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Multidisciplinary meeting (MDM) is a core element in the diagnosis of interstitial lung diseases (ILD). The aim of the study was to investigate the implementation and key elements related to ILD MDMs in Finnish specialized care, which is characterized by long travel distances and a large number of small centers treating patients suffering from ILDs. An electronic questionnaire was sent to ILD experts working at five academic centers of Finland regarding the implementation of ILD MDMs with the focus on utilization of virtual communication. Responses were received from all academic centers of Finland (n = 5) whose catchment areas cover all of Finland. ILD MDMs were organized in each center approximately every two weeks and the core participants included a radiologist, respiratory physicians, junior staff, pathologist and a rheumatologist. All non-academic centers could refer their patients to be evaluated in ILD MDM of an academic center. Virtual communication was utilized by all academic centers in the implementation of ILD MDMs, being most common among small centers located in Eastern and Northern Finland. Virtual access to ILD MDM of an academic center was available in most parts of Finland, enabling small centers to benefit from the ILD expertise of academic centers. publishedVersion

Objective: To illustrate the views of chief physicians in Finnish primary healthcare health centres (HCs) on the existing research capacity of their centres, their attitudes to practice-based research network activity, and research topics of interest to them. Design: A cross-sectional survey study. Setting: Finnish HCs. Subjects: Chief physicians in Finnish HCs. Main outcome measures: We used a questionnaire that included five-point Likert scales and multiple choice and open-ended questions to identify the chief physician’s profile, the HC content, the attitudes of chief physicians towards engagement in research, research topics of interest to them, and factors that may influence their motivation. Descriptive methods were used for the analysis of the quantitative data, while the qualitative data were processed using inductive thematic analysis. Results: There was a relatively good representation of all hospital districts. One-third of HCs had at least one person doing research, and 61% of chief physicians would support research in their setting. Their stimulus for research was primarily testing new therapies, protocols, and care processes, as well as effectiveness and healthcare improvement. The expected benefits that motivate engagement in Practice-based research networks (PBRNs) are evidence-based practice and raised professional capacity and profile of the HC. Conclusions: Chief physicians regard research as an elementary part of the development of primary care practices and health policy. Their motivation to engage in PBRN activity is determined by the relevance of the research to their interests and the management of competing priorities and resource limitations. publishedVersion

Background: This phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in healthy infants. V114 contains all 13 serotypes in PCV13 and additional serotypes 22F and 33F. Methods: Healthy infants were randomized to two primary doses and one toddler dose (2+1 regimen) of V114 or PCV13 at 3, 5, and 12 months of age; diphtheria, tetanus, pertussis (DTaP), inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib), hepatitis B (HepB) vaccine was administered concomitantly. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series, immediately prior to toddler dose, and 30 days post-toddler dose. Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for serotypes 22F and 33F. Results: 1191 healthy infants were randomized to V114 (n = 595) or PCV13 (n = 596). Proportions of participants with solicited AEs and serious AEs were comparable between groups. V114 met non-inferiority criteria for 13 shared serotypes, based on difference in proportions with serotype-specific IgG ≥0.35 μg/mL (lower bound of two-sided 95% confidence interval [CI] >−10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5) at 30 days post-toddler dose. V114 met superiority criteria for serotypes 22F and 33F, based on response rates (lower bound of two-sided 95% CI >10.0) and IgG GMC ratios (lower bound of two-sided 95% CI >2.0) at 30 days post-toddler dose. Antibody responses to DTaP-IPV-Hib-HepB met non-inferiority criteria, based on antigen-specific response rates. Conclusion: A two-dose primary series plus toddler dose of V114 was well-tolerated in healthy infants. Compared with PCV13, V114 provided non-inferior immune responses to 13 shared serotypes and superior immune responses to additional serotypes 22F and 33F. publishedVersion

To evaluate heart rate (HR), the presence of extrasystoles and other Holter findings among healthy newborns, and to collect data for new normal limits for Holter parameters in newborns. For this cross-sectional study, 70 healthy term newborns were recruited to undergo 24-h Holter monitoring. Linear regression analysis was used in HR analyses. The age-specific limits for HRs were calculated using linear regression analysis coefficients and residuals. The mean (SD) age of the infants was 6.4 (1.7) days during the recording. Each consecutive day of age raised the minimum and mean HR by 3.8 beats per minute (bpm) (95% CI: 2.4, 5.2; P P Conclusion: The present study shows an increase of 20 bpm in both the minimum and mean HRs of healthy term newborns between the 3rd and 9th days of life. Daily reference values for HR could be adopted in the interpretation of HR monitoring results in newborns. A small number of extrasystoles are common in healthy newborns, and isolated short tachycardias may be normal in this age group. What is Known: • The current definition of bradycardia in newborns is 80 beats per minute. • This definition does not fit into the modern clinical setting of continuously monitored newborns, where benign bradycardias are commonly observed. What is New: • A linear and clinically significant increase in heart rate was observed in infants between the ages of 3 and 9 days. • It appears as though lower normal limits for heart rate could be applied to the youngest newborns.

BACKGROUND: Chronic total occlusions (CTO) are frequent among patients with coronary artery disease. Revascularization with percutaneous coronary intervention (PCI) is safe and feasible in experienced hands. However, randomized data are needed to demonstrate symptomatic as well as prognostic effect of CTO-PCI compared to optimal medical therapy alone.METHODS AND DESIGN: This trial aims to evaluate the effect of CTO PCI in patients with a CTO lesion and target vessel diameter ≥ 2.5 mm, and myocardial ischemia in the relevant territory. First, all patients are subjected to optimal medical therapy (OMT) for at least for 3 months and non-CTO lesions are managed according to guidelines. Subsequently, prior to randomization myocardial ischemia and quality of life (Seattle Questionnaire (SAQ)) is assessed. Patients are divided into two cohorts based on their SAQ score and randomized to either OMT alone or OMT and CTO-PCI. Cohort A is defined as Low- or asymptomatic patients with a quality-of-life score > 60 and/or CCS class < 2, and more than 10 % ischemia in the left ventricle (LV). Cohort B is symptomatic patients with a quality-of-life score < 60 or CCS class angina > 1 and at least ischemia in 5% of the LV. The primary end-point in cohort A is a composite of major adverse cardiac and cerebral events, hospitalization for heart failure and malignant ventricular arrhythmias. The primary endpoint in cohort B is difference in quality of life 6 months after randomization.IMPLICATIONS: This trial is designed to investigate if CTO-PCI improves QoL and MACCE. Both positive and negative outcome of the trial will affect future guidelines and recommendations on how to treat patients with CTO.

Myocardial sleeves around pulmonary veins (PVs) are highly innervated structures with heterogeneous morphological and electrophysiological characteristics. Autonomic nerve dysfunction in the myocardium may be associated with an increased risk of cardiovascular morbidity and mortality. This article studied autonomic neural remodeling in myocardial sleeves around PVs and atrial-PV ostia with immunohistochemical and morphometric methods with clinicopathological correlations. PVs were collected from 37 and atrial-PV ostia from 17 human autopsy hearts. Immunohistochemical analysis was performed using antibodies against tyrosine hydroxylase (TH), choline acetyltransferase (CHAT), and growth-associated protein 43 (GAP43). In the PV cohort, subjects with immediate cardiovascular cause of death had significantly decreased sympathetic nerve density in fibro-fatty tissue vs those with non-cardiovascular cause of death (1624.53 vs 2522.05 µm2/mm2, p=0.038). In the atrial-PV ostia cohort, parasympathetic nerve density in myocardial sleeves was significantly increased in subjects with underlying cardiovascular cause of death (19.48 µm2/mm2) than subjects with underlying non-cardiovascular cause of death with no parasympathetic nerves detected ( p=0.034). Neural growth regionally varied in sympathetic nerves and was present in most of the parasympathetic nerves. Heterogeneous autonomic nerve distribution and growth around PVs and atrial-PV ostia might play a role in cardiovascular morbidity and mortality. No association in nerve density was found with atrial fibrillation.

Aim To evaluate the significance of severe hyponatraemia presented at the emergency department (ED). Methods A retrospective hospital records study of all patients with plasma sodium levels of < 116 mmol/l from 2016 to 2020 in a single tertiary referral centre. Results A total of 394 visits of 363 individual severely hyponatraemic patients represented 0.08% of all ED visits. The mean age was 68 years and the male-to-female ratio was 1:1.3. The symptoms and signs were diffuse and varying, while half of the patients had neurologic symptoms. The aetiology of hyponatraemia was often multifactorial. The aetiologies varied by age, and the most common ones were the syndrome of inappropriate antidiuresis (34%), diuretic use (27%), alcohol-related (19%) and dehydration (19%). The mean sodium correction rates were 6.6, 4.9 and 3.8 mmol/l/24 h at 24, 48 and 72 h, respectively. The mean maximum correction rate over any 24-h time interval was 10.2 mmol/l. The vital signs (National Early Warning Score, NEWS) of severely hyponatraemic patients were mostly normal. All-cause mortality was 18% for 1-year follow-up. Malignancies, especially small-cell lung cancer, and end-stage liver disease caused most of the deaths. Osmotic demyelination syndrome (ODS) was diagnosed in five (1.4%) patients. Conclusion Patients with severe hyponatraemia in the ED presented with non-specific complaints. The aetiology of hyponatraemia was often multifactorial and varied by age. The need for intensive care was poorly predicted by NEWS. The one-year mortality rate was 18% and the incidence of ODS 1.4% after an episode of severe hyponatraemia.

Background and Purpose: The biallelic repeat expansion (AAGGG)exp in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late-onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)exp and includes now various nonclassical phenotypes. Biallelic (AAGGG)exp in RFC1 in patients with clinically confirmed Parkinson's disease (PD) has recently been found. Methods: A nationwide cohort of 273 Finnish patients with early-onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)exp was first screened using extra long polymerase chain reactions (Extra Large-PCRs) and flanking multiplex PCR. The presence of biallelic (AAGGG)exp was then confirmed by repeat-primed PCR and, finally, the repeat length was determined by long-read sequencing. Results: Three patients were found with the biallelic (AAGGG)exp in RFC1 giving a frequency of 1.10% (0.23%–3.18%; 95% confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40–48 years and their disease course had been unremarkable apart from the early onset. Conclusions: Our results suggest that (AAGGG)exp in RFC1 is a rare cause of early-onset PD. Other populations should be examined in order to determine whether our findings are specific to the Finnish population. publishedVersion

Introduction: Fear of childbirth (FOC) is a common obstetrical challenge that affects the health of women. The epidemiology of FOC has not been studied in Finland for the last decade. The aim of this study was to analyze the epidemiology and risk factors for FOC and to evaluate the association between FOC and the rate of elective cesarean section (CS) as an intended mode of delivery. Material and methods: Data from the National Medical Birth Register were used to evaluate the epidemiology of FOC and to determine the main risk factors for FOC in Finland between 2004 and 2018. Nulliparous and multiparous women were analyzed separately. Logistic regression model was used to determine the main risk factors for FOC. Multivariable logistic regression model was used to assess the intended mode of delivery in those pregnancies with diagnosed maternal FOC. Adjusted odds ratios (aOR) with 95% confidence intervals (CIs) were calculated. Results: A total of 1 million pregnancies were included. The annual rate of pregnancies with maternal FOC increased from 1.5% (CI: 1.4–1.6) in 2004 to 9.1% (CI: 8.7–9.3) in 2018 for all women. For nulliparous women, the rate increased from 1.1% (CI: 1.0–1.3) in 2004 to 7.1% (CI: 6.7–7.5) in 2018, and from 1.8% (CI: 1.7–2.0) in 2004 to 10.3% (10.0–10.7) in 2018 for multiparous women. The strongest risk factors for maternal FOC were higher maternal age and gestational diabetes. For multiparous women, the strongest risk factors were gestational diabetes and previous CS. The total odds for elective CS were notably higher among women with FOC (aOR 8.63, CI: 8.39–8.88). Conclusions: The incidence of maternal FOC rose six-fold during our study period. However, the numbers of elective CS among women with this diagnosis, which had earlier risen in parallel, leveled off in 2014. publishedVersion

Background: The QT interval in the electrocardiogram (ECG) is a fundamental risk measure for arrhythmic adverse cardiac events. However, the QT interval depends on the heart rate and must be corrected accordingly. The present QT correction (QTc) methods are either simple models leading to under- or overcorrection, or impractical in requiring long-term empirical data. In general, there is no consensus on the best QTc method. Objective: We introduce a model-free QTc method—AccuQT—that computes QTc by minimizing the information transfer from R-R to QT intervals. The objective is to establish and validate a QTc method that provides superior stability and reliability without models or empirical data. Methods: We tested AccuQT against the most commonly used QT correction methods by using long-term ECG recordings of more than 200 healthy subjects from PhysioNet and THEW databases. Results: AccuQT overperforms the previously reported correction methods: the proportion of false-positives is reduced from 16% (Bazett) to 3% (AccuQT) for the PhysioNet data. In particular, the QTc variance is significantly reduced and thus the RR-QT stability is increased. Conclusion: AccuQT has significant potential to become the QTc method of choice in clinical studies and drug development. The method can be implemented in any device recording R-R and QT intervals. publishedVersion

Aim: To compare 4D flow magnetic resonance imaging (MRI) and 2D phase contrast (PC) MRI when evaluating bicuspid (BAV) and tricuspid (TAV) aortic valves. Materials and Methods: A total of 83 subjects (35 BAV, 48 TAV) were explored with 4D flow and 2D PC MRI. Systolic peak velocity, peak flow and regurgitation fraction were analysed at two pre-defined aortic levels (aortic root, mid-tubular). Furthermore, the two methods of 4D flow analysis (Heart and Artery) were compared. Results: Correlation between the 2D PC MRI and 4D flow MRI derived parameters ranged from moderate (R=0.58) to high (R=0.90). 4D flow MRI yielded significantly higher peak velocities in the tubular aorta in both groups. Regarding the aortic root, peak velocities were significantly higher in the TAV group with 4D flow MRI, but in the BAV group 4D flow MRI yielded non-significantly lower values. Findings on peak flow differences between the two modalities followed the same pattern as the differences in peak velocities. 4D flow MRI derived regurgitation fraction values were lower in both locations in both groups. Interobserver agreement for different 4D flow MRI acquired parameters varied from poor (ICC=0.07) to excellent (ICC=1.0) in the aortic root, and it was excellent in the tubular aorta (ICC=0.8-1.0). Conclusion: 4D flow MRI seems to be accurate in comparison to 2D PC MRI in normal aortic valves and in BAV with mild to moderate stenosis. However, the varying interobserver reproducibility and impaired accuracy at higher flow velocities should be taken into account in clinical practice when using the 4D flow method. publishedVersion

The objective of the study was to investigate the associations of sedentary time, physical activity, and cardiorespiratory fitness with skeletal muscle glucose uptake (GU).Sedentary time and physical activity were measured with accelerometers and VOSedentary time (β = -0.374), standing (β = 0.376), steps (β = 0.351), and VOBody composition is a more important determinant of muscle GU in this population than sedentary time, physical activity, or fitness.

Background:Preexisting hypertension increases risk for preeclampsia. We examined whether a generic blood pressure polygenic risk score (BP-PRS), compared with a preeclampsia-specific polygenic risk score (PE-PRS), could better predict hypertensive disorders of pregnancy.Methods:Our study sample included 141 298 genotyped FinnGen study participants with at least one childbirth and followed from 1969 to 2021. We calculated PRSs for SBP and preeclampsia using summary statistics for greater than 1.1 million single nucleotide polymorphisms.Results:We observed 8488 cases of gestational hypertension (GHT) and 6643 cases of preeclampsia. BP-PRS was associated with GHT [multivariable-adjusted hazard ratio for 1SD increase in PRS (hazard ratio 1.38; 95% CI 1.35-1.41)] and preeclampsia (1.26, 1.23-1.29), respectively. The PE-PRS was also associated with GHT (1.16; 1.14-1.19) and preeclampsia (1.21, 1.18-1.24), but with statistically more modest magnitudes of effect (P = 0.01). The model c-statistic for preeclampsia improved when PE-PRS was added to clinical risk factors (P = 4.6 × 10-15). Additional increment in the c-statistic was observed when BP-PRS was added to a model already including both clinical risk factors and PE-PRS (P = 1.1 × 10-14).Conclusion:BP-PRS is strongly associated with hypertensive disorders of pregnancy. Our current observations suggest that the BP-PRS could capture the genetic architecture of preeclampsia better than the current PE-PRSs. These findings also emphasize the common pathways in the development of all BP disorders. The clinical utility of a BP-PRS for preeclampsia prediction warrants further investigation. publishedVersion

Purpose Periodontal diseases and caries are common oral diseases that predispose to tooth loss if untreated. In this study, we investigated whether loss of teeth or caries associate with intracranial aneurysm (IA) pathology similar to periodontal diseases. Methods A total of 166 patients with either IA or aneurysmal subarachnoid hemorrhage (aSAH) underwent oral examination in Kuopio University Hospital and Tampere University Hospital. Findings were compared to geographically matched controls acquired from cross-sectional Health2000 survey. This study consisted of three sequential steps. First, we compared the number of missing teeth and prevalence of caries in IA and aSAH patients and geographically matched control population, second step was a multivariate analysis including other risk factors, and third step was a 13-year follow-up of the Health2000 survey participants with missing teeth or caries at baseline. Results Loss of teeth did not significantly differ between IA patients and controls. In logistic regression model adjusted for known risk factors and demographic data, 1–4 caries lesions (OR: 0.40 95%Cl 0.2–0.9, p = 0.031) was associated with lack of IAs, while age (OR: 1.03 95%Cl 1.01.1 p = 0.024), current smoking (OR: 2.7 95%Cl 1.4–5.1, p = 0.003), and severe periodontitis (OR: 5.99 95%Cl 2.6–13.8, p p = 0.020) during a 13-year follow-up, while caries or missing teeth did not. Conclusion Unlike severe periodontitis, caries does not increase the risk of IAs and aSAHs. However, cariogenic bacteria may participate to IA pathology by disseminating to circulation via inflamed gingival tissue.

BACKGROUND AND AIMS: The early outcomes of ulcerative colitis (UC) after rescue therapy with cyclosporine A (CyA) are well known. Published data on the safety of this treatment in perioperative use and data on the long-term prognosis are scarce and are investigated here. METHODS: All UC patients treated with CyA in Tampere University Hospital between 2009 and 2018 were reviewed from patient records. RESULTS: A total of 182 patients were included with the median follow-up of 3.8 (range 0-13) years. Of all patients, 139 (76%) responded to CyA. A quarter of the responders achieved long-term remission and used thiopurines as maintenance therapy at the end of follow-up. Altogether 83 (46%) needed further enhancement of treatment with corticosteroids (Cs) and 57 (31%) with biologicals or small molecules. Of the nonresponders 27 (55%) were treated surgically within admission to index flare. Infliximab was used as a third-line rescue therapy for 16 patients of whom four benefitted. The overall colectomy rate in this series was 45%. When compared to Cs alone CyA did not increase the risk for severe postoperative complications in patients treated for severe treatment-refractory UC. CONCLUSION: In conclusion, despite the good initial response to CyA, a large proportion of patients relapsed during long-term follow-up and the colectomy rates remain high. Other therapy attempts after failure of CyA merely postpone surgery in many. We therefore recommend informing patients about the possibility of surgery prior to the initiation of rescue therapy. publishedVersion

Background: In patients with some cardiovascular disease conditions, slightly elevated body mass index (BMI) is associated with a lower mortality risk (termed “obesity paradox”). It is uncertain, however, if this obesity paradox exists in patients who have had invasive cardiology procedures. We evaluated the association between BMI and mortality in patients who underwent coronary angiography. Methods: We utilised the KARDIO registry, which comprised data on demographics, prevalent diseases, risk factors, coronary angiographies, and interventions on 42,636 patients. BMI was categorised based on WHO cut-offs or transformed using P-splines. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for all-cause mortality. Results: During a median follow-up of 4.9 years, 4688 all-cause deaths occurred. BMI was nonlinearly associated with mortality risk: compared to normal weight category (18.5–25 kg/m2), the age-adjusted HRs (95% CIs) for all-cause mortality were 1.90 (1.49, 2.43), 0.96 (0.92, 1.01), 1.04 (0.99, 1.09), 1.08 (0.96, 1.20), and 1.45 (1.22, 1.72) for underweight (40 kg/m2), respectively. The corresponding multivariable adjusted HRs (95% CIs) were 2.00 (1.55, 2.58), 0.92 (0.88, 0.97) 1.01 (0.95, 1.06), 1.10 (0.98, 1.23), and 1.49 (1.26, 1,78), respectively. Conclusions: In patients undergoing coronary angiography, underweight and obesity class III are associated with increased mortality risk, and the lowest mortality was observed in the preobesity class. It appears the obesity paradox may be present in patients who undergo invasive coronary procedures. publishedVersion

Background: Celiac disease has been associated with increased mortality, but data on long-term mortality are scarce. Aims: To determine long-term mortality in celiac disease. Methods: The study cohort consisted of all celiac disease patients (n=1,392) diagnosed in Tampere University Hospital catchment area 1960 – 2000. Patients were categorized into subgroups based on demographic (age, gender, decade of diagnosis) and celiac disease characteristics (e.g., phenotype, severity of villous atrophy) collected from medical records. Overall and cause-specific mortality was compared to those of age-, sex-, and place of residence matched reference individuals (n=4,177) over time. Results: During the 41 years of follow-up (median 26.5 years), 376 celiac disease patients and 1,155 reference individuals died. All-cause mortality was not increased (hazard ratio (HR) 0.96, 95% confidence intervals (CI) 0.85–1.08). Mortality from lymphoproliferative diseases and diseases of the central nervous system was increased (HR 2.42, 95% CI 1.38–4.24 and HR 2.14, 95% CI 1.05–4.36 respectively) while the risk from alcohol related diseases was decreased (HR 0.31, 95% CI 0.09–1.00). Examination of various celiac disease phenotypes revealed no significant differences in mortality Conclusions: Overall mortality was not increased in any celiac disease phenotype during a very long-term follow-up. publishedVersion

Background: Even though surgery generally improves sexual function and alleviates dyspareunia related to pelvic organ prolapse (POP), knowledge of the long-term effects is scarce. Objective: To describe changes in sexual activity and dyspareunia rates after POP surgery and to identify potential risk factors for the occurrence of dyspareunia. Design, setting, and participants: This was a prospective longitudinal cohort study of women aged over 18 yr undergoing POP surgery in Finland during 2015. Out of 3515 participants, sexual activity and dyspareunia data were available at baseline, 6 mo, 2 yr, and 5 yr for 79%, 68%, 63%, and 57%, respectively. Intervention: Native tissue, transvaginal mesh, and abdominal mesh repair. Outcome measurements and statistical analysis: Rates of sexual activity and dyspareunia were assessed using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) at baseline and at 6 mo, 2 yr, and 5 yr after surgery. As a secondary outcome, risk factors for overall, persisting, and de novo dyspareunia were assessed using logistic regression models. Results and limitations: The proportion of sexually active women increased from 40.7% to 43% after surgery. Preoperative dyspareunia resolved in >50% of cases during the first 6 mo, irrespective of the surgical approach. De novo dyspareunia rates were low at all time points (1.9–3.1%). Several potential risk factors associated with preoperative and postoperative dyspareunia were identified: younger age, lower preoperative body mass index, lower prolapse stage at baseline, either pelvic pain or dyspareunia at baseline, prior surgery (stress urinary incontinence surgery, posterior colporrhaphy, POP surgery, hysterectomy), and posterior repair. Conclusions: Dyspareunia is significantly reduced after POP repair irrespective of the surgical approach. However, multiple factors seem to be associated with persisting and de novo symptoms, which should be considered in preoperative counseling. Patient summary: Our 5-year follow-up study demonstrates that surgery to repair pelvic organ prolapse (POP) in women improves sexual activity and reduces painful intercourse. Multiple factors, such as preoperative pain, previous POP surgery, and prolapse stage, may be associated with painful intercourse after surgery. publishedVersion

Introduction: The electrocardiographic interpretation of end conduction delay (ECD) in the right ventricular branch of the heart has already generated some hypotheses that this right branch is not single, as anatomically demonstrated, and can be divided into distinct terminal branches when we analyze tracings through the vectorcardiogram. Methods: There were 227 electrocardiograms selected, with typical characteristics defined as ECD of patients from the electrocardiography service of the Centro Universitário Saúde ABC, of both sexes, in the age range of 18 to 87 years, with varied ethnicities, weight and height, with cardiovascular risk factors or without them. We performed vectorcardiograms in these patients to observe the behavior of the final portion of electrical conduction. Results: Analyzing the vectorcardiographic tracings of patients who presented ECD in electrocardiogram, we confirmed in the recording by the frontal plane, the presence of ECD but recorded in three distinct regions; 103 patients in the right upper quadrant between -120° and -150°, 45 patients in the right lower quadrant between +170° and -170°, and medial, and 79 patients in the right lower quadrant between +110° and + 140°. Conclusion: Electrical depolarization of the heart in the right ventricle in electrocardiographic tracings apparently records typical alterations that we can diagnose as depolarization of a single bundle; but when we performed vectorcardiograms, we recorded three distinct zones of right ventricular depolarization with delay; i.e., three distinct sectors of right ventricle free wall delay, such as type I (upper), type II (lower) and type III (medial). publishedVersion

Background: Hyperuricemia may predispose to renal damage, but in end-stage renal disease lower uric acid concentrations have been associated with higher mortality. In experimental studies, uric acid has promoted renal fibrosis and inflammation, but some studies have shown nephroprotective effects probably due to alleviated oxidative stress. We studied the influence of moderate hyperuricemia on kidney morphology in 5/6 nephrectomized rats.Methods: Three weeks after subtotal nephrectomy or sham-operation, rats were put on 2.0% oxonic acid (uricase inhibitor) diet for 9 weeks. Blood pressure was monitored using tail-cuff. At close of the study, blood, urine, and kidney samples were taken, and renal histology, mast cell count, and oxidative stress markers were determined. Kidney tissue inflammation and fibrosis were evaluated using RT‑PCR and immunohistochemistry.Results: Oxonic acid diet increased plasma uric acid levels by >80 µmol/l without influencing blood pressure. Creatinine clearance was reduced by ~60% in both remnant kidney groups, and by ~30% in hyperuricemic sham-operated rats. In remnant kidney rats with suppressed plasma renin activity, moderate hyperuricemia decreased glomerulosclerosis, tubulointerstitial damage, and kidney mast cell count, but did not influence the fibrosis marker collagen I mRNA content. In both hyperuricemic groups, the mast-cell product 11-epi-prostaglandin-F2α excretion to the urine and kidney tissue COX‑2 levels were decreased.Conclusions: Hyperuricemic remnant kidney rats displayed improved kidney morphology and reduced markers of oxidative stress and inflammation. Thus, moderately increased plasma uric acid had beneficial effects on the kidney in this low-renin model of experimental chronic renal insufficiency.

Background: Cardiac sarcoidosis (CS) predisposes to sudden cardiac death (SCD). Guidelines for implantable cardioverter defibrillators (ICDs) in CS have been issued by the Heart Rhythm Society in 2014 and the American College of Cardiology/American Heart Association/Heart Rhythm Society consortium in 2017. How well they discriminate high from low risk remains unknown. Methods: We analyzed the data of 398 patients with CS detected in Finland from 1988 through 2017. All had clinical cardiac manifestations. Histological diagnosis was myocardial in 193 patients (definite CS) and extracardiac in 205 (probable CS). Patients with and without Class I or IIa ICD indications at presentation were identified, and subsequent occurrences of SCD (fatal or aborted) and sustained ventricular tachycardia were recorded, as were ICD indications emerging first on follow-up. Results: Over a median of 4.8 years, 41 patients (10.3%) had fatal (n=8) or aborted (n=33) SCD, and 98 (24.6%) experienced SCD or sustained ventricular tachycardia as the first event. By the Heart Rhythm Society guideline, Class I or IIa ICD indications were present in 339 patients (85%) and absent in 59 (15%), of whom 264 (78%) and 30 (51%), respectively, received an ICD. Cumulative 5-year incidence of SCD was 10.7% (95% CI, 7.4%–15.4%) in patients with ICD indications versus 4.8% (95% CI, 1.2%–19.1%) in those without (χ 2 =1.834, P =0.176). The corresponding rates of SCD were 13.8% (95% CI, 9.1%–21.0%) versus 6.3% (95% CI, 0.7%–54.0%; χ 2 =0.814, P =0.367) in definite CS and 7.6% (95% CI, 3.8%–15.1%) versus 3.3% (95% CI, 0.5%–22.9%; χ 2 =0.680, P =0.410) in probable CS. In multivariable regression analysis, SCD was predicted by definite histological diagnosis ( P =0.033) but not by Class I or IIa ICD indications ( P =0.210). In patients without ICD indications at presentation, 5-year incidence of SCD, sustained ventricular tachycardia, and emerging Class I or IIa indications was 53% (95% CI, 40%–71%). By the American College of Cardiology/American Heart Association/Heart Rhythm Society guideline, all patients with complete data (n=245) had Class I or IIa indications for ICD implantation. Conclusions: Current ICD guidelines fail to distinguish a truly low-risk group of patients with clinically manifest CS, the 5-year risk of SCD approaching 5% despite absent ICD indications. Further research is needed on prognostic factors, including the role of diagnostic histology. Meanwhile, all patients with CS presenting with clinical cardiac manifestations should be considered for an ICD implantation.

BACKGROUND: Cephalosporins are recommended as first-line antibiotic prophylaxis in total joint replacement surgery. Studies have shown an increased risk for periprosthetic joint infection (PJI) when non-cephalosporin antibiotics have been used. This study examines the effect of non-cephalosporin antibiotic prophylaxis on the risk for PJI. METHODS: Patients with a primary hip or knee replacement performed from 2012 to 2020 were identified (27 220 joint replacements). The primary outcome was the occurrence of a PJI in a one-year follow-up. The association between perioperative antibiotic prophylaxis and the outcome was examined using logistic regression analysis. DISCUSSION: Cefuroxime was used as prophylaxis in 26,467 operations (97.2%), clindamycin in 654 (2.4%) and vancomycin in 72 (0.3%). The incidence of PJI was 0.86% (228/26,467) with cefuroxime and 0.80% (6/753) with other prophylactic antibiotics. There was no difference in the risk for PJI with different prophylactic antibiotics in the univariate (OR 1.06, 95% CI 0.47-2.39) or multivariable analysis (OR 1.02, 95% CI 0.45-2.30). CONCLUSION: Non-cephalosporin antibiotic prophylaxis in primary total joint replacement surgery was not associated with an increased risk for PJI. publishedVersion

Objectives: The authors aimed to investigate the impact of severe bleeding and use of red blood cell (RBC) transfusion on the development of postoperative stroke after surgical (SAVR) and transcatheter aortic valve replacement (TAVR), taken from the FinnValve registry. Design: Nationwide, retrospective observational study. Setting: Five Finnish university hospitals participated in the registry. Participants: A total of 6,463 patients who underwent SAVR (n = 4,333) or TAVR (n = 2,130). Interventions: Patients who underwent TAVR or SAVR with a bioprosthesis with or without coronary revascularization. Measurements and Main Results: The incidence of postoperative stroke after SAVR was 3.8%. In multivariate analysis, the number of trans-fused RBC units (odds ratio [OR], 1.098; 95% confidence interval [CI], 1.064-1.133) was one of the independent predictors of postoperative stroke. The incidence of stroke increased, along with the severity of perioperative bleeding, according to the European Coronary Artery Bypass Grafting (E-CABG) bleeding grades were as follows: grade 0, 2.2% (reference group); grade 1, 3.4% (adjusted OR, 1.841; 95% CI, 1.105-3.066); grade 2, 5.5% (adjusted OR, 3.282; 95% CI, 1.948-5.529); and grade 3, 14.8% (adjusted OR, 7.103; 95% CI, 3.612-13.966). The inci-dence of postoperative stroke after TAVR was 2.5%. The number of transfused RBC units was an independent predictor of stroke after TAVR (adjusted OR, 1.155; 95% CI, 1.058-1.261). The incidence of postoperative stroke increased, along with the severity of perioperative bleeding, as stratified by the E-CABG bleeding grades: E-CABG grade 0, 1.7%; grade 1, 5.3% (adjusted OR, 1.270; 95% CI, 0.532-3.035); grade 2, 10.0% (adjusted OR, 2.898; 95% CI, 1.101-7.627); and grade 3, 30.0% (adjusted OR, 10.706; 95% CI, 2.389-47.987). Conclusions: Perioperative bleeding requiring RBC transfusion and/or reoperation for intrathoracic bleeding is associated with an increased risk of postoperative stroke after SAVR and TAVR. Patient blood management and meticulous preprocedural planning and operative technique aiming to avoid significant perioperative bleeding may reduce the risk of cerebrovascular complications. (C) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The emotional outcomes of leisure time physical activity have previously been explored in laboratory experiments. To increase understanding of lived experiences, this paper explores the phenomenon through a qualitative lens, exploring real-life stories of how individuals experience emotions when engaging in leisure time physical activity. To illustrate our findings, we present six vignettes reflecting different activity patterns at work and at leisure. Whereas previous research largely focuses on positive emotional outcomes, our findings indicate that both sedentary and physically active adults experience both positive and negative physical activity-induced emotions during leisure. In addition, while previous research has highlighted the calming effect of the socio-spatial activity environment, particularly green spaces, our findings indicate that socio-emotional outcomes may be a key motivator for leisure time physical activity. These findings have significant implications for our understanding of the complexity of physical activity-induced emotions, influencing also physical activity promotion and servicescapes. publishedVersion

Background: Obesity is a heritable complex phenotype that can increase the risk of age-related outcomes. Biological age can be estimated from DNA methylation (DNAm) using various “epigenetic clocks.” Previous work suggests individuals with elevated weight also display accelerated aging, but results vary by epigenetic clock and population. Here, we utilize the new epigenetic clock GrimAge, which closely correlates with mortality. Objectives: We aimed to assess the cross-sectional association of body mass index (BMI) with age acceleration in twins to limit confounding by genetics and shared environment. Methods and results: Participants were from the Finnish Twin Cohort (FTC; n = 1424), including monozygotic (MZ) and dizygotic (DZ) twin pairs, and DNAm was measured using the Illumina 450K array. Multivariate linear mixed effects models including MZ and DZ twins showed an accelerated epigenetic age of 1.02 months (p-value = 6.1 × 10–12) per one-unit BMI increase. Additionally, heavier twins in a BMI-discordant MZ twin pair (ΔBMI >3 kg/m2) had an epigenetic age 5.2 months older than their lighter cotwin (p-value = 0.0074). We also found a positive association between log (homeostatic model assessment of insulin resistance) and age acceleration, confirmed by a meta-analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p-value = 4.1 × 10–25) from adjusted models. Conclusion: We identified significant associations of BMI and insulin resistance with age acceleration based on GrimAge, which were not due to genetic effects on BMI and aging. Overall, these results support a role of BMI in aging, potentially in part due to the effects of insulin resistance. publishedVersion

Introduction: There are several potential causes of QRS-axis deviation in the ECG, but there is limited data on the prognostic significance of QRS-axis deviation in ACS patients. Subjects and methods: We evaluated the long-term prognostic significance of acute phase frontal plane QRS-axis deviation and its shift during hospital stay in ACS patients. A total of 1026 patients who met the inclusion criteria were divided into three categories: normal (n = 823), left (n = 166) and right/extreme axis (n = 37). Results: The median survival time was 9.0 years (95% CI 7.9—10.0) in the normal, 3.6 years (95% CI 2.4—4.7) in the left and 1.3 years (95% CI 0.2—2.4) in the right/extreme axis category. Both short and long-term all-cause mortality was lowest in the normal axis category and highest in the right/extreme axis category. Compared to normal axis, both admission phase QRS-axis deviation groups were independently associated with a higher risk of all-cause mortality. When including left ventricular hypertrophy in the ECG, only the right/extreme axis retained its statistical significance (aHR 1.76; 95% CI 1.16—2.66, p = 0.007). Axis shift to another axis category had no effect on mortality. Conclusion: In ACS patients, acute phase QRS-axis deviation was associated with higher risk of all-cause mortality. Among the axis deviation groups, right/extreme QRS-axis deviation was the strongest predictor of mortality in the multivariable analysis. Further studies are required to investigate to what extent this association is caused by pre-existing or by ACS-induced axis deviations. QRS-axis shift during hospital stay had no effect on all-cause mortality. publishedVersion

Brugada syndrome (BrS) is an inherited clinicalelectrocardiographic arrhythmic entity with an autosomal dominant genetic pattern of inheritance or de novo variant. The syndrome has low worldwide prevalence, but is endemic in Southeast Asian countries (Thailand, Philippines and Japan). The BrS is a subtle structural heart disease (SHD), and the diagnosis is only possible when the so-called type 1 Brugada ECG pattern is spontaneously present or induced for example with fever. Repolarization-depolarization disturbances in BrS patients can be caused by genetic mutations, abnormal neural crest cell migration, low expression of connexin-43 gap junction protein, or connexome disturbances. A recent autopsy study revealed increase in biventricular collagen with myocardial fibrosis when compared with control subjects although the main affected cardiac territory is the right ventricular outflow tract (RVOT). In this location, there is abnormally low expression of significant connexin-43 gap junction responsible for the electro-vectorcardiographic manifestations of terminal QRS conduction delay in the right standard precordial leads (V1-V2), high right precordial leads (V1H-V2H), as well as in the unipolar aVR lead (“the forgotten lead”). Based on their location, these leads reflect the electrical activity of the RVOT. publishedVersion

Background: An increased risk of kidney disease in patients with celiac disease has been reported, but the association has remained obscure. Only few studies have investigated the association between renal comorbidities and dermatitis herpetiformis, a cutaneous manifestation of celiac disease. Objectives: We investigated whether patients with different phenotypes of celiac disease are at higher risk of kidney diseases than age- and sex-matched references. Methods: The diagnoses of glomerulonephritis, diabetic nephropathy, interstitial nephritis, and end-stage renal disease obtained from the National Hospital Discharge Register between 1970 and 2015 were identified in celiac disease (Marsh III, n = 1072) and dermatitis herpetiformis (n = 368) patients diagnosed at Tampere University Hospital catchment region and in 4296 reference subjects. Using the Cox proportional hazards model, we compared the risk of kidney diseases between patients and references. The study protocol was approved by the Regional Ethics Committee of Tampere University Hospital (R16090). As the study was register based, no consent from patients was required. Results: Even after adjusting for type 1 diabetes, celiac disease was associated with an elevated risk of kidney disease (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.12–3.03), glomerulonephritis (HR 3.37, 95% CI 1.64–6.95), and IgA nephropathy (IgAN) (HR 18.98, 95% CI 2.29–157.63). No similarly elevated risk was found among dermatitis herpetiformis patients (HR 1.50, 95% CI 0.63–3.55; HR 2.21, 95% CI 0.77–6.38; and HR 5.87, 95% CI 0.53–64.79, respectively). Conclusion: Celiac disease patients were at increased risk of kidney diseases, notably IgAN. The risk was dependent on the celiac disease phenotype and was not seen in patients with dermatitis herpetiformis. Awareness of possible renal manifestations is recommended when treating celiac disease patients. publishedVersion

Objectives. Quality of life (QoL) is possibly the most important variable for the patient when subjective results of heart procedures are evaluated. The purpose of this study was to analyze the change in the quality of life 1 year after surgical aortic valve replacement (SAVR). Design. A Finnish single-center prospective cohort intervention study was performed from 2013 to 2018. QoL was assessed with the EQ-5D-3L VAS questionnaire before surgery and 6 and 12 months after surgery. We used univariate analysis to assess the change in the number of people experiencing problems and logistic regression analysis to assess the patients’ characteristics on the change in QoL. Results. At one year follow-up, patients’ quality of life improved in all EQ-5D dimensions. The greatest decreases in patients experiencing problems 12 months after surgery occurred in the dimension “mobility” (–24.1% change in reporting problems, p

Background Surgical gastrojejunostomy has traditionally been the palliative treatment of choice for patients with advanced malignancies and gastric outlet obstruction syndrome. Recently, palliative endoscopic duodenal stenting has increased in popularity. We report outcomes after gastrojejunostomy and duodenal stenting when used for palliative indications. Methods Consecutive patients undergoing palliative gastrojejunostomy or palliative endoscopic duodenal stenting in a Finnish tertiary referral center between January 2015 and December 2020 were included. The postoperative outcomes of these two palliative interventions were compared. The main outcome measures were mortality and morbidity, rate of reoperations, postoperative oral intake ability, and length of hospital stay. Results A total of 88 patients, 46 (52%) patients underwent palliative gastrojejunostomy and 42 (48%) duodenal stenting. All patients had malignant disease, most typically hepatopancreatic cancer. Nineteen (44%) patients in duodenal stenting group and 4 (8.7%) patients in gastrojejunostomy group required subsequent interventions due to persisting or progressing symptoms (p p p p Conclusions Patients undergoing endoscopic duodenal stenting are more able to initiate rapid oral intake and have shorter hospital stay. On the other hand, there are significantly more reoperations in stenting group. If the patient’s life expectancy is short, we recommend stenting, but for patients whose life expectancy is longer, gastrojejunostomy could be a better procedure, for the reasons mentioned above.

Objectives: The literature concerning the overall use of labor analgesia among women with trials of labor after cesarean section (TOLAC) is lacking. The primary aim of this study is to report the rate of different labor analgesia methods among women with TOLAC. The secondary aim was to compare the use of labor analgesia between women with the first TOLAC and control group consisting of nulliparous women. Study design. Data from the National Medical Birth Register was used to evaluate the usage of labor analgesia in TOLACs. The use of labor analgesia in the first TOLAC is compared to the pregnancies of nulliparous women. The analgesia methods were stratified into neuraxial analgesia, pudendal, paracervical, nitrous oxide, other medical, other non-medical, and no analgesia. These are analyzed as categorized dichotomy (yes or no) variables. Results: A total of 38 596 TOLACs as second pregnancy of the mother was found during our study period. The control group consisted of a total of 327 464 pregnancies of nulliparous women. Epidural analgesia (61.6% vs 67.1%), nitrous oxide (56.1% vs 62.0%), and non-medical analgesia (30.1% vs 35.0%) were less consumed among women with TOLAC. The rate of spinal analgesia was higher among women with TOLAC (10.1% vs 7.6%) when compared to the control group. However, when only vaginal deliveries were included, the rate of labor analgesia increased especially in the TOLAC group. Conclusions: The main finding of this study is that women with TOLAC had a generally lower rate of labor analgesia. However, the rate of spinal analgesia was higher among women with TOLAC when compared to the control group, however. The results of this study inform midwives, obstetricians, and anesthesiologists on current practices and how to improve the analgetic treatment in TOLAC. publishedVersion

Objectives: The Puumala virus (PUUV) is a hantavirus that causes hemorrhagic fever with renal syndrome. Studies showing an increased risk of lymphoid malignancies after hantavirus infection, together with the observation that PUUV infects B cells, motivated us to study the risk of lymphoid malignancies after PUUV infection. Methods: We linked data from the Finnish Cancer Registry and National Infectious Diseases Register for 2009-2019. We used a time-dependent Cox regression model to evaluate the hazard of the lymphoid malignancies grouped according to the HAEMACARE classification. Results: We identified 68 cases of lymphoid malignancies after PUUV infection among 16,075 PUUV-infected individuals during 61,114,826 person-years of observation. A total of 10 cases occurred within 3

Adherence to inhaled corticosteroids (ICS) has been described as poor. In adherence studies, if the actual prescribed dosing is not available, generic defined daily doses (DDD) are applied instead when assessing adherence. We evaluated asthma patients’ adherence in a large prospective follow-up survey. We also analysed whether World Health Organization (WHO) and Global Initiative for Asthma (GINA) reference doses give different results. The current study was cross-sectional and included respondents attending to HeSSup follow-up questionnaire in 2012. Altogether 1,141 of 12,854 adult participants answered positively to the question about having asthma. According to the Finnish Social Insurance Institutions’ medication register, 686 of them had purchased ICS medication during 2011. DDDs for ICS by WHO as well as medium doses from GINA report were used as reference doses to evaluate adherence. To estimate adherence to ICS, the proportion of days covered (PDC) over one year was calculated for every patient. If the lower limit of GINA medium ICS dose was used as a reference, 65% of the patients were adherent (PDC ≥ 80%). Use of WHO’s DDD as reference halved the proportion of adherent patients. Adherence was higher among those using a combination inhaler of corticosteroid and long-acting β2-agonist compared to those using steroid only inhalers. Use of WHO’s daily defined doses as reference values may lead to underestimation of adherence to inhaled corticosteroids. Thus, attention should be paid when choosing the reference doses for the evaluation of adherence to inhaled corticosteroids in asthma. publishedVersion

Introduction Pharmacological thromboprophylaxis effectively prevents venous thromboembolism (VTE) after total knee (TKA) and total hip arthroplasty (THA). Less is known about the influence of fast-track arthroplasty on VTE risk. We conducted a register-based study to determine the incidence of VTE after fast-track TKA and THA in Finland using long thromboprophylaxis. Materials and methods All primary TKAs and THAs operated during 2015–2016 in 3 fast-track hospitals were identified from the Finnish Arthroplasty Register. Pulmonary embolism (PE) and deep vein thrombosis (DVT) diagnosed in this patient cohort within 90 days of surgery were identified from the Finnish Hospital Discharge Register. The recommended length of thromboprophylaxis was 10 to 14 days for TKA and 28 days for THA during study period. Results During the study period, 3 831 THAs, 4 394 TKAs and 286 bilateral TKAs (BTKAs) were performed. Of all these patients, 60% were females. Venous thromboembolism (VTE) incidence within 90 days of surgery was 0.3% (95% CI 0.2–0.4). These VTEs comprised 10 PEs and 15 DVTs. None of the VTE patients´ died within the 90-day period. Conclusion VTE incidence is low in Finnish fast-track TKA and THA patients with long thromboprophylaxis.

Background The ten-joint juvenile arthritis disease activity score (JADAS10) is designed to measure the level of disease activity in non-systemic juvenile idiopathic arthritis by providing a single numeric score. The clinical JADAS10 (cJADAS10) is a modification of the JADAS10 that excludes erythrocyte sedimentation rate (ESR). Three different sets of JADAS10/cJADAS10 cut-offs for disease activity states have been published, i.e., the Backström, Consolaro, and Trincianti cut-offs. The objective of this study was to investigate the performance of existing JADAS10 cut-offs in real-life settings using patient data from The Finnish Rheumatology Quality Register (FinRheuma). Methods Data were collected from the FinRheuma register. The proportion of patients with an active joint count (AJC) above zero when classified as being in clinically inactive disease (CID) or low disease activity (LDA) groups according to existing JADAS10/cJADAS10 cut-off levels were analyzed. Results A significantly larger proportion of the patients classified as being in CID had an AJC > 0 when using the JADAS10/cJADAS10 cut-offs by Trincianti et al. compared to those for the other cut-offs. In the LDA group, a significantly larger proportion of the polyarticular patients (35%/29%) had an AJC of two when Trincianti JADAS10/cJADAS10 cut-offs were used compared with when Backström (11%/10%) and Consolaro (7%/3%) JADAS10/cJADAS10 cut-offs were used. Conclusions We found the cut-offs proposed by Consolaro et al. to be the most feasible, since these cut-off levels for CID do not result in the misclassification of active disease as remission, and the proportion of patients with AJC > 1 in the LDA group is lowest using these cut-offs.

Background We characterized the relation of primary treatment approaches to the need of later surgical interventions and the outcomes of patellar dislocation in patients with patellofemoral osteochondral fracture (OCF). Methods Overall, 134 patients with OCF were categorized in two groups according to treatment approach: primary surgery (operation within 90 days from injury) and conservative treatment. Data on surgical procedures, OCF characteristics, and patellofemoral anatomy were retrospectively collected. To measure subjective outcomes, 54 patients completed the knee-specific patient-reported outcome measures (PROMs) Kujala score, Tegner activity scale, the knee injury and osteoarthritis outcome score (KOOS) quality of life (QoL) subscale, and visual analog scale pain items. Results The mean follow-up time was 4.9 years [standard deviation (SD) 2.7 years]. The primary treatment approach was surgery in 73 patients (54%) and conservative in 61 patients (46%) of whim 18 (30%) needed late surgery. Of primary surgery patients, the OCF was reimplanted in 45 patients (62%) and removed in the rest. Of all patients, 31 needed surgery in the later phase after the primary treatment approach (either reoperation or surgery after insufficient outcome of conservative treatment). In conservatively treated patients, OCF was smaller and patellofemoral joint malformation was more severe than in surgery group. Among patients who completed the PROMs, the outcomes appeared generally acceptable in both groups. Conclusions Although a majority of the primary treatment approaches for OCF after patellar dislocation were definitive, one-fourth of patients required surgery in the later phase. PROMs did not indicate major differences between the study groups.

Electronic health services (eHealth) have increased rapidly in the last few years. These services hold the potential to facilitate today’s challenging primary care. The aim of the study was to examine how digitalisation manifests in Finnish health centres in 2021. We aimed to find out which digital tools are used in health centres and how they are exploited. In addition, we were interested in general practitioners’ attitudes towards digitalisation in their everyday work. An online survey was distributed to general practitioners (GPs) working in primary health care centres throughout Finland, and 265 GPs replied. A health portal and various digital calculators were used daily. In remote communication with their patients, general practitioners preferred telephone calls over new tools (chat/video). Attitudes towards eHealth were positive, but digital tools were not yet commonly used. The implementation of digital solutions still needs more effort. publishedVersion

Maternal malaria and infections during pregnancy are risk factors for fetal growth restriction. We assessed the impact of preventive treatment in pregnancy on maternal malaria and fetal growth. Between 2003 and 2006, we enrolled 1,320 pregnant Malawian women, 14–26 gestation weeks, in a randomized trial and treated them with two doses of sulfadoxine-pyrimethamine (SP, control) at enrollment and between 28–34 gestation weeks; with monthly SP from enrollment until 37 gestation weeks; or with monthly SP and azithromycin twice, at enrollment and between 28 and 34 gestation weeks (AZI-SP). Participants were seen at 4-week intervals until 36 completed gestation weeks and weekly thereafter. At each visit, we collected dried blood spots for real-time polymerase chain reaction diagnosing of malaria parasitemia and, in a random subgroup of 341 women, we measured fetal biparietal diameter and femur length with ultrasound. For the monthly SP versus the control group, the odds ratios (OR) (95% CI) of malaria parasitemia during the second, third, and both trimesters combined were 0.79 (0.46–1.37), 0.58 (0.37–0.92), and 0.64 (0.42–0.98), respectively. The corresponding ORs for the AZI-SP versus control group were 0.47 (0.26–0.84), 0.51 (0.32–0.81), and 0.50 (0.32–0.76), respectively. Differences between the AZI-SP and the monthly SP groups were not statistically significant. The interventions did not affect fetal biparietal diameter and femur length growth velocity. The results suggest that preventive maternal treatment with monthly SP reduced malaria parasitemia during pregnancy in Malawi and that the addition of azithromycin did not provide much additional antimalarial effect.

Background Childhood exposure to dyslipidemia is associated with adult atherosclerosis, but it is unclear whether the long‐term risk associated with dyslipidemia is attenuated on its resolution by adulthood. We aimed to address this question by examining the links between childhood and adult dyslipidemia on carotid atherosclerotic plaques in adulthood. Methods and Results The Cardiovascular Risk in Young Finns Study is a prospective follow‐up of children that began in 1980. Since then, follow‐up studies have been conducted regularly. In 2001 and 2007, carotid ultrasounds were performed on 2643 participants at the mean age of 36 years to identify carotid plaques and plaque areas. For childhood lipids, we exploited several risk factor measurements to determine the individual cumulative burden for each lipid during childhood. Participants were categorized into the following 4 groups based on their childhood and adult dyslipidemia status: no dyslipidemia (reference), incident, resolved, and persistent. Among individuals with carotid plaque, linear regression models were used to study the association of serum lipids with plaque area. The prevalence of plaque was 3.3% (N=88). In models adjusted for age, sex, and nonlipid cardiovascular risk factors, the relative risk for carotid plaque was 2.34 (95% CI, 0.91–6.00) for incident adult dyslipidemia, 3.00 (95% CI, 1.42–6.34) for dyslipidemia resolved by adulthood, and 5.23 (95% CI, 2.57–10.66) for persistent dyslipidemia. Carotid plaque area correlated with childhood total, low‐density lipoprotein, and non–high‐density lipoprotein cholesterol levels. Conclusions Childhood dyslipidemia, even if resolved by adulthood, is a risk factor for adult carotid plaque. Furthermore, among individuals with carotid plaque, childhood lipids associate with plaque size. These findings highlight the importance of primordial prevention of dyslipidemia in childhood to reduce atherosclerosis development.

Serum carcinoembryonic antigen (CEA) is frequently monitored to detect colorectal cancer (CRC) recurrence after surgery. The clinical significance of transiently increased CEA during adjuvant chemotherapy is poorly understood. Serum CEA, CA19-9, CRP, YKL-40, and IL-6 were measured before, during, and after adjuvant 5-fluorouracil-based chemotherapy in the randomised LIPSYT study population. The biomarker kinetic patterns were classified into three groups: no increase, a transient increase (≥10% increase followed by a decrease), and a persistent increase during the adjuvant treatment, and the associations of these patterns with disease free-survival (DFS) and overall survival (OS) were investigated by using Cox regression analyses. The findings were validated in two single-centre cohorts that received modern adjuvant chemotherapy. A transient increase in CEA occurred in about a half of the patients during chemotherapy, in all the cohorts. The patients with a transient increase had a roughly similar DFS and OS to the patients with no increase, and a more favourable survival compared to the patients with a persistent increase. In the LIPSYT cohort, the hazard ratio was 0.21 for DFS (CI95% 0.07–0.66) and 0.24 for OS (CI95% 0.08–0.76). Transient increases in CA19-9 and YKL-40 tended to be associated with a favourable survival. A transient increase in CEA during adjuvant chemotherapy is associated with a favourable survival when compared with a persistent increase. publishedVersion

Background Effects of antibiotics on gut bacteria have been widely studied, but very little is known about the consequences of such treatments on the fungal microbiota (mycobiota). It is commonly believed that fungal load increases in the gastrointestinal tract following antibiotic treatment, but better characterization is clearly needed of how antibiotics directly or indirectly affect the mycobiota and thus the entire microbiota. Design We used samples from humans (infant cohort) and mice (conventional and human microbiota-associated mice) to study the consequences of antibiotic treatment (amoxicillin-clavulanic acid) on the intestinal microbiota. Bacterial and fungal communities were subjected to qPCR or 16S and ITS2 amplicon-based sequencing for microbiota analysis. In vitro assays further characterized bacterial-fungal interactions, with mixed cultures between specific bacteria and fungi. Results Amoxicillin-clavulanic acid treatment triggered a decrease in the total fungal population in mouse feces, while other antibiotics had opposite effects on the fungal load. This decrease is accompanied by a total remodelling of the fungal population with the enrichment in Aspergillus, Cladosporium, and Valsa genera. In the presence of amoxicillin-clavulanic acid, microbiota analysis showed a remodeling of bacterial microbiota with an increase in specific bacteria belonging to the Enterobacteriaceae. Using in vitro assays, we isolated different Enterobacteriaceae species and explored their effect on different fungal strains. We showed that Enterobacter hormaechei was able to reduce the fungal population in vitro and in vivo through yet unknown mechanisms. Conclusions Bacteria and fungi have strong interactions within the microbiota; hence, the perturbation initiated by an antibiotic treatment targeting the bacterial community can have complex consequences and can induce opposite alterations of the mycobiota. Interestingly, amoxicillin-clavulanic acid treatment has a deleterious effect on the fungal community, which may have been partially due to the overgrowth of specific bacterial strains with inhibiting or competing effects on fungi. This study provides new insights into the interactions between fungi and bacteria of the intestinal microbiota and might offer new strategies to modulate gut microbiota equilibrium.

Background: Poor medication management may negatively impact the health and functional capacity of older adults. This cross-sectional study aimed to identify medication-related risk factors in home-dwelling residents using a validated self-assessment as part of comprehensive health screening. Methods: The data were derived from comprehensive health screening (PORI75) for older adults of 75 years living in Western Finland in 2020 and 2021. One of 30 validated measures in health screening focused on identifying medication-related risk factors (LOTTA Checklist). The Checklist items were divided into (1) systemic risk factors (10 items) and (2) potentially drug-induced symptoms (10 items). Polypharmacy was categorized according to the number of used drugs: (1) no polypharmacy (5 drugs, that is, having polypharmacy. Of the systemic risk factors most common was that the resident had more than one physician responsible for the treatment (48% of the residents), followed by missing drug list (43%), missing regular monitoring (35%), and unclear durations of the medication (35%). The most experienced potentially drug-induced symptoms were self-reported constipation (21%), urinating problems (20%), and unusual tiredness (17%). An increasing number of drugs in use, particularly excessive polypharmacy, was associated with various medication-related risk factors. Conclusion: As a part of comprehensive health screening the LOTTA Checklist provides useful information to prevent medication-related risk factors in home-dwelling older adults. The Checklist could be used to guide planning and implementing health services in the future. publishedVersion

BackgroundPatients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life.MethodsThis was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions.ResultsIn the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p ConclusionsIn real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use. Background: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. Methods: This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions. Results: In the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p < 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs. 20.55% reduction; p = 0.023). There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). Conclusions: In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.

Background Etanercept (ETN) is widely used tumour necrosis factor (TNF) blocker in the treatment of juvenile idiopathic arthritis (JIA) when traditional synthetic disease modifying antirheumatic drug (sDMARD) therapy is not sufficient. There is limited information about the effects of methotrexate (MTX) on serum ETN concentration in children with JIA. We aimed to investigate whether ETN dose and concomitant MTX would effect ETN serum trough levels in JIA patients, and whether concomitant MTX have an influence on the clinical response in patients with JIA receiving ETN. Methods In this study, we collected the medical record data of 180 JIA patients from eight Finnish pediatric rheumatological centres. All these patients were treated with ETN monotherapy or combination therapy with DMARD. To evaluate the ETN concentrations, blood samples of the patients were collected between injections right before the subsequent drug. Free ETN level was measured from serum. Results Ninety-seven (54%) of the patients used concomitant MTX, and 83 (46%) received either ETN monotherapy or used sDMARDs other than MTX. A significant correlation was noted between ETN dose and drug level [r = 0.45 (95% CI: 0.33–0.56)]. The ETN dose and serum drug level were correlated (p = 0.030) in both subgroups – in MTX group [r = 0.35 (95% CI: 0.14–0.52)] and in non-MTX group [r = 0.54 (95% CI: 0.39–0.67)]. Conclusion In the present study, we found that concomitant MTX had no effect on serum ETN concentration or on clinical response. In addition, a significant correlation was detected between ETN dose and ETN concentration.

Background In recent years, biologic drug therapies have altered the course of juvenile idiopathic arthritis (JIA) possibly also improving the patients’ physical fitness. However, studies measuring both cardiorespiratory and muscular fitness in children with JIA are sparse and have failed to show consistent results. Our aim was to assess both cardiorespiratory and neuromuscular fitness and contributing factors in children and adolescents with JIA in the era of biologic drug therapies. Methods This cross-sectional study consisted of 73 JIA patients (25 boys, 48 girls) aged 6.8- 17.5 years and 73 healthy age- and sex-matched controls, investigated in 2017–2019. Cardiorespiratory fitness was assessed by maximal ergospirometry and neuromuscular fitness by speed, agility, balance, and muscle strength tests. Results Means (± SD) of maximal workload (Wmax/kg) and peak oxygen uptake (VO2peak/kg,) were lower in JIA patients than in controls (Wmax/kg: 2.80 ± 0.54 vs. 3.14 ± 0.50 Watts, p peak/kg: 38.7 ± 7.53 vs. 45.8 ± 6.59 ml/min/kg, p p p p Conclusions JIA patients were physically less active and had lower cardiorespiratory and neuromuscular fitness than their same aged controls with no JIA. Therefore, JIA patients should be encouraged to engage in physical activities as a part of their multidisciplinary treatment protocols to prevent adverse health risks of low physical activity and fitness.

Objective: To assess pain relief and overall birth experience in induced vs. spontaneous-onset labours and to clarify variables among induced parturients determining satisfaction and dissatisfaction. Study design: A prospective study of 2042 women. 575 women with induced and 1467 with spontaneous-onset labour answered multiple questions in a questionnaire regarding the experience of birth giving. Satisfaction was numerically assessed via a visual analogue scale (VAS 0–10). Results: Induction of labour (IOL) did not worsen the average experience of pain relief, but the proportion of women dissatisfied with pain relief was slightly higher after IOL compared with spontaneous-onset labour (SOL). IOL was associated with lower satisfaction with overall birth experience compared with SOL (VAS 8.0 vs. 8.4; p < 0.001). Among IOL parturients incorrect timing of pain relief was strongly associated with dissatisfaction with pain relief, as were deficient information and induction with misoprostol. Epidural blockade was the most important factor preventing dissatisfaction with pain relief. Unsatisfactory overall experience of birth was associated with deficient pain relief, its incorrect timing or deficient information, as well as vacuum extraction as the mode of delivery. Conclusions: Induction of labour is a risk factor of dissatisfaction regarding pain relief and overall birth experience. The strongest impact on dissatisfaction among induced parturients concerning pain relief was delayed timing of effective labour analgesia. Poor pain relief, its incorrect timing and deficient information on pain relief were strong predictive factors of dissatisfaction with the overall birth experience. publishedVersion

Background There are several national and international criteria available for identifying potentially inappropriate medications (PIMs) for older people. The prevalence of PIM use may vary depending on the criteria used. The aim is to examine the prevalence of potentially inappropriate medication use in Finland according to the Meds75+ database, developed to support clinical decision-making in Finland, and to compare it with eight other PIM criteria. Methods This nationwide register study consisted of Finnish people aged 75 years or older (n = 497,663) who during 2017–2019 purchased at least one prescribed medicine considered as a PIM, based on any of the included criteria. The data on purchased prescription medicines was collected from the Prescription Centre of Finland. Results The annual prevalence of 10.7–57.0% was observed for PIM use depending on which criteria was used. The highest prevalence was detected with the Beers and lowest with the Laroche criteria. According to the Meds75+ database, annually every third person had used PIMs. Regardless of the applied criteria, the prevalence of PIM use decreased during the follow-up. The differences in the prevalence of medicine classes of PIMs explain the variance of the overall prevalence between the criteria, but they identify the most commonly used PIMs quite similarly. Conclusion PIM use is common among older people in Finland according to the national Meds75+ database, but the prevalence is dependent on the applied criteria. The results indicate that different PIM criteria emphasize different medicine classes, and clinicians should consider this issue when applying PIM criteria in their daily practice.

With over 17 million annual deaths, cardiovascular diseases (CVDs) dominate the cause of death statistics. CVDs can deteriorate the quality of life drastically and even cause sudden death, all the while inducing massive healthcare costs. This work studied state-of-the-art deep learning techniques to predict increased risk of death in CVD patients, building on the electronic health records (EHR) of over 23,000 cardiac patients. Taking into account the usefulness of the prediction for chronic disease patients, a prediction period of six months was selected. Two major transformer models that rely on learning bidirectional dependencies in sequential data, BERT and XLNet, were trained and compared. To our knowledge, the presented work is the first to apply XLNet on EHR data to predict mortality. The patient histories were formulated as time series consisting of varying types of clinical events, thus enabling the model to learn increasingly complex temporal dependencies. BERT and XLNet achieved an average area under the receiver operating characteristic curve (AUC) of 75.5% and 76.0%, respectively. XLNet surpassed BERT in recall by 9.8%, suggesting that it captures more positive cases than BERT, which is the main focus of recent research on EHRs and transformers. publishedVersion

BACKGROUND: Prosthetic joint infection (PJI) is one of the most devastating complications after total hip arthroplasty (THA), and comorbidities increase the risk. We examined whether there was a temporal change in the demographics, especially regarding comorbidities, of patients who have PJIs and were treated over a 13-year study period at a high-volume academic joint arthroplasty center. In addition, the surgical methods used and the microbiology of the PJIs were assessed. METHODS: Revisions (n=423, 418 patients) due to PJI of the hip performed at our institution between 2008 and September 2021 were identified. All included PJIs fulfilled the 2013 International Consensus Meeting diagnostic criteria. The surgeries were categorized into one of the following categories: debridement, antibiotics, and implant retention, one-stage revision, and two-stage revision. Infections were classified as early, acute hematogenous and chronic infections. RESULTS: There was no change in the median age of the patients, but the proportion of ASA-class 4 patients increased from 10.5 to 20%. The incidence of early infections increased from 0.11 per 100 primary-THAs in 2008 to 1.09 in 2021. The incidence of one-stage revisions increased the most, rising from 0.10 per 100 primary-THAs in 2010 to 0.91 per 100 primary-THAs in 2021. Furthermore, the proportion of infections caused by Staphylococcus aureus increased from 26.3% in 2008 to 2009 to 40% in 2020 to 2021. CONCLUSIONS: The comorbidity burden of PJI patients increased during the study period. This increase may present a treatment challenge, as comorbidities are known to have a negative effect on PJI treatment outcomes. publishedVersion

Background Obesity-related hypertension and the associated metabolic abnormalities are considered as a distinct hypertensive phenotype. Here we examined how abdominal fat content, as judged by waist:height ratio, influenced blood pressure and hemodynamic profile in normotensive subjects and never-treated hypertensive patients. Methods The 541 participants (20–72 years) underwent physical examination and laboratory analyses and were divided into age and sex-adjusted quartiles of waist:height ratio. Supine hemodynamics were recorded using whole-body impedance cardiography, combined with analyses of radial tonometric pulse wave form and heart rate variability. Results Mean waist:height ratios in the quartiles were 0.46, 0.51, 0.55 and 0.62. Radial and aortic blood pressure, systemic vascular resistance, pulse wave velocity, markers of glucose and lipid metabolism, leptin levels and C-reactive protein were higher in quartile 4 when compared with quartiles 1 and 2 (p Conclusion Higher waist:height ratio was associated with elevated blood pressure, systemic vascular resistance, and arterial stiffness, but not with alterations in cardiac sympathovagal modulation or activation of the circulating renin-angiotensin-aldosterone system. Although obesity-related elevation of blood pressure has distinct phenotypic features, these results suggest that its main characteristics correspond those of primary hypertension. Trial registration ClinicalTrails.gov NCT01742702 (date of registration 5th December 2012).