Diagnostic Guidelines for Familial Hemophagocytic Lymphohistiocytosis Revisited.

Current HLH-2004-based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here we performed a case-control study to test and possibly improve these clinical criteria. We also developed two complementary expert opinion-based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (n=366) were children <16 years with verified familial and/or genetic FHL (n=341) or Griscelli syndrome type 2 (GS2) (n=25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329+361 children in two cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on the number of diagnostic criteria fulfilled from 17 variables studied, reveled almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%). Notably, assessment of the original HLH-2004 criteria revealed accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Since cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without NK-cell function was also studied which showed accuracy 99.0% (sensitivity 96.2%; specificity 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis.

Multisite assessment of reproducibility in high-content cell migration imaging data.

High-content image-based cell phenotyping provides fundamental insights into a broad variety of life science disciplines. Striving for accurate conclusions and meaningful impact demands high reproducibility standards, with particular relevance for high-quality open-access data sharing and meta-analysis. However, the sources and degree of biological and technical variability, and thus the reproducibility and usefulness of meta-analysis of results from live-cell microscopy, have not been systematically investigated. Here, using high-content data describing features of cell migration and morphology, we determine the sources of variability across different scales, including between laboratories, persons, experiments, technical repeats, cells, and time points. Significant technical variability occurred between laboratories and, to lesser extent, between persons, providing low value to direct meta-analysis on the data from different laboratories. However, batch effect removal markedly improved the possibility to combine image-based datasets of perturbation experiments. Thus, reproducible quantitative high-content cell image analysis of perturbation effects and meta-analysis depend on standardized procedures combined with batch correction.

Risk of Postoperative Ischemic Stroke and Myocardial Infarction in Patients Operated for Cancer.

BACKGROUND: Risk assessment for ischemic stroke (IS) and myocardial infarction (MI) is done routinely before surgery, but the increase in risks associated with surgery is not known. The aim of this study is to assess the risk of arterial ischemic events during the first year after oncological surgery. METHODS: We used Swedish healthcare databases to identify 443,300 patients who underwent cancer surgery between 1987 and 2016 and 4,127,761 matched comparison subjects. We estimated odds ratios (ORs) for myocardial infarction and ischemic stroke during the hospitalization with logistic regression and calculated 1-year cumulative incidences and hazard ratios (HRs) with 95% confidence intervals (CIs) for the outcomes after discharge. RESULTS: The cumulative incidences of myocardial infarction and ischemic stroke during the first postoperative year were 1.33% and 1.25%, respectively. In the comparison cohort, the corresponding 1-year cumulative incidences were 1.04% and 1.00%. During the hospitalization, the OR for myocardial infarction was 8.81 (95% CI 8.24-9.42) and the OR for ischemic stroke was 6.71 (95% CI 6.22-7.23). After discharge, the average HR during follow-up for 365 days was 0.90 (95% CI 0.87-0.93) for myocardial infarction and 1.02 (95% CI 0.99-1.05) for ischemic stroke. CONCLUSIONS: We found an overall increased risk of IS and MI during the first year after cancer surgery that was attributable to events occurring during the hospitalization period. After discharge from the hospital, the overall risk of myocardial infarction was lower among the cancer surgery patients than among matched comparison subjects.

Performance of the 2017 EULAR/ACR Classification Criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a scoping review.

The 2017 EULAR/ACR classification criteria for adult/juvenile idiopathic inflammatory myopathies (IIM) were established using a data-driven approach by an international group of myositis experts to allow classification of IIM and its major subtypes. Since their publication, the performance of the criteria has been tested in multiple cohorts worldwide and significant limitations have been identified. Moreover, the understanding and classification of IIM have evolved since 2017. This scoping review was undertaken as part of a large international project to revise the EULAR/ACR criteria and aims to i) summarise the evidence from the current literature on the performance characteristics of the 2017 EULAR/ACR classification criteria in various cohorts and IIM subtypes, and ii) delineate the factors that need to be considered in the revision of the classification criteria. A systematic search of Medline (via PubMed), Cumulative Index to Nursing and Allied Health Literature, and conference abstract archives was conducted independently by three investigators for studies on the EULAR/ACR criteria published between October 2017 and January 2023. This scoping review of 19 articles and 13 abstracts revealed overall good performance characteristics of the EULAR/ACR criteria for IIM, yet deficiencies in lack of inclusion of certain IIM subtypes, such as immune mediated necrotising myopathy, amyopathic dermatomyositis, antisynthetase syndrome and overlap myositis. Published modifications that may improve the performance characteristics of the criteria for classification of IIM subtypes were also summarised. The results of this review suggest that a revision of the EULAR/ACR criteria is warranted.

Plasticity of Individual Lung Function States from Childhood to Adulthood.

Rationale: Recent evidence highlights the importance of optimal lung development during childhood for health throughout life. Objectives: To explore the plasticity of individual lung function states during childhood. Methods: Prebronchodilator FEV1 z-scores determined at age 8, 16, and 24 years in the Swedish population-based birth cohort BAMSE (Swedish abbreviation for Child [Barn], Allergy, Milieu, Stockholm, Epidemiological study) (N = 3,069) were used. An unbiased, data-driven dependent mixture model was applied to explore lung function states and individual state chains. Lung function catch-up was defined as participants moving from low or very low states to normal or high or very high states, and growth failure as moving from normal or high or very high states to low or very low states. At 24 years, we compared respiratory symptoms, small airway function (multiple-breath washout), and circulating inflammatory protein levels, by using proteomics, across states. Models were replicated in the independent Dutch population-based PIAMA (Prevention and Incidence of Asthma and Mite Allergy) cohort. Measurements and Main Results: Five lung function states were identified in BAMSE. Lung function catch-up and growth failure were observed in 74 (14.5%) BAMSE participants with low or very low states and 36 (2.4%) participants with normal or high or very high states, respectively. The occurrence of catch-up and growth failure was replicated in PIAMA. Early-life risk factors were cumulatively associated with the very low state, as well as with catch-up (inverse association) and growth failure. The very low state as well as growth failure were associated with respiratory symptoms, airflow limitation, and small airway dysfunction at adulthood. Proteomics identified IL-6 and CXCL10 (C-X-C motif chemokine 10) as potential biomarkers of impaired lung function development. Conclusions: Individual lung function states during childhood are plastic, including catch-up and growth failure.

Alcohol as a risk factor for mortality in liver transplant patients in Sweden.

OBJECTIVES: Liver transplantation (LT) is the only available cure for end-stage liver disease and one of the best treatment options for hepatocellular carcinomas (HCC). Patients with known alcohol-associated cirrhosis (AC) are routinely assessed for alcohol dependence or abuse before LT. Patients with other liver diseases than AC may consume alcohol both before and after LT. The aim of this study was to assess the effects of alcohol drinking before and after LT on patient and graft survival regardless of the etiology of liver disease. MATERIALS AND METHODS: Between April 2012 and December 2015, 200 LT-recipients were interviewed using the Lifetime Drinking History and the Addiction Severity Index questionnaire. Patients were categorized as having AC, n = 24, HCC and/or hepatitis C cirrhosis (HCV), n = 69 or other liver diseases, n = 107. Patients were monitored and interviewed by transplantation-independent staff for two years after LT with questions regarding their alcohol consumption. Patient and graft survival data were retrieved in October 2019. RESULTS: Patients with AC had an increased hazard ratio (HR) for death after LT (crude HR: 4.05, 95% CI: 1.07-15.33, p = 0.04) and for graft loss adjusted for age and gender (adjusted HR: 3.24, 95% CI 1.08-9.77, p = 0.04) compared to the other patients in the cohort. There was no significant effect of the volume of alcohol consumed before or after LT on graft loss or overall survival. CONCLUSION: Patients transplanted for AC have a worse prognosis, but we found no correlation between alcohol consumed before or after LT and graft or patient survival.

The Stockholm Stroke Triage Project: Outcomes of Endovascular Thrombectomy Before and After Triage Implementation.

BACKGROUND AND PURPOSE: The Stockholm Stroke Triage System (SSTS) is a prehospital algorithm for detection of endovascular thrombectomy (EVT)-eligible patients, combining symptom severity assessment and ambulance-to-hospital teleconsultation, leading to a decision on primary stroke center bypass. In the Stockholm Region (6 primary stroke centers, 1 EVT center), SSTS implementation in October 2017 reduced onset-to-EVT time by 69 minutes. We compared clinical outcomes before and after implementation of SSTS in an observational study. METHODS: We prospectively recruited patients transported by Code Stroke ambulance within the Stockholm region under the SSTS, treated with EVT during October 2017 to October 2019, and compared to EVT patients from 2 previous years. OUTCOMES: shift in modified Rankin Scale (mRS) scores, mRS score 0 to 1, mRS score 0 to 2, and death (all 3 months), National Institutes of Health Stroke Scale (NIHSS) score change 24-hour post-EVT, recanalization (Thrombolysis in Cerebral Infarction 2b-3), and symptomatic intracranial hemorrhage. mRS outcomes were adjusted for age and baseline NIHSS. RESULTS: Patients with EVT in the SSTS group (n=244) were older and had higher baseline NIHSS versus historical controls (n=187): median age 74 (interquartile range, 63-81) versus 71 (61-78); NIHSS score 17 (11.5-21) versus 15 (10-20). During SSTS, median onset-to-puncture time was 136 versus 205 minutes (P<0.001). Adjusted common odds ratio for lower mRS in SSTS patients was 1.7 (95% CI, 1.2-2.3) versus controls. During SSTS, 83/240 (34.6%) versus 44/186 (23.7%) reached 3-month mRS score 0 to 1 (P=0.014), adjusted common odds ratio 2.3 (95% CI, 1.4-3.6). Median NIHSS change 24-hour post-EVT was 6 versus 4 (P=0.005). Differences in Thrombolysis in Cerebral Infarction, symptomatic intracranial hemorrhage, and death were nonsignificant. CONCLUSIONS: With an onset to arterial puncture time reduction by 69 minutes, outcomes in thrombectomy-treated patients improved significantly after region-wide large artery occlusion triage system implementation. These results warrant replication studies in other geographic and organizational circumstances.

Risk of primary liver cancer in acute hepatic porphyria patients: A matched cohort study of 1244 individuals.

BACKGROUND: The acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict PLC risk are unknown. In this register-based, matched cohort study, we assessed the PLC risk in relation to biochemical and clinical porphyria severity, genotype, age, and sex. METHODS: All patients in the Swedish porphyria register with acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) during 1987-2015 were included. This AHP cohort was compared with age-, sex-, and county-matched reference individuals from the general population. National register-based hospital admissions for AHP were used to indicate the clinical severity. For AIP, the most common AHP type, patients were stratified by genotype and urinary porphobilinogen (U-PBG). Incident PLC data were collected from national health registers. RESULTS: We identified 1244 individuals with AHP (1063 [85%] AIP). During a median follow-up of 19.5 years, we identified 108 incident PLC cases, including 83 AHP patients (6.7%) and 25 of 12,333 reference individuals (0.2%). The adjusted hazard ratio for AHP-PLC was 38.0 (95% confidence interval: 24.3-59.3). Previously elevated U-PBG and hospitalizations for porphyria, but not AIP genotype or sex, were associated with increased PLC risk. Patients aged >50 years with previously elevated U-PBG (n = 157) had an annual PLC incidence of 1.8%. CONCLUSION: This study confirmed a high PLC risk and identified a strong association with clinical and biochemical AIP activity. Regular PLC surveillance is motivated in patients older than 50 years with a history of active AIP.

Ambient air pollution and inflammation-related proteins during early childhood.

BACKGROUND AND AIM: Experimental studies show that short-term exposure to air pollution may alter cytokine concentrations. There is, however, a lack of epidemiological studies evaluating the association between long-term air pollution exposure and inflammation-related proteins in young children. Our objective was to examine whether air pollution exposure is associated with inflammation-related proteins during the first 2 years of life. METHODS: In a pooled analysis of two birth cohorts from Stockholm County (n = 158), plasma levels of 92 systemic inflammation-related proteins were measured by Olink Proseek Multiplex Inflammation panel at 6 months, 1 year and 2 years of age. Time-weighted average exposure to particles with an aerodynamic diameter of <10 µm (PM10), <2.5 µm (PM2.5), and nitrogen dioxide (NO2) at residential addresses from birth and onwards was estimated via validated dispersion models. Stratified by sex, longitudinal cross-referenced mixed effect models were applied to estimate the overall effect of preceding air pollution exposure on combined protein levels, "inflammatory proteome", over the first 2 years of life, followed by cross-sectional protein-specific bootstrapped quantile regression analysis. RESULTS: We identified significant longitudinal associations of inflammatory proteome during the first 2 years of life with preceding PM2.5 exposure, while consistent associations with PM10 and NO2 across ages were only observed among girls. Subsequent protein-specific analyses revealed significant associations of PM10 exposure with an increase in IFN-gamma and IL-12B in boys, and a decrease in IL-8 in girls at different percentiles of proteins levels, at age 6 months. Several inflammation-related proteins were also significantly associated with preceding PM10, PM2.5 and NO2 exposures, at ages 1 and 2 years, in a sex-specific manner. CONCLUSIONS: Ambient air pollution exposure influences inflammation-related protein levels already during early childhood. Our results also suggest age- and sex-specific differences in the impact of air pollution on children's inflammatory profiles.

Caregiver burden and emotional wellbeing in informal caregivers to ICU survivors-A prospective cohort study.

BACKGROUND: Informal caregivers to intensive care unit (ICU) survivors may develop post-intensive care syndrome family (PICS-F), including depression, anxiety and post-traumatic stress (PTS). Our primary aim was to investigate associations between caregiver burden in informal caregivers cohabiting with ICU survivors and patients' physical and psychological outcomes. METHODS: A prospective, multicentre cohort study in four ICUs in Sweden. Adults cohabiting with ICU patients included in a previous study were eligible for inclusion. Three months post-ICU, informal caregivers received questionnaires assessing caregiver burden, health-related quality of life (HRQL) and symptoms of depression, anxiety and PTS. In parallel, patients reported their three-month physical and psychological status via validated questionnaires. The primary outcome of this study was to compare caregiver burden in informal caregivers to patients with and without adverse physical and psychological outcomes 3 months post-ICU. Secondary outcomes were correlations between caregiver burden and informal caregivers' mental HRQL. RESULTS: Among 62 included informal caregivers, 55 (89%) responded to the follow-up questionnaires. Caregiver burden was higher among informal caregivers to patients with an adverse outcome, compared to informal caregivers to patients without an adverse outcome, caregiver burden scale score mean (±standard deviation) 52 (11) and 41 (13) respectively (p = 0.003). There was strong negative correlation between caregiver burden and informal caregivers' mental HRQL (rs -0.74, p < 0.001). CONCLUSION: Informal caregivers to ICU survivors with adverse physical or psychological outcome experience a higher caregiver burden. A higher caregiver burden correlates with worse caregiver mental HRQL. ICU follow-up programs should consider screening and follow-up of informal caregivers for mental health problems.

The SITS Open Study: A Prospective, Open Label Blinded Evaluation Study of Thrombectomy in Clinical Practice.

BACKGROUND AND PURPOSE: We designed SITS (Safe Implementation of Treatment in Stroke) Open to determine benefit and safety of thrombectomy in clinical practice for large artery occlusion stroke, using selected stent retrievers plus standard care versus standard care alone. METHODS: SITS Open was a prospective, open, blinded evaluation, international, multicenter, controlled, nonrandomized registry study. Centers lacking access to thrombectomy contributed controls. Primary end point was categorical shift in modified Rankin Scale score at 3 months in the per protocol (PP) population. Principal secondary outcomes were symptomatic intracranial hemorrhage, functional independency (modified Rankin Scale score 0-2) and death at 3 months. Patients independently evaluated by video-recorded modified Rankin Scale interviews blinded to treatment or center identity by central core laboratory were regarded as PP population. Propensity score matching with covariate adjusted analysis was performed. RESULTS: During 2014 to 2017, 293 patients (257 thrombectomy, 36 control) from 26 centers in 10 countries fulfilled intention-to-treat and 200 (170 thrombectomy, 30 control) PP criteria; enrollment of controls was limited by rapid uptake of thrombectomy. In PP analysis, median age was 71 versus 71 years, and baseline National Institutes of Health Stroke Scale 17 versus 17 in the thrombectomy and control arms, respectively. The propensity score matching analysis for PP showed a significant shift for modified Rankin Scale at 3 months favoring the thrombectomy group (odds ratio, 3.8 [95% CI, 1.61-8.95]; P=0.002). Regarding safety, there were 4 cases of symptomatic intracranial hemorrhage in the thrombectomy group (2.4%) and none in the control group. CONCLUSIONS: In clinical practice, thrombectomy for patients with large artery occlusion stroke is superior to standard of care in our study. Registration: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT02326428.

Monocytes in sarcoidosis are potent tumour necrosis factor producers and predict disease outcome.

BACKGROUND: Pulmonary sarcoidosis is an inflammatory disease characterised by granuloma formation and heterogeneous clinical outcome. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine contributing to granuloma formation and high levels of TNF have been shown to associate with progressive disease. Mononuclear phagocytes (MNPs) are potent producers of TNF and highly responsive to inflammation. In sarcoidosis, alveolar macrophages have been well studied. However, MNPs also include monocytes/monocyte-derived cells and dendritic cells, which are poorly studied in sarcoidosis, despite their central role in inflammation. OBJECTIVE: To determine the role of pulmonary monocyte-derived cells and dendritic cells during sarcoidosis. METHODS: We performed in-depth phenotypic, functional and transcriptomic analysis of MNP subsets from blood and bronchoalveolar lavage (BAL) fluid from 108 sarcoidosis patients and 30 healthy controls. We followed the clinical development of patients and assessed how the repertoire and function of MNP subsets at diagnosis correlated with 2-year disease outcome. RESULTS: Monocytes/monocyte-derived cells were increased in blood and BAL of sarcoidosis patients compared to healthy controls. Interestingly, high frequencies of blood intermediate monocytes at time of diagnosis associated with chronic disease development. RNA sequencing analysis showed highly inflammatory MNPs in BAL of sarcoidosis patients. Furthermore, frequencies of BAL monocytes/monocyte-derived cells producing TNF without exogenous stimulation at time of diagnosis increased in patients that were followed longitudinally. In contrast to alveolar macrophages, the frequency of TNF-producing BAL monocytes/monocyte-derived cells at time of diagnosis was highest in sarcoidosis patients that developed progressive disease. CONCLUSION: Our data show that pulmonary monocytes/monocyte-derived cells are highly inflammatory and can be used as a predictor of disease outcome in sarcoidosis patients.

Patient Age and Survival After Surgery for Esophageal Cancer.

BACKGROUND: Esophagectomy for esophageal cancer is associated with a substantial risk of life-threatening complications and a limited long-term survival. This study aimed to clarify the controversial questions of how age influences short-term and long-term survival. METHODS: This population-based cohort study included almost all patients who underwent curatively intended esophagectomy for esophageal cancer in Sweden in 1987-2010, with follow-up through 2016. The exposure was age, analyzed both as a continuous and categorical variable. The probability of mortality was computed using a novel flexible parametric model approach. The reported probabilities are proper measures of the risk of dying, and the related odds ratios (OR) are therefore more suitable measures of association than hazard ratios. The outcomes were 90-day all-cause mortality, 5-year all-cause mortality, and 5-year disease-specific mortality. A novel flexible parametric model was used to derive the instantaneous probability of dying and the related OR along with 95% confidence intervals (CIs), adjusted for sex, education, comorbidity, tumor histology, pathological tumor stage, and resection margin status. RESULTS: Among 1737 included patients, the median age was 65.6 years. When analyzed as a continuous variable, older age was associated with slightly higher odds of 90-day all-cause mortality (OR 1.05, 95% CI 1.02-1.07), 5-year all-cause mortality (OR 1.02, 95% CI 1.01-1.03), and 5-year disease-specific mortality (OR 1.01, 95% CI 1.01-1.02). Compared with patients aged < 70 years, those aged 70-74 years had no increased risk of any mortality outcome, while patients aged ≥ 75 years had higher odds of 90-day mortality (OR 2.85, 95% CI 1.68-4.84), 5-year all-cause mortality (OR 1.56, 95% CI 1.27-1.92), and 5-year disease-specific mortality (OR 1.38, 95% CI 1.09-1.76). CONCLUSIONS: Patient age 75 years or older at esophagectomy for esophageal cancer appears to be an independent risk factor for higher short-term mortality and lower long-term survival.

Rotational thromboelastometry results are associated with care level in COVID-19.

High prevalence of thrombotic events in severely ill COVID-19 patients have been reported. Pulmonary embolism as well as microembolization of vital organs may in these individuals be direct causes of death. The identification of patients at high risk of developing thrombosis may lead to targeted, more effective prophylactic treatment. The primary aim of this study was to test whether rotational thromboelastometry (ROTEM) at admission indicates hypercoagulopathy and predicts the disease severity, assessed as care level, in COVID-19 patients. The study was designed as a prospective, observational study where COVID-19 patients over 18 years admitted to hospital were eligible for inclusion. Patients were divided into two groups depending on care level: (1) regular wards or (2) wards with specialized ventilation support. Conventional coagulation tests, blood type and ROTEM were taken at admission. 60 patients were included; age 61 (median), 67% men, many with comorbidities (e.g. hypertension, diabetes). The ROTEM variables Maximum Clot Firmness (EXTEM-/FIBTEM-MCF) were higher in COVID-19 patients compared with in healthy controls (p < 0.001) and higher in severely ill patients compared with in patients at regular wards (p < 0.05). Our results suggest that hypercoagulopathy is present early in patients with mild to moderate disease, and more pronounced in severe COVID-19 pneumonia. Non-O blood types were not overrepresented in COVID-19 positive patients. ROTEM variables showed hypercoagulopathy at admission and this pattern was more pronounced in patients with increased disease severity. If this feature is to be used to predict the risk of thromboembolic complications further studies are warranted.

Sickness absence and disability pension among women with breast cancer: a population-based cohort study from Sweden.

BACKGROUND: Women's return to work after diagnosis of breast cancer (BC) is becoming more prevalent. However, register-based national investigation on sickness absence (SA) and disability pension (DP) in BC women is lacking. The aim of the study was to explore SA and DP before and after a first BC diagnosis and the possibility to predict new cancer-related SA by using disease-related and sociodemographic factors. METHODS: A longitudinal register study of the 3536 women in Sweden aged 19-64 with a first BC diagnosis in 2010 was conducted by linkage of five nationwide registers. Particularly, detailed information on SA and DP was obtained from the National Social Insurance Agency. Descriptive statistics on SA and DP 2 years before through 3 years after the BC diagnosis were performed. The risk of having a new SA spell due to BC or BC-related diagnoses was modeled using logistic regression. RESULTS: The proportion of women with SA increased during the year following the BC diagnosis date and declined over the next 2 years to proportions before diagnosis. At the time of BC diagnosis, half of the women began a new SA spell > 14 days with cancer, cancer-related, or mental diagnosis. Disease-related and sociodemographic factors including occupational sector, living area, age, cancer stage, educational level, and number of previous SA days showed statistical significance (p < 0.05) in predicting a new SA around BC diagnosis. By using these factors, it was possible to correctly predict 67% of the new SA spell. CONCLUSIONS: SA among women with BC was elevated mainly in the first year after diagnosis. New SA following BC diagnosis can accurately be predicted.

Predicting the duration of sickness absence due to knee osteoarthritis: a prognostic model developed in a population-based cohort in Sweden.

BACKGROUND: Predicting the duration of sickness absence (SA) among sickness absent patients is a task many sickness certifying physicians as well as social insurance officers struggle with. Our aim was to develop a prediction model for prognosticating the duration of SA due to knee osteoarthritis. METHODS: A population-based prospective study of SA spells was conducted using comprehensive microdata linked from five Swedish nationwide registers. All 12,098 new SA spells > 14 days due to knee osteoarthritis in 1/1 2010 through 30/6 2012 were included for individuals 18-64 years. The data was split into a development dataset (70 %, nspells =8468) and a validation data set (nspells =3690) for internal validation. Piecewise-constant hazards regression was performed to prognosticate the duration of SA (overall duration and duration > 90, >180, or > 365 days). Possible predictors were selected based on the log-likelihood loss when excluding them from the model. RESULTS: Of all SA spells, 53 % were > 90 days and 3 % >365 days. Factors included in the final model were age, sex, geographical region, extent of sickness absence, previous sickness absence, history of specialized outpatient healthcare and/or inpatient healthcare, employment status, and educational level. The model was well calibrated. Overall, discrimination was poor (c = 0.53, 95 % confidence interval (CI) 0.52-0.54). For predicting SA > 90 days, discrimination as measured by AUC was 0.63 (95 % CI 0.61-0.65), for > 180 days, 0.69 (95 % CI 0.65-0.71), and for SA > 365 days, AUC was 0.75 (95 % CI 0.72-0.78). CONCLUSION: It was possible to predict patients at risk of long-term SA (> 180 days) with acceptable precision. However, the prediction of duration of SA spells due to knee osteoarthritis has room for improvement.

Effect of an Internet-Delivered Stepped-Care Program vs In-Person Cognitive Behavioral Therapy on Obsessive-Compulsive Disorder Symptoms in Children and Adolescents: A Randomized Clinical Trial.

Importance: In most countries, young people with obsessive-compulsive disorder have limited access to specialist cognitive behavioral therapy (CBT), a first-line treatment. Objective: To investigate whether internet-delivered CBT implemented in a stepped-care model is noninferior to in-person CBT for pediatric obsessive-compulsive disorder. Design, Setting and Participants: A randomized clinical noninferiority trial conducted at 2 specialist child and adolescent mental health clinics in Sweden. Participants included 152 individuals aged 8 to 17 years with obsessive-compulsive disorder. Enrollment began in October 2017 and ended in May 2019. Follow-up ended in April 2020. Interventions: Participants randomized to the stepped-care group (n = 74) received internet-delivered CBT for 16 weeks. Nonresponders at the 3-month follow-up were then offered a course of traditional face-to-face treatment. Participants randomized to the control group (n = 78) immediately received in-person CBT for 16 weeks. Nonresponders at the 3-month follow-up received additional face-to-face treatment. Main Outcomes and Measures: The primary outcome was the masked assessor-rated Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) score at the 6-month follow-up. The scale includes 10 items rated from 0 (no symptoms) to 4 (extreme symptoms), yielding a total score range of 0 to 40, with higher scores indicating greater severity. Assessors were masked to treatment allocation at pretreatment, posttreatment, 3-month follow-up, and 6-month follow-up assessments. The predefined noninferiority margin was 4 points on the CY-BOCS. Results: Among the 152 randomized participants (mean age, 13.4 years; 94 [62%] females), 151 (99%) completed the trial. At the 3-month follow-up, 34 participants (46%) in the stepped-care group and 23 (30%) in the in-person CBT group were nonresponders. At the 6-month follow-up, the CY-BOCS score was 11.57 points in the stepped-care group vs 10.57 points in the face-to-face treatment group, corresponding to an estimated mean difference of 0.91 points ([1-sided 97.5% CI, -∞ to 3.28]; P for noninferiority = .02). Increased anxiety (30%-36%) and depressive symptoms (20%-28%) were the most frequently reported adverse events in both groups. There were 2 unrelated serious adverse events (1 in each group). Conclusions and Relevance: Among children and adolescents with obsessive-compulsive disorder, treatment with an internet-delivered CBT program followed by in-person CBT if necessary compared with in-person CBT alone resulted in a noninferior difference in symptoms at the 6-month follow-up. Further research is needed to understand the durability and generalizability of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT03263546.

DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life.

DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak p ≤ 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.

Blood Pressure After Endovascular Thrombectomy: Modeling for Outcomes Based on Recanalization Status.

Background and Purpose- The optimal level for blood pressure after endovascular thrombectomy in acute ischemic stroke is not well established. We sought to evaluate the association of post-endovascular thrombectomy systolic blood pressure (SBP) levels with clinical outcomes. Methods- We included endovascular thrombectomy-treated patients registered from 2014 to 2017 in the Safe Implementation of Treatments in Stroke International Thrombectomy Registry. The mean 24-hour SBP after endovascular thrombectomy treatment was analyzed both as a continuous variable and in intervals. The primary outcome was 3-month functional independence (modified Rankin Scale score of 0-2). The secondary outcomes were symptomatic intracerebral hemorrhage (SICH) and 3-month mortality. The SBP interval with the highest proportion of functional independence was chosen as reference. All analyses were performed for successful or unsuccessful recanalization (modified Treatment in Cerebral Ischemia score ≥2b or <2b, respectively). The results were adjusted for known confounders in logistic regression models. Results- In the multivariable analyses, a higher SBP value as a continuous variable was associated unfavorably with all outcomes in patients with successful recanalization (n=2920) and with more SICH in patients with unsuccessful recanalization (n=711). SBP interval ≥160 mm Hg was associated with less functional independence (adjusted odds ratio, 0.28 [95% CIs, 0.15-0.53]) and more SICH (adjusted odds ratio, 6.82 [95% CIs, 1.53-38.09]) compared with reference 100 to 119 mm Hg in patients with successful recanalization. SBP ≥160 mm Hg was associated with more SICH (adjusted odds ratio, 6.62 [95% CIs, 1.07-51.05]) compared with reference 120 to 139 mm Hg in patients with unsuccessful recanalization. Conclusions- Higher SBP values were associated with less functional independence at 3 months in patients with successful recanalization and with more SICH regardless of recanalization status.

Postcolonoscopy Colorectal Cancer in Sweden From 2003 to 2012: Survival, Tumor Characteristics, and Risk Factors.

BACKGROUND & AIMS: The rate of postcolonoscopy colorectal cancer (PCCRC) is a measure of colonoscopy quality, but there are conflicting results from studies of survival times of patients with PCCRC. We assessed survival times of patients with PCCRC and characterized the microscopic and macroscopic features of postcolonoscopy colorectal tumors. METHODS: We performed a population-based cohort study using data from a database in Sweden, on 458,937 colonoscopies (54.0% women) performed from 2003 through 2012. Rates of colorectal cancer within 3 years of a colonoscopy were calculated based on the World Endoscopy Organization guidelines. Risk factors were evaluated using Poisson regression analysis. We used Cox regression models and Kaplan-Meier analyses, stratified by sex, to assess conditional survival. Logistic regression models were used to evaluate features of postcolonoscopy colorectal tumors, including stage location (right, left, or rectum) differentiation grade (high or low), synchronous tumors, perineural growth, resection margins, and mucinous and vessel characteristics. RESULTS: Within 36 months after a colonoscopy, there were 19,184 individuals who had received a diagnosis of CRC; 1384 of these were PCCRCs (7.2%). The proportion of individuals with PCCRC decreased from 9.4% in 2003 to 6.1% in 2012. The largest risk factors for PCCRC were a prior diagnosis of CRC (relative risk [RR], 3.31; 95% CI, 2.71-4.04), ulcerative colitis (RR, 5.44; 95% CI, 4.75-6.23), Crohn's disease (RR, 3.81; 95% CI, 2.98-4.87), and prior polypectomy (RR, 2.32; 95% CI, 1.97-2.72). Individuals with PCCRCs had shorter survival times than individuals with CRCs detected during the index colonoscopy. Multivariate hazard ratios for PCCRC were 2.75 for men (95% CI, 2.21-3.42) and 2.00 for women (95% CI, 1.59-2.52), respectively. Individuals with left-side PCCRC had shorter survival times than patients with CRC detected during the index colonoscopy. Postcolonoscopy colorectal tumors had increased odds of low differentiation grade (odds ratio, 1.27; 95% CI, 1.09-1.49) compared with colorectal tumors detected during the index colonoscopy. CONCLUSIONS: In an analysis of colonoscopies in Sweden, the rate of PCCRCs decreased from 9.4% in 2003 to 6.1% in 2012. Diseases that require surveillance (such as prior colorectal neoplasms and inflammatory bowel diseases) are the largest risk factors for PCCRC. Patients with PCCRC have shorter survival times than patients with CRC detected during their initial colonoscopy-especially women and patients with left-side tumors.