2.23-9.07), and other malperfusion (OR, 2.10; 95% CI, 1.55-2.86). Perioperative predictors were cardiopulmonary bypass time (per 10 minutes; OR, 1.04; 95% CI, 1.02-1.07) and red blood cell transfusion (OR per transfused unit, 1.08; 95% CI, 1.06-1.10). Rates of 30-day mortality were 17.0% in the AKI group compared with 6.6% in the non-AKI group (P < .001). In 30-day survivors AKI was an independent predictor of long-term mortality (hazard ratio, 1.86; 95% CI; 1.24-2.79). Conclusions: AKI is a common complication after surgery for ATAAD and independently predicts adverse long-term outcome. Of note one-third of patients presenting with renal malperfusion did not develop postoperative AKI, possibly because of restoration of renal blood flow with surgical repair. Mortality risk persists beyond the perioperative period, indicating that close clinical follow-up of these patients is required.

Background and purpose The diagnostic accuracy of new imaging techniques requires validation, preferably by histopathological verification. The aim of this study was to develop and present a registration procedure between histopathology and in-vivo magnetic resonance imaging (MRI) of the prostate, to estimate its uncertainty and to evaluate the benefit of adding a contour-correcting registration. Materials and methods For twenty-five prostate cancer patients, planned for radical prostatectomy, a 3D-printed prostate mold based on in-vivo MRI was created and an ex-vivo MRI of the specimen, placed inside the mold, was performed. Each histopathology slice was registered to its corresponding ex-vivo MRI slice using a 2D-affine registration. The ex-vivo MRI was rigidly registered to the in-vivo MRI and the resulting transform was applied to the histopathology stack. A 2D deformable registration was used to correct for specimen distortion concerning the specimen’s fit inside the mold. We estimated the spatial uncertainty by comparing positions of landmarks in the in-vivo MRI and the corresponding registered histopathology stack. Results Eighty-four landmarks were identified, located in the urethra (62%), prostatic cysts (33%), and the ejaculatory ducts (5%). The median number of landmarks was 3 per patient. We showed a median in-plane error of 1.8 mm before and 1.7 mm after the contour-correcting deformable registration. In patients with extraprostatic margins, the median in-plane error improved from 2.1 mm to 1.8 mm after the contour-correcting deformable registration. Conclusions Our registration procedure accurately registers histopathology to in-vivo MRI, with low uncertainty. The contour-correcting registration was beneficial in patients with extraprostatic surgical margins.

Background In previous studies of predictors of gastrointestinal (GI) bleeding in the intensive care unit (ICU), most patients received pharmacological stress ulcer prophylaxis (SUP). We aimed to assess associations between potential predictors of clinically important GI bleeding (CIB) and overt GI bleeding in adult ICU patients, while considering the effect and potential interaction with use of SUP. Methods We included 3291 acutely admitted adult ICU patients with risk factors for GI bleeding randomized to SUP (pantoprazole) or placebo in the SUP-ICU trial. We used logistic regression models adjusted for allocation to SUP to estimate associations between 23 potential predictors and CIB (primary outcome) and overt GI bleeding (secondary outcome). Furthermore, we assessed associations between potential predictors and both outcomes in each allocation group and assessed potential interaction with allocation to SUP. Results Increasing SAPS II and SOFA scores, use of circulatory support and renal replacement therapy were associated with increased risk of CIB and overt GI bleeding; chronic lung disease was associated with increased risk of overt GI bleeding. Results for the remaining potential predictors were compatible with both no difference or increased and decreased risks. We found no strong evidence for any interaction between treatment allocation and any potential predictors. Conclusion In adult ICU patients at risk of GI bleeding, severity of illness, use of circulatory support and renal replacement therapy were associated with higher odds of CIB, with no strong evidence of interaction with SUP.

Background Coronavirus disease 2019 (COVID‐19) may be associated with cardiac arrhythmias in hospitalized patients, but data from the ICU setting are limited. We aimed to describe the epidemiology of cardiac arrhythmias in ICU patients with COVID‐19. Methods We conducted a multicenter, retrospective cohort study including all ICU patients with an airway sample positive for severe acute respiratory syndrome corona‐virus 2 from March 1st to June 1st in the Capital Region of Denmark (1.8 million inhabitants). We registered cardiac arrhythmias in ICU, potential risk factors, interventions used in ICU and outcomes. Results From the seven ICUs we included 155 patients with COVID‐19. The incidence of cardiac arrhythmias in the ICU was 57/155 (37%, 95% confidence interval 30‐45), and 39/57 (68%) of these patients had this as new‐onset arrhythmia. Previous history of tachyarrhythmias and higher disease severity at ICU admission were associated with cardiac arrhythmias in the adjusted analysis. Fifty‐four of the 57 (95%) patients had supraventricular origin of the arrhythmia, 39/57 (68%) received at least one intervention against arrhythmia (eg amiodarone, IV fluid or magnesium) and 38/57 (67%) had recurrent episodes of arrhythmia in ICU. Patients with arrhythmias in ICU had higher 60‐day mortality (63%) as compared to those without arrhythmias (39%). Conclusion New‐onset supraventricular arrhythmias were frequent in ICU patients with COVID‐19 and were related to previous history of tachyarrhythmias and severity of the acute disease. The mortality was high in these patients despite the frequent use of interventions against arrhythmias.

Drug, alcohol and tobacco use disorders are a global burden affecting millions of people. Despite decades of research, treatment options are sparse or missing, and relapse rates are high. Glucagon-like peptide 1 (GLP-1) is released in the small intestine, promotes blood glucose homeostasis, slows gastric emptying and reduces appetite. GLP-1 receptor agonists approved for treating Type 2 diabetes mellitus and obesity have received attention as a potential anti-addiction treatment. Studies in rodents and non-human primates have demonstrated a reduction in intake of alcohol and drugs of abuse, and clinical trials have been initiated to investigate whether the preclinical findings can be translated to patients. This review will give an overview of current findings and discuss the possible mechanisms of action. We suggest that effects of GLP-1 in alcohol and substance use disorders is mediated centrally, at least partly through dopamine signalling, but precise mechanisms are still to be uncovered. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Background : Full dose cabozantinib for metastatic renal cell carcinoma (mRCC) is 60mg, but adverse events (AEs) may require dose reductions. Limited data exist comparing efficacy among cabozantinib doses. We compared AEs and clinical outcomes in mRCC patients treated with full versus reduced starting cabozantinib dose. Methods : We performed a retrospective analysis of 87 mRCC patients treated with cabozantinib at Winship Cancer Institute from 2016-2019. Overall survival (OS), progression-free survival (PFS), and objective response (OR) rate measured clinical outcomes. AEs were collected from clinic notes and the most common were hypertension, mucositis/hand-foot skin reaction (HFSR), or gastrointestinal toxicity. Univariate analysis (UVA) between starting doses and AEs with clinical outcomes was performed using logistic regression model. Multivariable analysis (MVA) was also performed using Cox proportional hazard model. Results : Most patients were male (71%) with clear-cell RCC (72%). The majority were IMDC intermediate (58%) or poor (35%) risk. One third received first-line cabozantinib and 64% had ≥3 baseline metastatic sites. Most patients (68%) required dose reduction from 60mg or started at reduced dose without escalation. Reduced dose patients were more likely to have ≥3 distant metastatic sites (70% vs 58%) and ≥ 2 prior lines of systemic therapy (50% vs 40%) compared to full dose patients. UVA revealed a trend towards shorter OS (HR: 1.78, p=0.095), PFS (HR: 1.50, p=0.107), and lower chance of OR (HR:0.42, p=0.149) among reduced dose patients. This trend did not hold in MVA (OS HR: 1.20, p=0.636; PFS HR: 1.23, p=0.4662). Mucositis/HFSR and hypertension were significantly associated with improved outcomes in UVA. Conclusions : Although we found a trend favoring full dose cabozantinib, this is likely due to worse baseline disease characteristics among patients starting on a reduced dose. Hypertension and mucositis/HFSR may be associated with improved outcomes. Larger studies are warranted to validate these findings.

The aim was to assess the validity of bioimpedance in the assessment of fat free mass (FFM) among women and to study if the validity differs between women with and without Rheumatoid Arthritis (RA).38 women with RA and 24 non-rheumatic controls were included. FFM was measured in the non-fasting state using DXA (Lunar Prodigy), multi-frequency bioelectrical impedance analysis (BIA) (MF-BIA [Tanita MC-180 MA]), single-frequency BIA (SF-BIA) and bioelectrical impedance spectroscopy (BIS) (both Impedimed SFB7). BIS raw data were also used to calculate FFM from equations by Matthie, Jaffrin and Moissl. Results were compared using correlation, Bland Altman analysis, Mann Whitney U test and Wilcoxon Signed Ranks Test.Women with RA had different body water distribution compared to women without RA (p 0.05). Median bias in FFM assessed by bioimpedance was 0.62-7.87 kg with wide limits of agreement for all methods. Median FFM differed significantly from DXA by all bioimpedance methods except for BIS by Jaffrin. Women with RA had significantly smaller biases compared to non-rheumatic controls using BIS equations by Matthie (p = 0.012) and Moissl (p = 0.025). Correlations between FFM measured by DXA and bioimpedance (r = 0.73-0.85, all p 0.001) did not differ between groups. The sensitivity of bioimpedance to detect low fat free mass index (FFMI) was 0-47%.The results of this study show that bioimpedance has similar validity in women with RA compared to non-rheumatic controls, despite differences in body water distribution. Agreement with DXA improved when applying specific equations, but the clinical utility of bioimpedance is questionable as all methods failed to identify low FFMI with acceptable precision.Clinicaltrials.org, NCT04247009.

ObjectivesDiffusion-weighted magnetic resonance imaging (DWI) of the musculoskeletal system has various applications, including visualization of bone tumors. However, DWI acquired with echo-planar imaging is susceptible to distortions due to static magnetic field inhomogeneities. This study aimed to estimate spatial displacements of bone and to examine whether distortion corrected DWI images more accurately reflect underlying anatomy.MethodsWhole-body MRI data from 127 prostate cancer patients were analyzed. The reverse polarity gradient (RPG) technique was applied to DWI data to estimate voxel-level distortions and to produce a distortion corrected DWI dataset. First, an anatomic landmark analysis was conducted, in which corresponding vertebral landmarks on DWI and anatomic T2-weighted images were annotated. Changes in distance between DWI- and T2-defined landmarks (i.e., changes in error) after distortion correction were calculated. In secondary analyses, distortion estimates from RPG were used to assess spatial displacements of bone metastases. Lastly, changes in mutual information between DWI and T2-weighted images of bone metastases after distortion correction were calculated.ResultsDistortion correction reduced anatomic error of vertebral DWI up to 29 mm. Error reductions were consistent across subjects (Wilcoxon signed-rank p−20). On average (±SD), participants’ largest error reduction was 11.8 mm (±3.6). Mean (95% CI) displacement of bone lesions was 6.0 mm (95% CI: 5.1-7.0); maximum displacement was 17.1 mm. Corrected diffusion images were more similar to structural MRI, as evidenced by consistent increases in mutual information (Wilcoxon signed-rank p−12).DiscussionThese findings support the use of distortion correction techniques to improve localization of bone on DWI.Key Points-Diffusion weighted images of bone tissue undergo substantial spatial distortions when acquired with echo-planar imaging.-These distortions can be efficiently corrected with the reverse polarity gradient technique to generate diffusion images that more accurately reflect underlying anatomy.-In the context of bone tumor imaging where precise localization may be required, distortion correction techniques, such as reverse polarity gradient, should be applied.

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging.

Summary After the discovery of ERβ, a novel role for dihydrotestosterone (DHT) in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERβ agonist 5α-androstane-3β, 17β-diol (3βAdiol), an estrogen which does not require aromatase for its synthesis. ERβ was found to oppose androgen signaling and thus is a potential target for treatment of prostate cancer. ERβ was also found to have effects that were independent of androgen signaling, particularly in the CNS. Although in rodent models of neurodegenerative diseases (Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease), ERβ agonists are very effective in relieving symptoms and improving pathologies, this has not proven to be the case in humans. In this review we will focus on the main differences in ERβ signaling between rodents and humans and will make the point that a very important difference between the two species is in the splice variants which are expressed in humans and not rodents. The main conclusion at this point is that before we think of using ERβ agonists clinically, much more work on ERβ signaling in the human or in primates needs to be done.

Introduction For patients with advanced wrist osteoarthritis (OA), total wrist fusion (TWF) is the standard surgical treatment, although total wrist arthroplasty (TWA) has become a plausible motion-preserving alternative. Purpose To explore patients' experiences of living with advanced wrist OA before and after surgery with either a TWF or a TWA. Furthermore, we wanted to explore the expectations of surgery, appraisal of results, and the adaptation strategies used to overcome challenges in everyday life. Study Design Qualitative descriptive. Methods A purposive sample of 13 patients with advanced wrist OA surgically treated with TWF (n = 7) or TWA (n = 6) was recruited. Semistructured interviews were conducted and analyzed using qualitative content analysis. Results Four categories are described: the problematic wrist, the breakpoint, appraisal of the results, and adaptation to challenges in everyday life. Pain relief was the primary expectation of surgery, and involvement in the discussion regarding different surgical options had a positive effect on the appraisal of results. The participants' ability to perform tasks in everyday life appeared to be more related to their level of pain than the range of wrist motion. Successful coping strategies were developed, enabling the participants to become more independent and adapt to challenges in daily life. Conclusions Previous surgical experiences, occupation, and amount of wrist motion influenced the participants' expectations, surgical choice with either a TWF or a TWA, and the appraisal of results. The findings contribute valuable insights to both surgeons and hand therapists about the importance of having the patient's individual expectations and needs in focus.

Medical societies have a social responsibility to disseminate knowledge and inform health authorities on threats to public health posed by various diseases. Advocacy for health protection programmes and for medical research funding is now embedded into the missions of most scientific societies. To promote kidney research funding in Europe, the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), rather than acting as an individual society advocating for the fight against kidney disease, has actively helped to create an alliance of national associations centred on kidney diseases, the European Kidney Health Alliance (EKHA), and joined the Biomedical Alliance (BMA). The ERA-EDTA is fully committed to supporting its working groups (WGs) and consortia of its members to allow them to produce valuable kidney research. The framing and formalization of projects, and the regulatory issues related to submission to the European Commission, are complex. To help WGs to gain expert advice from agencies with specific know-how, the ERA-EDTA has adopted a competitive approach. The best research projects proposed by WGs and consortia of other European investigators will receive seed funding to cover the costs of consultancy by expert agencies. Via its broader platforms, the EKHA and the BMA, the ERA-EDTA will strive towards broader recognition of kidney disease and related clusters of non-communicable diseases, by European and national agencies, as major threats to the qualities of life of their populations and their economies.

Background: In the onset 5 trial, fast-acting insulin aspart (faster aspart) was noninferior to insulin aspart (IAsp) for change from baseline glycated hemoglobin at 16 weeks, when used in continuous subcutaneous insulin infusion by participants with type 1 diabetes. The aim of this post hoc analysis was to investigate whether infusion set wear-time was associated with changes in sensor glucose, measured using continuous glucose monitoring (CGM). Materials and Methods: This was a post hoc analysis of onset 5 data. Mean infusion set wear-time and duration of CGM-wearing period were assessed. Mean CGM sensor glucose 24 h before and 24 h after were used to calculate the before–after difference (CGM sensor glucose drift). Results: Mean infusion set wear-time was 2.9 and 3.0 days in the faster aspart and IAsp arms, respectively. At 16 weeks, the average duration of the CGM wearing period was 13.7 and 13.8 days, respectively. Mean CGM sensor glucose before versus after an infusion set change, at week 16, was 10.14 versus 9.39 mmol/L with faster aspart and 9.48 versus 9.47 mmol/L with IAsp. The estimated treatment difference in CGM sensor glucose drift at 16 weeks for faster aspart versus IAsp was +0.72 mmol/L (95% confidence interval: 0.48–0.96, P

BACKGROUND: The outcome in patients after surgery for acute type A aortic dissection without replacement of the part of the aorta containing the primary tear is undefined.METHODS: Data of 1122 patients who underwent surgery for acute type A aortic dissection in eight Nordic centers from Jan 2005 to Dec 2014 were retrospectively analyzed. The patients with primary tear location either unfound, unknown, not confirmed or not recorded (n=243, 21.7%) were excluded from the analysis. The patients were divided into two groups according to whether the aortic reconstruction encompassed the portion of the primary tear (TR group, n=730) or not (TNR group, n=149). The restricted mean survival time ratios adjusted for patient characteristics and surgical details between the groups were calculated for all-cause mortality and aortic reoperation-free survival. The median follow-up time was 2.57 (inter-quartile range 0.53-5.30) years.RESULTS: For the majority of the patients in the TR group, the primary tear was located in the ascending aorta (83.6%). The reconstruction encompassed both aortic root and the aortic arch in 7.4% in the TR group as compared with 0.7% in the TNR patients (PCONCLUSIONS: Primary tear resection alone does not determine the mid-term outcome after surgery for acute type A aortic dissection.

OBJECTIVE To investigate the nature of the relationship between HbA1c and sepsis among individuals with type 2 diabetes, and to assess the association between sepsis and all-cause mortality in such patients. RESEARCH DESIGN AND METHODS We included 502,871 individuals with type 2 diabetes recorded in the Swedish National Diabetes Register and used multivariable Cox regression and restricted cubic spline analyses to assess the association between time-updated HbA1c values and sepsis occurrence between 1 January 2005 and 31 December 2015. The association between sepsis and death was examined using multivariable Cox regression analysis. RESULTS Overall, 14,534 (2.9%) patients developed sepsis during the study period. On multivariable Cox regression analysis, compared with an HbA1c of 48–52 mmol/mol (6.5–6.9%), the adjusted hazard ratio for sepsis was 1.15 (95% CI 1.07–1.24) for HbA1c 82 mmol/mol (9.7%). In the cubic spline model, a reduction of the adjusted risk was observed within the lower HbA1c range until 53 mmol/mol (7.0%), with a hazard ratio of 0.78 (0.73–0.82) per SD; it increased thereafter (P for nonlinearity CONCLUSIONS In a nationwide cohort of individuals with type 2 diabetes, we found a U-shaped association between HbA1c and sepsis and a fourfold increased risk of death among those developing sepsis.

Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children’s Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (

Purpose To determine and compare the sensitivity, specificity, and proportion of patients eligible for discharge by the Brain Injury Guidelines and the Mild TBI Risk Score in patients with mild traumatic brain injury and concomitant intracranial injury. Methods Retrospective review of the medical records of adult patients with traumatic intracranial injuries and an initial Glasgow Coma Scale score of 14–15, who sought care at Helsingborg Hospital between 2014/01/01 and 2019/12/31. Both guidelines were theoretically applied. The sensitivity, specificity, and percentage of the cohort that theoretically could have been discharged by either guideline were calculated. The outcome was defined as death, in-hospital intervention, admission to the intensive care unit, requiring emergency intubation due to intracranial injury, decreased consciousness, or seizure within 30 days of presentation. Results Of the 538 patients included, 8 (1.5%) and 10 (1.9%) were eligible for discharge according to the Brain Injury Guidelines and the Mild TBI Risk Score, respectively. Both guidelines had a sensitivity of 100%. The Brain Injury Guidelines had a specificity of 2.3% and the Mild TBI Risk Score had a specificity of 2.9%. Conclusion There was no difference between the two guidelines in sensitivity, specificity, or proportion of the cohort eligible for discharge. Specificity and proportion of cohort eligible for discharge were lower than each guideline’s original study. At present, neither guideline can be recommended for implementation in the current or similar settings.

Purpose: Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions. Experimental Design: We profiled 93 genes in tissue from 193 patients with early breast cancer. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR) and residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release. Results: At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR = 0.062; 95% CI, 0.01–0.48; P = 0.0077). Of 31 patients with detectable ctDNA at MT, 30 patients (96.8%) were nonresponders (RCB II, n = 8; RCB III, n = 22) and only one patient responded to the treatment (RCB I). Considering all 145 patients with baseline (BL) plasma, none of the patients with RCB 0 and only 6.7% of patients with RCB I had ctDNA detectable at MT, whereas 30.6% and 29.6% of patients with RCB II/III, respectively, had a positive ctDNA result. Conclusions: Overall, our results demonstrate that the detection and persistence of ctDNA at MT may have the potential to negatively predict response to neoadjuvant treatment and identify patients who will not achieve pCR or be classified with RCB II/III.

Objective To determine short and midterm outcomes of a pre-loaded fenestrated thoracic endograft (f-TEVAR) for exclusion of distal aortic arch pathologies. Methods This was a multicentre, retrospective study including consecutive patients from six experienced European vascular centres undergoing f-TEVAR for distal arch pathologies. Primary endpoints included peri-operative mortality and peri-operative stroke and/or spinal cord ischaemia rates. Secondary outcomes were technical success and mid to late events, including death and re-interventions. Statistical analysis was performed with SPSS 26. Mid to late term events were calculated using Kaplan–Meier survival analysis. Results One hundred and eight patients were included (mean age 68 ± 11 years, 70% men). A total of 38% (n = 42) had a prior history of aortic dissection, and 24% (n = 26) prior aortic surgery. The mean aneurysm diameter was 59 ± 12 mm and the most frequent indication for treatment was post-dissection aneurysms (n = 42, 39%). Technical success was 99% (n = 107) despite intra-operative wire entanglement occurring in 29% (n = 31). The 30 day mortality rate was 3.7% (n = 4), with a 5.6% major stroke incidence (n = 6) and 3.7% (n = 4) spinal cord ischaemia rate. Three cases of retrograde dissection occurred (two of which were fatal), all in post-type B dissecting aneurysm patients without prior aortic surgery (three of 19, 15.8%). Median follow up was 12 months (range, 1 – 26). Endoleaks were documented during follow up, with 3.5% type Ia (4/104) and 2.9% type Ib (3/104) as a result of persistent false lumen perfusion. The one, two, and three year survivals and freedom from re-intervention rates were 93.2% and 92.1%, 89.1% and 86.3%, and 84.4% and 73%, respectively. Conclusion This multicentre study shows that treatment of the distal aortic arch by f-TEVAR is feasible, with promising 30 day mortality, stroke, and spinal cord ischaemia rates.

We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (ps ≤ 0.012), and a GCA-by-lifestyle interaction on both (ps ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals.

BACKGROUND & AIMS: Data on liver fibrosis evolution and its involvement in liver-related morbidity are scarce in individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) co-infection during treatment. We identified profiles of liver fibrosis evolution in coinfected patients undergoing tenofovir (TDF). METHODS: We included 169 HIV-HBV-coinfected patients on TDF-based antiretroviral therapy. Virological and clinical data were obtained at TDF-initiation and every 6-12 months. From data on non-invasive liver fibrosis assessments collected yearly (FibroTest®), we established clusters of individuals with similar liver fibrosis evolution using group-based trajectory models. RESULTS: Four profiles of liver fibrosis evolution were established from a median follow-up of 7.6 years (IQR = 3.1-13.1): low fibrosis with no progression (29.6%, profile A), low fibrosis with progression (22.5%, profile B), moderate fibrosis with high fluctuation (39.6%, profile C), and cirrhosis with no regression (8.3%, profile D). When compared to profile A, baseline HBeAg-positive status was associated with profiles B (P = .007) and C (P = .004), older age with profiles C (P