Thromboembolic and bleeding complications after elective cardioversion of atrial fibrillation: a nationwide cohort study.

AIMS: Elective cardioversion (ECV) is routinely used in atrial fibrillation (AF) to restore sinus rhythm. However, it includes a risk of thromboembolism even during adequate oral anticoagulation treatment. The aim of this study was to evaluate the risk of thromboembolic and bleeding complications after ECV in a real-life setting utilizing data from a large AF population. METHODS AND RESULTS: This nationwide register-based study included all (n = 9625) Finnish AF patients undergoing their first-ever ECV between 2012 and 2018. The thromboembolic and bleeding complications within 30 days after ECV were analysed. The mean age of the patients was 67.7 ± 9.9 years, 61.2% were men, and the mean CHA2DS2-VASc score was 2.6 ± 1.6. Warfarin was used in 6245 (64.9%) and non-vitamin K oral anticoagulants (NOACs) in 3380 (35.1%) cardioversions. Fifty-two (0.5%) thromboembolic complications occurred, of which 62% were ischaemic strokes, 25% transient ischaemic attacks, and 13% other systemic embolisms. Thromboembolic events occurred in 14 (0.4%) NOAC-treated patients and in 38 (0.6%) warfarin-treated patients (odds ratio 0.77; confidence interval: 0.42-1.39). The median time from ECV to the thromboembolic event was 2 days, and 78% of the events occurred within 10 days. Age and alcohol abuse were significant predictors of thromboembolic events. Among warfarin users, thromboembolic complications were more common with international normalized ratio (INR) <2.5 than INR ≥2.5 (0.9% vs. 0.4%, P = 0.026). Overall, 27 (0.3%) bleeding events occurred. CONCLUSION: The rate of thromboembolic and bleeding complications related to ECV was low without significant difference between NOAC- and warfarin-treated patients. With warfarin, INR ≥2.5 at the time of cardioversion reduced the risk of thromboembolic complications.

Neurological Diseases and Prevalence of Antineuronal Antibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1 - A National Cohort Study.

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic disease caused by mutations in the autoimmune regulator gene. Although the disease-associated autoantibodies mostly target endocrine organs, autoantibodies from patients with APS-1 bind also to rat brain structures. The patients often have GAD65-antibodies, that can cause autoimmune encephalitis. However, neurological manifestations of APS-1 have not been systematically explored. We conducted a retrospective chart review on 44 Finnish patients with APS-1 (median age 38 years, 61% females) and collected all their neurological diagnoses. To assess the prevalence of serum antineuronal antibodies in APS-1, serum samples of 24 patients (median age 36 years, 63% females) were analyzed using a fixed cell-based assay. Of the 44 APS-1 patients, 10 (23%) had also received a diagnosis of a neurological disease. Of these neurological comorbidities, migraine (n = 7; 16%), central nervous system infections (n = 3; 7%), and epilepsy (n = 2; 5%) were the most prevalent. Other diagnoses recorded for single patients were axonal sensorimotor polyneuropathy, essential tremor, idiopathic intracranial hypertension, ischemic stroke, and trigeminal neuralgia. Serum antineuronal antibodies were detected in 42% of patients tested (10/24, 50% females, median age 42 years), GAD65 antibodies being the most common finding. Antibodies against glycine and aquaporin 4 were found in low titers. In four patients, relatively high titers of GAD65 antibodies without coexisting type 1 diabetes were found, but none presented with GAD65-encephalitis. Our study suggests an association between APS-1 and neurological disorders, the mechanisms of which are to be further investigated.

Early-life circumstances and late life loneliness trajectories among Finnish older adults.

BACKGROUND: Later life loneliness has become a significant public health concern worldwide. Research has focused on the prevalence, risk factors and consequences of loneliness in different age groups. This study aimed to advance the understanding of the impact of early-life circumstances on later life loneliness by examining the associations between adversities in childhood and youth and loneliness trajectories in Finnish older adults. METHODS: The data were derived from the 10-year follow-up survey study Good Aging in the Lahti Region (n = 1552, mean age 64.89 years). The baseline study was conducted in 2002 with a regionally and locally stratified random sample of older persons living in the Lahti Region located in southern Finland. The follow-up surveys were carried out in 2005, 2008 and 2012. Loneliness was measured using a single question at the three follow-ups. Childhood conditions were retrospectively assessed at baseline with questions regarding the death of parents, household affection, relocation, and fear of a family member. Latent class growth analysis with time invariant covariates was used to identify loneliness trajectories and to examine the associations between loneliness trajectories and adverse circumstances in childhood and youth. RESULTS: The results identified three distinct loneliness trajectories: low, moderate, and severe, including 36%, 50% and 14%, respectively, of the study population. The non-significant slopes of the three trajectories indicate that trajectories were stable during the seven years of follow-up. Being afraid of a family member, having a cold childhood, and death of a father or mother in childhood or youth significantly increased the odds of having a severe loneliness trajectory as compared to low loneliness trajectory. None of the early-life circumstances differentiated between severe and moderate levels of loneliness. CONCLUSIONS: The findings suggest that some adverse early-life circumstances increase the odds of an unfavorable loneliness trajectory in later life. The results highlight the need to recognize the role of diverse life-course adversities in loneliness research and interventions. The study also underscores the importance of identifying individuals who are at risk of long-term and severe loneliness and providing them with appropriate support to decrease and/or prevent the negative health consequences of loneliness in old age.

Wastewater-based surveillance is an efficient monitoring tool for tracking influenza A in the community.

Around the world, influenza A virus has caused severe pandemics, and the risk of future pandemics remains high. Currently, influenza A virus surveillance is based on the clinical diagnosis and reporting of disease cases. In this study, we apply wastewater-based surveillance to monitor the amount of the influenza A virus RNA at the population level. We report the influenza A virus RNA levels in 10 wastewater treatment plant catchment areas covering 40 % of the Finnish population. Altogether, 251 monthly composite influent wastewater samples (collected between February 2021 and February 2023) were analysed from supernatant fraction using influenza A virus specific RT-qPCR method. During the study period, an influenza A virus epidemic occurred in three waves in Finland. This study shows that the influenza A virus RNA can be detected from the supernatant fraction of 24 h composite influent wastewater samples. The influenza A virus RNA gene copy number in wastewater correlated with the number of confirmed disease cases in the Finnish National Infectious Diseases Register. The median Kendall's τ correlation strength was 0.636 (min= 0.486 and max=0.804) and it was statistically significant in all 10 WTTPs. Wastewater-based surveillance of the influenza A virus RNA is an independent from individual testing method and cost-efficiently reflects the circulation of the virus in the entire population. Thus, wastewater monitoring complements the available, but often too sparse, information from individual testing and improves health care and public health preparedness for influenza A virus pandemics.

Association between trajectories of the neighborhood social exposome and mental health in late adolescence: A FinnTwin12 cohort study.

BACKGROUND: Adolescent mental health problems impose a significant burden. Exploring evolving social environments could enhance comprehension of their impact on mental health. We aimed to depict the trajectories of the neighborhood social exposome from middle to late adolescence and assess the intricate relationship between them and late adolescent mental health. METHODS: Participants (n = 3965) from the FinnTwin12 cohort with completed questionnaires at age 17 were used. Nine mental health measures were assessed. The social exposome comprised 28 neighborhood social indicators. Trajectories of these indicators from ages 12 to 17 were summarized via latent growth curve modeling into growth factors, including baseline intercept. Mixture effects of all growth factors were assessed through quantile-based g-computation. Repeated generalized linear regressions identified significant growth factors. Sex stratification was performed. RESULTS: The linear-quadratic model was the most optimal trajectory model. No mixture effect was detected. Regression models showed some growth factors saliently linked to the p-factor, internalizing problems, anxiety, hyperactivity, and aggression. The majority of them were baseline intercepts. Quadratic growth factors about mother tongues correlated with anxiety among sex-combined participants and males. The linear growth factor in the proportion of households of couples without children was associated with internalizing problems in females. LIMITATIONS: We were limited to including only neighborhood-level social exposures, and the multilevel contextual exposome situation interfered with our assessment. CONCLUSIONS: Trajectories of the social neighborhood exposome modestly influenced late adolescent mental health. Tackling root causes of social inequalities through targeted programs for living conditions could improve adolescent mental health.

Radiological features of screening-detected and interval breast cancers and subsequent survival in Eastern Finnish women.

Interval breast cancers are diagnosed between scheduled screenings and differ in many respects from screening-detected cancers. Studies comparing the survival of patients with interval and screening-detected cancers have reported differing results. The aim of this study was to investigate the radiological and histopathological features and growth rates of screening-detected and interval breast cancers and subsequent survival. This retrospective study included 942 female patients aged 50-69 years with breast cancers treated and followed-up at Kuopio University Hospital between January 2010 and December 2016. The screening-detected and interval cancers were classified as true, minimal-signs, missed, or occult. The radiological features were assessed on mammograms by one of two specialist breast radiologists with over 15 years of experience. A χ2 test was used to examine the association between radiological and pathological variables; an unpaired t test was used to compare the growth rates of missed and minimal-signs cancers; and the Kaplan-Meier estimator was used to examine survival after screening-detected and interval cancers. Sixty occult cancers were excluded, so a total of 882 women (mean age 60.4 ± 5.5 years) were included, in whom 581 had screening-detected cancers and 301 interval cancers. Disease-specific survival, overall survival and disease-free survival were all worse after interval cancer than after screening-detected cancer (p < 0.001), with a mean follow-up period of 8.2 years. There were no statistically significant differences in survival between the subgroups of screening-detected or interval cancers. Missed interval cancers had faster growth rates (0.47% ± 0.77%/day) than missed screening-detected cancers (0.21% ± 0.11%/day). Most cancers (77.2%) occurred in low-density breasts (< 25%). The most common lesion types were masses (73.9%) and calcifications (13.4%), whereas distortions (1.8%) and asymmetries (1.7%) were the least common. Survival was worse after interval cancers than after screening-detected cancers, attributed to their more-aggressive histopathological characteristics, more nodal and distant metastases, and faster growth rates.

Determinants of echocardiographic epicardial adipose tissue in a general middle-aged population - The Cardiovascular Risk in Young Finns Study.

Epicardial adipose tissue (EAT) is the cardiac visceral fat depot proposed to play a role in the etiology of various cardiovascular disease outcomes. Little is known about EAT determinants in a general population. We examined cardiometabolic, dietary, lifestyle and socioeconomic determinants of echocardiograpghically measured EAT in early adulthood. Data on cardiometabolic, dietary, lifestyle and socioeconomic factors were collected from participants of the Cardiovascular Risk in Young Finns Study (YFS; N = 1667; age 34-49 years). EAT thickness was measured from parasternal long axis echocardiograms. Multivariable regression analysis was used to study potential EAT determinants. Possible effect modification of sex was addressed. Mean EAT thickness was 4.07 mm (95% CI 4.00-4.17). Multivariable analysis [ß indicating percentage of change in EAT(mm) per one unit increase in determinant variable] indicated female sex (ß = 11.0, P < 0.0001), type 2 diabetes (ß = 14.0, P = 0.02), waist circumference (cm) (ß = 0.38, P < 0.0001), systolic blood pressure (mmHg) (ß = 0.18, P = 0.02) and red meat intake (g/day) (ß = 0.02, P = 0.05) as EAT determinants. Sex-specific analysis revealed age (year) (ß = 0.59, P = 0.01), alcohol intake (drinks/day) (ß = 4.69, P = 0.006), heavy drinking (yes/no) (ß = 30.4, P < 0.0001) as EAT determinants in women and fruit intake (g/day) (ß = -1.0, P = 0.04) in men. In the YFS cohort, waist circumference, systolic blood pressure and red meat intake were directly associated with EAT among all participants. In women, age, alcohol intake, heavy drinking and type 2 diabetes associated directly with EAT, while an inverse association was observed between fruit intake and EAT in men.

Complications and complaints in craniofacial fractures - Finnish national data for 20 years.

OBJECTIVE: Research on reasons for malpractice claims in oral and maxillofacial surgery is scarce. The aim of this study was to investigate the causes and prevalence of permanent harm among craniofacial fracture related malpractice claims. MATERIALS AND METHODS: A retrospective register study was designed and implemented. All patients with a complaint and a diagnosis of facial or cranial fracture were included. The main outcome was the presence of permanent harm, and the predictor variable was the cause of complaint. Chi-square test was used for estimation of statistical significance. RESULTS: Delay in correct diagnosis was the leading cause of malpractice claims (63.2%), and permanent harm was found in 23.1% of the population. 82.4% of injuries were facial fractures in total population. 65.3% (n = 98) of facial trauma were related with delayed diagnostics (p < 0.001). Permanent harm was more frequent in patients with delayed diagnosis (71.4%) than those without (60.7%, p = 0.299). CONCLUSIONS: Claims of craniofacial trauma are related with under-diagnostics, and un-diagnosed facial fracture can lead to a high rate of permanent harm. Systematic clinical evaluation and facial trauma specialist consultation is recommended to set early correct diagnosis for and improve treatment of craniofacial trauma patients.

Outbreak of Listeria monocytogenes in hospital linked to a fava bean product, Finland, 2015 to 2019.

Listeria monocytogenes (Lm) is a bacterium widely distributed in the environment. Listeriosis is a severe disease associated with high hospitalisation and mortality rates. In April 2019, listeriosis was diagnosed in two hospital patients in Finland. We conducted a descriptive study to identify the source of the infection and defined a case as a person with a laboratory-confirmed Lm serogroup IIa sequence type (ST) 37. Six cases with Lm ST 37 were notified to the Finnish Infectious Diseases Registry between 2015 and 2019. Patient interviews and hospital menus were used to target traceback investigation of the implicated foods. In 2021 and 2022, similar Lm ST 37 was detected from samples of a ready-to-eat plant-based food product including fava beans. Inspections by the manufacturer and the local food control authority indicated that the food products were contaminated with Lm after pasteurisation. Our investigation highlights the importance that companies producing plant-based food are subject to similar controls as those producing food of animal origin. Hospital menus can be a useful source of information that is not dependent on patient recall.

Mental health after the COVID-19 pandemic among Finnish youth: a repeated, cross-sectional, population-based study.

BACKGROUND: High levels of mental health problems among young people were reported during the COVID-19 pandemic, but studies of the post-pandemic period are scarce. We assessed mental health problems among Finnish youth before, during, and after the COVID-19 pandemic using nationwide population-based samples. Our aim was to examine in which direction the heightened levels of adolescent mental health problems have developed after the pandemic. METHODS: In this national, repeated cross-sectional, population-based study in Finland, we recruited students at lower and upper secondary level (aged 13-20 years) who were taking part in the Finnish School Health Promotion (SHP) survey in 2015-23 (119 681-158 897 participants per round). The SHP is based on total sampling and conducted biennially between March and May. Self-reports covered the seven-item Generalized Anxiety Disorder Scale; the two-item Patient Health Questionnaire for depression; the Mini Social Phobia Inventory for social anxiety; the Short Warwick-Edinburgh Mental Wellbeing Scale for mental wellbeing; loneliness; the Sick, Control, One Stone, Fat, Food measure for disordered eating; and suicidality (suicidal ideation, deliberate self-harm, and suicide attempts). Scales were dichotomised using validated cutoffs. Presence of any and comorbid mental health problems was assessed. Logistic (for dichotomised outcomes) and linear (for Short Warwick-Edinburgh Mental Wellbeing Scale) mixed effects models were used to analyse the effect of survey year on mental health, controlling for sociodemographic background factors and stratified by gender and school level. Cisgender and transgender youth were compared. FINDINGS: Between 2015 and 2023, the SHP study recruited 722 488 students (371 634 [51·6%] girls and 348 857 [48·4%] boys) with a mean age of 15·8 years (SD 1·3) who were either in the eighth and ninth grades of comprehensive school or the first and second years of general and vocational upper secondary schools in Finland. The proportion of participants with generalised anxiety, depression, and social anxiety symptoms above the cutoff increased from pre-COVID-19 levels to 2021 and remained at these higher levels in 2023 among all study groups. Among girls in lower secondary education, prevalence of generalised anxiety, depression, and social anxiety symptoms increased from 2021 to 2023, as did social anxiety among girls in upper secondary education. Among boys, the proportion with social anxiety symptoms decreased between 2021 and 2023. Mental wellbeing scores decreased in all groups between 2021 and 2023, and disordered eating increased in girls, and in boys in lower secondary education. Suicidality increased in girls but not in boys. Loneliness was the only measure to show improvement in all groups from 2021 to 2023. In 2023, 55 895 (72·6%) of 76 994 girls and 22 718 (32·8%) of 69 205 boys reported at least one mental health problem, and 37 250 (48·4%) girls and 9442 (13·6%) boys reported comorbid mental health problems. Among both transfeminine and transmasculine youth, the prevalence of generalised anxiety and depression symptoms decreased from 2021 to 2023, but compared with cisgender youth, the proportions were significantly higher throughout. INTERPRETATION: The effects of the COVID-19 pandemic on youth mental health could be long lasting. In this study, the substantial change for the better among transgender youth was a positive exception. Providing adequate support and treatment for young people with poor mental health is essential, but solutions to the mental health crisis need to address a wider societal perspective and should be developed in partnership with young people. FUNDING: NordForsk, Research Council of Finland. TRANSLATIONS: For the Finnish and Swedish translations of the abstract see Supplementary Materials section.

Cumulative costs of severe traffic injuries in Finland: a 2-year retrospective observational study of 252 patients.

Road traffic injuries cause considerable financial strain on health care systems worldwide. We retrospectively analyzed injury-related costs of 252 severely injured (New Injury Severity Score, NISS ≥ 16) patients treated at Tampere University Hospital (TAUH) between 2013 and 2017, with 2-year follow-up. The costs were divided into direct treatment, indirect costs, and other costs. We analyzed various injury- and patient-related factors with costs. The total costs during the 2-year study period were 20 million euros. Median cost was 41,202 euros (Q1 23,409 euros, Q3 97,726 euros), ranging from 2,753 euros to 549,787 euros. The majority of costs (69.1%) were direct treatment costs, followed by indirect costs (28.4%). Other costs were small (5.4%). Treatment costs increased with the severity of the injury or when the injury affected the lower extremities or the face. Indirect costs were higher in working age patients and in patients with a higher level of education. The relative proportions of direct and indirect costs were constant regardless of the amount of the total costs. The largest share of costs was caused by a relatively small proportion of high-cost patients during the 1st year after injury. Combined, this makes planning of resource use challenging and calls for further studies to further identify factors for highest costs.

Health-Related Quality of Life in severely injured patients in Finland: an observational cohort study of 325 patients with 1-year follow-up.

BACKGROUND: Major trauma has a significant effect on Health-Related Quality of Life (HR-QoL). It is unclear, however, which factors most affect HR-QoL. This study aims to evaluate HR-QoL after severe injury in Finland and determine how different injury patterns and patient-related factors, such as level of education and socioeconomic group, are associated with HR-QoL. We also assess how well different injury scoring systems associate with HR-QoL. METHODS: We retrospectively analyzed 325 severely injured trauma patients (aged ≥ 18 years, New Injury Severity Score, (NISS) ≥ 16, and alive at 1 year after injury) treated in the Intensive Care Unit (ICU) or High Dependence Unit (HDU) of Tampere University Hospital (TAUH) from 2013 through 2016. HR-QoL was assessed with the EQ-5D-3L questionnaire completed during ICU stay and 1 year after injury. HR-QOL index values and reported problems were further compared with Finnish population norms. RESULTS: The severity of the injury (measured by ISS and NISS) had no significant association with the decrease in HR-QoL. Length of ICU stay had a weak negative correlation with post-injury HR-QoL and a weak positive correlation with the change in HR-QoL. The largest mean decrease in HR-QoL occurred in patients with spinal cord injury (Spine AIS ≥ 4) (-0.338 (SD 0.136)), spine injury in general (Spine AIS ≥ 2 (-0.201 (SD 0.279)), and a lower level of education (-0.157 (SD 0.231)). Patient's age, sex, or socioeconomic status did not seem to associate with smaller or greater changes in HR-QoL. CONCLUSIONS: After serious injury, many patients have permanent disabilities which reduce HR-QoL. Injury scoring systems intended for assessing the risk for death did not seem to associate with HR-QoL and are not, therefore, a meaningful way to predict the future HR-QoL of a severely injured patient. Recovery from the injury seems to be weaker in poorer educated patients and patients with spinal cord injury, and these patients may benefit from targeted additional measures. Although there were significant differences in baseline HR-QoL levels between different socioeconomic groups, recovery from injury appears to be similar, which is likely due to equal access to high-quality trauma care.

The brain insulin receptor gene network and associations with frailty index.

OBJECTIVE: To investigate longitudinal associations between variations in the co-expression-based brain insulin receptor polygenic risk score and frailty, as well as change in frailty across follow-up. METHODS: This longitudinal study included 1605 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network, which measure genetic variation in the function of the insulin receptor, were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Frailty was assessed in at baseline in 2001-2004, 2011-2013 and 2017-2018 by applying a deficit accumulation-based frailty index. Analyses were carried out by applying linear mixed models and logistical regression models adjusted for adult socioeconomic status, birthweight, smoking and their interactions with age. RESULTS: The FI levels of women were 1.19%-points (95% CI 0.12-2.26, P = 0.029) higher than in men. Both categorical and continuous hePRS-IR in women were associated with higher FI levels than in men at baseline (P < 0.05). In women with high hePRS-IR, the rate of change was steeper with increasing age compared to those with low or moderate hePRS-IR (P < 0.05). No associations were detected between mePRS-IR and frailty at baseline, nor between mePRS-IR and the increase in mean FI levels per year in either sex (P > 0.43). CONCLUSIONS: Higher variation in the function of the insulin receptor gene network in the hippocampus is associated with increasing frailty in women. This could potentially offer novel targets for future drug development aimed at frailty and ageing.

Insulin sensitivity estimates and their longitudinal association with coronary artery disease in type 1 diabetes. Does it matter?

BACKGROUND: Insulin resistance and chronic kidney disease are both associated with increased coronary artery disease risk. Many formulae estimating glucose disposal rate in type 1 diabetes infer insulin sensitivity from clinical data. We compare associations and performance relative to traditional risk factors and kidney disease severity between three formulae estimating the glucose disposal rate and coronary artery disease in people with type 1 diabetes. METHODS: The baseline glucose disposal rate was estimated by three (Williams, Duca, and Januszewski) formulae in FinnDiane Study participants and related to subsequent incidence of coronary artery disease, by baseline kidney status. RESULTS: In 3517 adults with type 1 diabetes, during median (IQR) 19.3 (14.6, 21.4) years, 539 (15.3%) experienced a coronary artery disease event, with higher rates with worsening baseline kidney status. Correlations between the three formulae estimating the glucose disposal rate were weak, but the lowest quartile of each formula was associated with higher incidence of coronary artery disease. Importantly, only the glucose disposal rate estimation by Williams showed a linear association with coronary artery disease risk in all analyses. Of the three formulae, Williams was the strongest predictor of coronary artery disease. Only age and diabetes duration were stronger predictors. The strength of associations between estimated glucose disposal rate and CAD incidence varied by formula and kidney status. CONCLUSIONS: In type 1 diabetes, estimated glucose disposal rates are associated with subsequent coronary artery disease, modulated by kidney disease severity. Future research is merited regarding the clinical usefulness of estimating the glucose disposal rate as a coronary artery disease risk factor and potential therapeutic target.

Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case-control study in Finland.

BACKGROUND: Agranulocytosis is a life-threatening side-effect of clozapine, the only approved drug for treatment-resistant schizophrenia. The long-term profile of this complication has not yet been well established. Here we aim to describe the risk of clozapine-induced agranulocytosis over the long term. METHODS: We used the entire population of Finland to identify people diagnosed with schizophrenia or schizoaffective disorder between 1972 and 2014 and developed a Kaplan-Meier model of time to diagnosis of agranulocytosis during clozapine versus non-clozapine treatment over a 22-year observation period (1996 to 2017). Next, we developed a nested case-control model for agranulocytosis matching by sex, age, time since diagnosis, and being in the incident cohort on a 1 to 5 ratio. Various durations of use for clozapine and non-clozapine antipsychotic treatment were compared to the modal antipsychotic use duration, deriving adjusted odds ratios (aORs) in a multivariable regression model. Recurrence and lethality rates for clozapine-induced agranulocytosis were described. These data reflect on all individuals with lived experience of schizophrenia in Finland during the study time, although individuals with lived experience were not included in the design of the study. FINDINGS: We identified 61 769 people with schizophrenia or schizoaffective disorder (14 037 individuals treated with clozapine and 47 732 individuals treated with non-clozapine antipsychotics), with a mean age of 46·67 years (IQR 34·44-57·61), of whom 30 721 (49·7%) were female and 31 048 (50·3%) were male (data on ethnicity not available). Among those, 398 individuals were diagnosed with agranulocytosis (231 individuals treated with clozapine and 167 individuals treated with non-clozapine antipsychotics), representing a cumulative incidence of agranulocytosis for 1·37% (95% CI 0·58-3·16) on clozapine and 0·13% (0·04-0·23) on non-clozapine antipsychotics. In the case (n=398) versus control (n=1987) model, the risk of clozapine-induced agranulocytosis decreased steeply over time from an aOR of 36·01 (95% CI 16·79-77·22) for less than 6 months on clozapine to 4·38 (1·86-10·34) for clozapine use of 54 months or more. Only one of 3559 individuals starting clozapine died because of clozapine-induced agranulocytosis. INTERPRETATION: The risk of clozapine-induced agranulocytosis decreases steeply over time but might be persistently greater than that of non-clozapine antipsychotics. This long-term risk excess seems small in absolute terms compared with the known magnitude of the advantages of clozapine in relevant outcomes, including life expectancy. Given the widespread underuse of clozapine, relaxing the long-term neutrophil monitoring could favour the advantages of long-term clozapine use, including greater life expectancy, without incurring the intolerable risk of clozapine-induced agranulocytosis. FUNDING: Northwell Health and Sigrid Jusèlius Foundation.

Recent Changes in the Incidence and Characteristics of Cutaneous Squamous Cell Carcinomas in Finland from 2006 to 2020: A Retrospective Cohort Study.

Registers recording only 1 tumour per patient do not enable assessment of the real burden of cutaneous squamous cell carcinoma. To investigate recent changes in the incidence and characteristics of tumours, a retrospective 15-year patient cohort study was performed in Finland. Histopathological diagnoses of cutaneous squamous cell carcinomas diagnosed between 2016 and 2020 were obtained from the pathology database and clinical data from patient medical records and combined with previously collected data for the years 2006-2015. Altogether 1,472 patients with 2,056 tumours were identified. The crude incidence increased from 19/100,000 persons in 2006 to 42 in 2020 (p < 0.001), increasing most in people aged over 80 years. The percentage of tumours located on the trunk increased from 5.3% during the first 5-year period, 2006-2010, to 9.0% in 2016-2020. Also, the location of tumours was significantly different between men and women, as men had more tumours on the scalp and ears, and women on the lower limbs. A slight change in the tumours from poorly to well differentiated and a decrease in the invasion depth were noted between 2006 and 2020. As the burden of tumours continues to increase, more attention should be paid to their prevention.

Association between human blood metabolome and the risk of gastrointestinal tumors.

BACKGROUND: The prevalence of gastrointestinal tumors continues to be significant. To uncover promising therapeutic targets for these tumors, we rigorously executed a Mendelian randomization (MR) study to comprehensively screen the blood metabolomes for potential causal mediators of five frequently encountered gastrointestinal tumors (Liver Cancer, Colorectal Cancer, Esophageal Cancer, Gastric Cancer and Pancreatic Cancer). METHODS: We selected a comprehensive set of 137 distinct blood metabolites derived from three large-scale genome-wide association studies (GWASs) involving a total of 147827 participants of European ancestry. The gastrointestinal tumors-related data were obtained from a GWAS conducted within the Finnish study. Through meticulous MR analyses, we thoroughly assessed the associations between blood metabolites and gastrointestinal tumors. Additionally, a phenome-wide MR (Phe-MR) analysis was employed to investigate the potential on-target side effects of metabolite interventions. RESULTS: We have identified 1 blood metabolites, namely isovalerylcarnitine (ORlog10: 1.01; 95%CI, 1.01-1.02; P = 1.81×10-7), as the potential causal mediators for liver cancer. However, no potential pathogenic mediators were detected for the other four tumors. CONCLUSIONS: The current systematic MR analysis elucidated the potential role of isovalerylcarnitine as a causal mediator in the development of liver cancer. Leveraging the power of Phe-MR study facilitated the identification of potential adverse effects associated with drug targets for liver cancer prevention. Considering the weighing of pros and cons, isovalerylcarnitine emerges as a promising candidate for targeted drug interventions in the realm of liver cancer prevention.