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In this study, clonal hematopoiesis with somatic mutations was found in 10% of otherwise healthy people older than 65. The risk of hematologic cancer was substantially increased among these persons; in two cases, the subsequent cancer was related to the clone that predated the cancer. The development of disease often involves dynamic processes that begin years or decades before the clinical onset. In many cases, however, the process of pathogenesis goes undetected until after the patient has symptoms and presents with clinically apparent disease. Cancer arises owing to the combined effects of multiple somatic mutations, which are likely to be acquired at different times. 1 Early mutations may be present many years before disease develops. In some models of cancer development, early mutations lead to clonal expansions by stem cells or other progenitor cells. 2 Such clonal expansions greatly increase the likelihood that later, cooperating mutations would . . .

Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate the genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) and non-TRD within ~4500 individuals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores (PRS) of antidepressants and lithium response for individuals with MDD and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1778 ECT-treated MDD cases, nearly all (94%) used antidepressants before their first ECT and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We did not observe a significant difference in the mean PRS of antidepressant response between TRD and non-TRD; however, we found that TRD cases had a significantly higher PRS of lithium response compared to non-TRD cases (OR = 1.10–1.12 under various definitions). The results support the evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.

Background The Sense of Coherence (SOC) scale was designed to measure an individual’s ability to perceive life as comprehensible, manageable, and meaningful. While low SOC is associated with various psychiatric disorders, its association with bipolar disorder remains unclear. This study explores SOC in individuals with bipolar disorder, its associations with clinical characteristics, and its stability and predictive value over 14 years. Methods We included 248 individuals with bipolar disorder and 113 healthy controls from the St. Göran Bipolar Project. SOC was assessed using Antonovsky’s 29-item scale at baseline and after 14 years. Clinical measures included the Montgomery-Åsberg Depression Rating Scale (MADRS), Sheehan Disability Scale, and comorbid psychiatric diagnoses. SOC’s predictive value for relapse, suicide attempts, and self-harm was evaluated using data from a 7-year follow-up visit. Results SOC scores were lower in individuals with bipolar disorder than in healthy controls ( p  < 0.001). Lower SOC correlated with greater functional impairment, residual depressive symptoms, and comorbid anxiety disorders. SOC was stable over 14 years, with modest increases in both groups. In the bipolar disorder group, baseline SOC predicted self-harm during the initial 7-year follow-up ( p  = 0.012) but was not associated with mood episode relapse or suicide attempts. Conclusion Although individuals with bipolar disorder exhibit lower SOC than healthy controls, the difference probably reflects broader psychopathology rather than core bipolar symptoms. SOC predicted self-harm during the 7-year follow-up period, but not mood episode relapse or suicide attempts. Targeting SOC in interventions may benefit comorbid conditions, but is unlikely to impact bipolar-specific outcomes.

Objective This Swedish nationwide cohort study used large-scale data to investigate the associations between bipolar disorder and somatic disorders and whether these risks differ by subtype, sex, or exposure to compulsory care. Methods 61,071 individuals diagnosed with bipolar disorder in inpatient (from 1973) or outpatient care (from 2001) care were compared with the general population without bipolar disorder. The cohort included individuals born in 1932 or later, with follow-up from 1973 to 2020. Cox regression models estimated associations with a range of somatic conditions, including cardiovascular, endocrine, neurological, and infectious diseases. Subtype-specific analyses were conducted in individuals with type 1 ( n  = 8,352) or type 2 ( n  = 9,674), and in those with a history of compulsory care ( n  = 6,748). Results Bipolar disorder was associated with significantly increased risks for most examined somatic conditions. The highest hazard ratios (HRs) were observed for sleep disorders (HR 3.79; 95% CI, 3.71–3.87) and dementias (HR 4.32; 95% CI, 3.82–4.79). Type 2 diabetes risk was elevated, while no association was found for type 1 diabetes. Most risks were comparable across bipolar subtypes, though certain conditions—such as migraine and fibromyalgia—were more strongly associated with type 2. Individuals with a history of compulsory psychiatric care showed elevated risks for several conditions. Conclusions Regardless of sex or subtype, bipolar disorder is associated with substantially higher lifetime risks of a broad range of somatic conditions. Integrated psychiatric and somatic health care may help reduce morbidity and improve outcomes.

An association between schizophrenia and subsequent breast cancer has been suggested; however the risk of schizophrenia following a breast cancer is unknown. Moreover, the driving forces of the link are largely unclear. Here, we report the phenotypic and genetic positive associations of schizophrenia with breast cancer and vice versa, based on a Swedish population-based cohort and GWAS data from international consortia. We observe a genetic correlation of 0.14 (95% CI 0.09–0.19) and identify a shared locus at 19p13 ( GATAD2A ) associated with risks of breast cancer and schizophrenia. The epidemiological bidirectional association between breast cancer and schizophrenia may partly be explained by the genetic overlap between the two phenotypes and, hence, shared biological mechanisms. Schizophrenia has been associated with increased risk of breast cancer, yet the risk of schizophrenia following breast cancer is unclear. Here, the authors show a bidirectional association between breast cancer and schizophrenia in Sweden and a shared genetic contribution to both diseases.

The etiopathology of bipolar disorder is largely unknown. We collected cerebrospinal fluid (CSF) samples from two independent case-control cohorts (total n = 351) to identify proteins associated with bipolar disorder. A panel of 92 proteins targeted towards central nervous system processes identified two proteins that replicated across the cohorts: the CSF concentrations of testican-1 were lower, and the CSF concentrations of C-type lectin domain family 1 member B (CLEC1B) were higher, in cases than controls. In a restricted subgroup analysis, we compared only bipolar type 1 with controls and identified two additional proteins that replicated in both cohorts: draxin and tumor necrosis factor receptor superfamily member 21 (TNFRSF21), both lower in cases than controls. This analysis additionally revealed several proteins significantly associated with bipolar type 1 in one cohort, falling just short of replicated statistical significance in the other (tenascin-R, disintegrin and metalloproteinase domain-containing protein 23, cell adhesion molecule 3, RGM domain family member B, plexin-B1, and brorin). Next, we conducted genome-wide association analyses of the case-control-associated proteins. In these analyses, we found associations with the voltage-gated calcium channel subunit CACNG4, and the lipid-droplet-associated gene PLIN5 with CSF concentrations of TNFRSF21 and CLEC1B, respectively. The reported proteins are involved in neuronal cell-cell and cell-matrix interactions, particularly in the developing brain, and in pathways of importance for lithium’s mechanism of action. In summary, we report four novel CSF protein associations with bipolar disorder that replicated in two independent case-control cohorts, shedding new light on the central nervous system processes implicated in bipolar disorder.

ObjectiveTo compare problems reported in the five EQ-5D-3L dimensions and EQ VAS scores at baseline and at 1-year follow-up among different patient groups and specific diagnoses in 11 National Quality Registers (NQRs) and to compare these with the general population.DesignLongitudinal, descriptive study.Participants2 66 241 patients from 11 NQRs and 49 169 participants from the general population were included in the study.Primary and secondary outcome measuresProportions of problems reported in the five EQ-5D-3L dimensions, EQ VAS scores of participants’ own health and proportions of participants and mean/median EQ VAS score in the Paretian Classification of Health Change (PCHC) categories.ResultsIn most of the included registers, and the general population, problems with pain/discomfort were the most frequently reported at baseline and at 1-year follow-up. Mean EQ VAS score (SD) ranged from 45.2 (22.4) among disc hernia patients to 88.1 (15.3) in wrist and hand fracture patients at baseline. They ranged from 48.9 (20.9) in pulmonary fibrosis patients to 83.3 (17.4) in wrist and hand fracture patients at follow-up. The improved category of PCHC, improvement in at least one dimension without deterioration in any other, accounted for the highest proportion in several diagnoses, corresponding with highest improvement in mean EQ VAS score.ConclusionsThe study documented self-reported health of several different patient groups using the EQ-5D-3L in comparing with the general population. This demonstrated the important role of patient-reported outcomes in routine clinical care, to assess and follow-up health status and progress within different groups of patients. The EQ-5D-3L descriptive system and EQ VAS have an important role in providing a ‘common denominator’, allowing comparisons across NQRs and specific diagnoses.Trial registration numberClinicalTrials.gov (NCT04359628).

Attention-deficit hyperactivity disorder (ADHD) is associated with bipolar disorder and schizophrenia, and it has been suggested that combined bipolar disorder and ADHD is aetiologically distinct from the pure disorders. To clarify whether ADHD shares genetic and environmental factors with bipolar disorder and schizophrenia. By linking longitudinal Swedish national registers, we identified 61 187 persons with ADHD (the proband group) and their first- and second-degree relatives, and matched them with a control group of people without ADHD and their corresponding relatives. Conditional logistic regression was used to determine the risks of bipolar disorder and schizophrenia in the relatives of the two groups. First-degree relatives of the ADHD proband group were at increased risk of both bipolar disorder (odds ratio (OR) = 1.84-2.54 for parents, offspring and full siblings) and schizophrenia (OR = 1.71-2.22 for parents, offspring and full siblings). The risks of bipolar disorder and schizophrenia among second-degree relatives were substantially lower than among full siblings. These findings suggest that the co-occurrence of ADHD and bipolar disorder as well as ADHD and schizophrenia is due to shared genetic factors, rather than representing completely aetiologically distinct subsyndromes.

There is a long-standing belief that creativity is coupled with psychopathology. To test this alleged association and to investigate whether any such association is the result of environmental or genetic factors. We performed a nested case-control study based on Swedish registries. The likelihood of holding a creative occupation in individuals who had received in-patient treatment for schizophrenia, bipolar disorder or unipolar depression between 1973 and 2003 and their relatives without such a diagnosis was compared with that of controls. Individuals with bipolar disorder and healthy siblings of people with schizophrenia or bipolar disorder were overrepresented in creative professions. People with schizophrenia had no increased rate of overall creative professions compared with controls, but an increased rate in the subgroup of artistic occupations. Neither individuals with unipolar depression nor their siblings differed from controls regarding creative professions. A familial cosegregation of both schizophrenia and bipolar disorder with creativity is suggested.

The treatment for transsexualism is sex reassignment, including hormonal treatment and surgery aimed at making the person's body as congruent with the opposite sex as possible. There is a dearth of long term, follow-up studies after sex reassignment. To estimate mortality, morbidity, and criminal rate after surgical sex reassignment of transsexual persons. A population-based matched cohort study. Sweden, 1973-2003. All 324 sex-reassigned persons (191 male-to-females, 133 female-to-males) in Sweden, 1973-2003. Random population controls (10:1) were matched by birth year and birth sex or reassigned (final) sex, respectively. Hazard ratios (HR) with 95% confidence intervals (CI) for mortality and psychiatric morbidity were obtained with Cox regression models, which were adjusted for immigrant status and psychiatric morbidity prior to sex reassignment (adjusted HR [aHR]). The overall mortality for sex-reassigned persons was higher during follow-up (aHR 2.8; 95% CI 1.8-4.3) than for controls of the same birth sex, particularly death from suicide (aHR 19.1; 95% CI 5.8-62.9). Sex-reassigned persons also had an increased risk for suicide attempts (aHR 4.9; 95% CI 2.9-8.5) and psychiatric inpatient care (aHR 2.8; 95% CI 2.0-3.9). Comparisons with controls matched on reassigned sex yielded similar results. Female-to-males, but not male-to-females, had a higher risk for criminal convictions than their respective birth sex controls. Persons with transsexualism, after sex reassignment, have considerably higher risks for mortality, suicidal behaviour, and psychiatric morbidity than the general population. Our findings suggest that sex reassignment, although alleviating gender dysphoria, may not suffice as treatment for transsexualism, and should inspire improved psychiatric and somatic care after sex reassignment for this patient group.