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Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (AI) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.

Aim This long-term follow-up study assessed substance related mortality by sex and compared it with the age-matched general population, with the aim of informing the development of treatment services. Methods Data included 10,891 former patients who had sought treatment for substance use between 1990 and 2009, and a special group of 1,076 children who had accompanied their parent(s) to family treatment. Treatment data were linked to national register data concerning education, hospitalizations and death by 2019. Age-specific death rates, standardized mortality ratios and causes of death were compared with the Finnish general population. Results By 2019, a larger proportion of the 7,334 treatment-seeking men (42.6%) than of the 3,557 women (27.4%) had died. The underlying cause of death was alcohol and/or drug related in one-third of the deaths and two-thirds when further causes were included. Age-specific comparisons with the general population revealed that the studied men and women had markedly higher death rates and the difference increased decade by decade, being highest among the youngest age-groups (standardized mortality ratios were 9.8 for men and 13.8 for women born in the 1980s). Out of the 1,076 children, 15 boys (2.8%) and four girls (0.7%) had died, mostly due to substance use or violence related causes. Conclusions Mortality was significantly increased for several years after treatment highlighting the need for long-term follow-up, as well as after-care and easy re-entry to treatment. Special attention should be paid to the relatively higher increase in mortality risk among women.

The largest excess mortality risk has been reported for combinations of psychiatric disorders that included substance use disorders. To study the associations of different non-substance-related in-patient psychiatric diagnoses with all-cause mortality and suicide up to 28 years of age after entering substance use treatment. National register data on psychiatric hospital admissions and death were combined with the treatment records of over 10 000 individuals in substance use treatment between 1990 and 2009. Cox regression was used to calculate hazard ratios (HRs) with 95% CIs for all-cause and suicide-specific mortality from the time of entering substance use treatment. Nearly one-third (31.4%; n = 3330) of the study population had died during follow-up or by their 65th birthday, with more than one in ten (n = 385) from suicide. Over half of the study population (53.2%) had undergone psychiatric in-patient care and 14.1% involuntary psychiatric care during the study period. Bipolar disorder and unipolar depression were associated with a 57% (HR 1.57, 95% CI 1.18-2.10) and 132% (HR 2.32, 95% CI 1.21-4.46) increase in risk of suicide, respectively. Involuntary psychiatric care was associated with a 40% increase in risk of suicide (HR 1.42, 95% CI 1.05-1.94). Severe psychiatric morbidity is common among individuals seeking treatment for alcohol and/or substance use and specifically mood disorders appear to increase the risk of suicide. Treatment service planning needs to focus on integrated care for concomitant substance use and psychiatric disorders to address this risk.

This report identifies human skeletal diseases associated with mutations in WNT1 in a family with dominantly inherited early-onset osteoporosis and in another family with recessive osteogenesis imperfecta. WNT1 is shown to be an important ligand for regulating bone mass. Osteoporosis is a common skeletal disorder characterized by low bone mineral density (BMD), impaired bone quality, and fragility fractures. 1 Although multiple genetic loci, including those for WNT ligands, have been defined on the basis of genomewide association studies in patients with osteoporosis, the known loci are generally associated with odds ratios for fracture that are below 1.1. 2 Recently, novel metabolic pathways in bone cells have been discovered in patients with osteogenesis imperfecta, a mendelian disease characterized by brittle bones. 3 The role of the WNT pathway in bone formation and maintenance has been extensively studied since the identification of mutations in . . .

Objective: We aimed to analyse patient outcomes following open (OAR) or endovascular repair (EVAR) of an abdominal aortic aneurysm (AAA) in Finland and Sweden from 1998 to 2017. Both intact and ruptured AAAs (rAAAs) were included in the analysis. Methods: Patient-level data from national registries in Finland and Sweden were analysed, pairing operations for intact and ruptured AAA repair with mortality data (date of death). All-cause mortality was the primary endpoint. Anonymized patient data from both countries were pooled, comprising a total of 32,324 operations. Ruptured and intact AAAs were considered separately. In total, EVAR was performed on 9619 intact AAAs and 1470 rAAAs, while OAR was performed on 13,241 intact AAAs and 7994 rAAAs. The patient’s age, sex and the date of operation were obtained as demographic information. Cox regression and Kaplan–Meier analyses were used to evaluate long-term (10-year) survival after the treatment of AAA or rAAA with either modality. Kaplan–Meier analysis was performed in three different age groups (<65 years, 65–79 years and ≥80 years). Results: Considering all age groups together, the 1-, 3- and 10-year Kaplan–Meier survival rates after EVAR were 93.4%, 80.5% and 35.3%, respectively, for intact AAA repair and 67.2%, 55.9% and 22.2%, respectively, for rAAA repair. For OAR of intact AAAs, the 1-, 3- and 10-year Kaplan–Meier survival rates were 92.1%, 84.8% and 48.7%, respectively. The respective rates for OAR of rAAAs were 55.4%, 49.3% and 24.6%. In a Cox regression analysis, a more recent year of operation was associated with improved survival, and older age affected survival negatively for both intact and ruptured AAA repair. If patients survived the first 90 days after the operation, the survival after intact AAA repair was 13.5 years for those <65 years (general population: 18.0 years), and 7.3 years for those ≥80 years (general population: 7.9 years). After rAAA repair, the mean survival was 13.1 years for patients <65 years and 5.5 years for patients ≥80 years, respectively. Conclusions: The long-term survival of patients undergoing intact AAA treatment at the age of 80 or older is close to that of the general population, provided they survive the operation. Conversely, for patients younger than 65, the long-term survival is markedly worse. The long-term survival of AAA patients has improved over time. Open surgery is still a safe and effective option for young patients undergoing intact AAA repair. Our results support the ESVS guidelines recommendation of EVAR being the first-line treatment for patients with rAAA.