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BACKGROUND AND PURPOSE To explore the prevalence, risk factors, time correlation, characteristics and clinical outcome of dural arteriovenous fistulas (dAVFs) in a cerebral venous thrombosis (CVT) population. METHODS We included patients from the International CVT Consortium registries. Diagnosis of dAVF was confirmed centrally. We assessed the prevalence and risk factors for dAVF among consecutive CVT patients and investigated its impact on clinical outcome using logistic regression analysis. We defined poor outcome as modified Rankin Scale score 3-6 at last follow-up. RESULTS dAVF was confirmed in 29/1218 (2.4%) consecutive CVT patients. The median (interquartile range [IQR]) follow-up time was 8��(5-23) months. Patients with dAVF were older (median [IQR] 53��[44-61] vs. 41��[29-53] years; p��30 days: 39% vs. 7%; p��

Background. Vaccination is the most effective method for reducing morbidity, disability, mortality from of various infections. However, there was a view for a long time that vaccines are ineffective and unsafe to use in people with rheumatological diseases, including juvenile idiopathic arthritis (JIA). Objective.The aim of the study is to analyze literature data on safety and efficacy of vaccination for JIA patients with live and non-live vaccines.Methods: literature analysis was based on data from medical databases PubMed and Google Scholar.Results. Both live and non-live vaccines are safe and immunogenic enough for children with JIA. Most studies confirm vaccination efficacy in patients with JIA when using glucocorticosteroids (GCS) and methotrexate, while therapy with disease-modifying antirheumatic drugs (DMARD) can reduce antibody titers over time. In general, antibodies levels preservation in previously vaccinated children with JIA is less than in global population. This indicates the need to administer booster doses for such patients. No adverse effects on the course of primary disease after vaccination and no post-vaccine complications were revealed.Conclusion. Vaccination of patients with JIA should be performed with reference to the therapy that the patient already receives, under the control of antibodies level. Booster doses should be implemented in case of titers decrease below the protective levels.

To investigate the association between a recorded procedure code for a medication review and adequate drug treatment management, and to explore factors associated with this code. Cross-sectional study; two primary health care centres, in Region Västra Götaland, Sweden. A total of 302 consecutive patients (≥65 years old, 59% female; median number of drugs: six) requiring a non-urgent consultation with a physician in October–November 2017. Adequate drug treatment management (treatment that did not require any further action), determined in consensus by two specialists in family medicine blinded to the medication review code. Adequate drug treatment management was, overall, less common in those with a recorded medication review over the last year: 63% versus 73% (p = 0.047). This negative association was evident among patients aged 65–74 years: 49% versus 74% (p = 0.003), but absent in those ≥75 years old: 67% versus 70% (p = 0.77). Recommendations from consensus included the search for additional information to be able to make a decision regarding initiation or withdrawal of a drug (n = 53), withdrawal of a drug (n = 41), or ordering a laboratory test (n = 25). Factors associated with a recorded procedure code included age above the remuneration limit of 75 years (odds ratio: 9.8; 95% confidence interval 5.0–19), type 2 diabetes (3.0 (1.5–6.2)), hypertension (2.4 (1.2–4.8)), and depression (2.5 (1.02–6.0)). The presence of a recorded medication review was not positively associated with adequate drug treatment management but was associated with the age limit for remuneration, and some chronic diseases.Key pointsTo improve drug treatment in older people in primary care, a remuneration system linked to recorded medication reviews has been introduced.In this study, fewer patients with than without a recorded medication review (63% versus 73%) had adequate drug treatment management.A recorded medication review was ten times more common in those ≥75 years, that is, the age limit for remuneration.Recorded codes for medication reviews were also common in those with type 2 diabetes, hypertension, and depression. To improve drug treatment in older people in primary care, a remuneration system linked to recorded medication reviews has been introduced. In this study, fewer patients with than without a recorded medication review (63% versus 73%) had adequate drug treatment management. A recorded medication review was ten times more common in those ≥75 years, that is, the age limit for remuneration. Recorded codes for medication reviews were also common in those with type 2 diabetes, hypertension, and depression.

PurposeThis meta-epidemiological study aimed to systematically review case reports regarding sports nutrition supplements and adverse events (AEs), specifically addressing the issue of causality assessments.MethodsThrough a systematic literature search we identified all published case reports of AEs associated with sports nutrition supplements between 1 January 2008 and 1 March 2019. Data regarding AEs, suspected supplements, relevant causality assessment factors and the reporting of clinical reasoning and/or systematic causality assessment methods were extracted.ResultsIn all, 72 publications were included, reporting 134 supplements and 37 different AEs in 97 patients (85% males; median age: 30 years [range: 14–60]). Information regarding previous health and regular prescription drugs was not presented in 30% (29/97) and 46% (45/97) of cases, respectively. In 23% (22/97) of the cases, no alternative cause was mentioned. Clinical reasoning was identified in 63% (61/97), and in 13% (8/61) of these, a systematic causality assessment method was applied. In cases with clinical reasoning, a theoretic rationale (92% vs 78%, P = 0.05), a description of previous cases (90% vs 72%, P = 0.021) and body fluid analysis (18% vs 3%, P = 0.027) were reported to a greater extent. Among cases with clinical reasoning, the application of a systematic causality assessment method captured additional important aspects: use of medication (100% vs 55%, P = 0.015), alcohol use (88% vs 43%, P = 0.020) and illicit drug use (88% vs 40%, P = 0.011).ConclusionsIn published case reports where sports nutrition supplements were suspected to have caused AEs, essential factors for causality assessment were left out in a non-negligible proportion. Clinical reasoning was identified in most cases whereas a systematic causality assessment method was applied in a minority. Factors of importance for causality assessment were reported to a greater extent in cases including clinical reasoning, and the application of a systematic causality assessment method captured additional aspects of importance.

ObjectiveTo examine the incidence, characteristics, treatment, and predictors of late seizures (LS) after cerebral venous thrombosis (CVT), we described these features in a registry of 1,127 patients with CVT.MethodsWe included consecutive adult patients from an international consortium of 12 hospital-based CVT registries. We excluded patients with a history of epilepsy or with 7 days after diagnosis of CVT. We used multivariable Cox regression to identify predictors of LS.ResultsWe included 1,127 patients with CVT. During a median follow-up of 2.0 years (interquartile range [IQR] 1.0–6.3), 123 patients (11%) experienced ≥1 LS (incidence rate for first LS 30 per 1,000 person-years, 95% confidence interval [CI] 25–35). Median time to first LS was 5 months (IQR 1–16 months). Baseline predictors of LS included status epilepticus in the acute phase (hazard ratio [HR] 7.0, 95% CI 3.9–12.6), decompressive hemicraniectomy (HR 4.2, 95% CI 2.4–7.3), acute seizure(s) without status epilepticus (HR 4.1, 95% CI 2.5–6.5), subdural hematoma (HR 2.3, 95% CI 1.1–4.9), and intracerebral hemorrhage (HR 1.9, 95% CI 1.1–3.1). Eighty-five patients (70% of patients with LS) experienced a recurrent seizure during follow-up, despite the fact that 94% received antiepileptic drug treatment after the first LS.ConclusionDuring a median follow-up of 2 years, ≈1 in 10 patients with CVT had LS. Patients with baseline intracranial bleeding, patients with acute symptomatic seizures, and those who underwent decompressive hemicraniectomy were at increased risk of developing LS. The high recurrence risk of LS justifies epilepsy diagnosis after a first LS.

A renewed interest in anterior cruciate ligament preservation has been noted using arthroscopic primary repair in patients with proximal tears, but the main concern remained the control of the rotational instability. Segond fracture occurs in less than 10% of cases of acute anterolateral instability, but it can result in continued rotation instability. The aim of this study is to describe the surgical technique to acutely repair both the anterior cruciate ligament and Segond fracture in the acute setting., Technique Video Video 1 This video describes the surgical technique used in this particular type of combined anterior cruciate ligaments and Segond fracture repair.

Contains fulltext : 238007.pdf (Publisher’s version ) (Closed access) IMPORTANCE: Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported within 4 to 28 days of vaccination with the ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad.26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines. An immune-mediated response associated with platelet factor 4/heparin antibodies has been proposed as the underlying pathomechanism. OBJECTIVE: To determine the frequencies of admission thrombocytopenia, heparin-induced thrombocytopenia, and presence of platelet factor 4/heparin antibodies in patients diagnosed with cerebral venous sinus thrombosis prior to the COVID-19 pandemic. DESIGN, SETTING, AND PARTICIPANTS: This was a descriptive analysis of a retrospective sample of consecutive patients diagnosed with cerebral venous sinus thrombosis between January 1987 and March 2018 from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium from Finland, the Netherlands, Switzerland, Sweden, Mexico, Iran, and Costa Rica. Of 952 patients, 865 with available baseline platelet count were included. In a subset of 93 patients, frozen plasma samples collected during a previous study between September 2009 and February 2016 were analyzed for the presence of platelet factor 4/heparin antibodies. EXPOSURES: Diagnosis of cerebral venous sinus thrombosis. MAIN OUTCOMES AND MEASURES: Frequencies of admission thrombocytopenia (platelet count 0.4, in a subset of patients with previously collected plasma samples). RESULTS: Of 865 patients (median age, 40 years [interquartile range, 29-53 years], 70% women), 73 (8.4%; 95% CI, 6.8%-10.5%) had thrombocytopenia, which was mild (100-149 ×103/μL) in 52 (6.0%), moderate (50-99 ×103/μL) in 17 (2.0%), and severe (

Purpose We assessed management and outcomes for intussusception at nine academic hospitals in South Africa. Methods Patients ≤ 3 years presenting with intussusception between September 2013 and December 2017 were prospectively enrolled at all sites. Additionally, patients presenting between July 2012 and August 2013 were retrospectively enrolled at one site. Demographics, clinical information, diagnostic modality, reduction methods, surgical intervention and outcomes were reviewed. Results Four hundred seventy-six patients were enrolled, [54% males, median age 6.5 months (IQR 2.6–32.6)]. Vomiting (92%), bloody stool (91%), abdominal mass (57%), fever (32%) and a rectal mass (29%) represented advanced disease: median symptom duration was 3 days (IQR 1–4). Initial reduction attempts included pneumatic reduction (66%) and upfront surgery (32%). The overall non-surgical reduction rate was 28% and enema perforation rate was 4%. Surgery occurred in 334 (70%), 68 (20%) patients had perforated bowel, bowel resection was required in 61%. Complications included recurrence (2%) and nosocomial sepsis (4%). Length of stay (LOS) was significantly longer in patients who developed complications. Six patients died—a mortality rate of 1%. There was a significant difference in reduction rates, upfront surgery, bowel resection, LOS and mortality between centres with shorter symptom duration compared longer symptom duration. Conclusion Delayed presentation was common and associated with low success for enema reduction, higher operative rates, higher rates of bowel resection and increased LOS. Improved primary health-care worker education and streamlining referral pathways might facilitate timely management.

To score dental arch development using the Great Ormond Street, London, and Oslo (GOSLON) yardstick index, following primary surgery in patients with a complete unilateral cleft lip and palate (UCLP), and to compare the outcome score with the GOSLON score of Cleft Care UK (CCUK) as well as with the Clinical Standards Advisory Group (CSAG), United Kingdom.Study models of patients (average age 12 years) with a non-syndromic complete UCLP, who had been surgically treated at the University of Pretoria Facial Cleft Deformity (UPFCD) clinic. They were assessed using the GOSLON yardstick index by certified raters from the Dental School in Dundee, Scotland. The mean outcome ratings were calculated from the scoring of 27 sets of plaster models. The other scoring rounds were used to calculate intraand inter-observer agreement using Cohen's weighted kappa and Fleiss's multi-rater kappa. There were strong intra- and inter-observer agreement, with a weighted kappa of 0.92. The Facial Cleft Deformity (FCD) clinic data showed a good treatment outcome with a mean GOSLON rating of 2.85 compared to a rating of 3.2 for the CSAG and 2.62 for the CCUK cohort studies. The UPFCD clinic primary surgical protocol displayed a good treatment outcome rating, in line with that of the CCUK cohort and better than the CSAG results.

Nearly all persons with spinal cord injury (SCI) will develop osteoporosis following injury, and further, up to 50% of all persons with SCI will sustain a fracture during their lives. The unique mechanisms driving osteoporosis following SCI remain unknown. The cannabinoid system modulation of bone metabolism through cannabinoid 1/2 (CB1/2) has been of increasing interest for the preservation of bone mass and density in models of osteoporosis. Using a thoracic vertebral level 8 (T8) complete transection in a mouse model, we performed daily treatment with a selective CB2 receptor agonist, HU308, compared with SCI-vehicle-treated and naive control animals either immediately after injury for 40 days, or in a delayed paradigm, following 3 months after injury. The goal was to prevent or potentially reverse SCI-induced osteoporosis. In the acute phase, administration of the CB2 agonist was not able to preserve the rapid loss of cancellous bone. In the delayed-treatment paradigm, in cortical bone, HU308 increased cortical-area to total-area ratio and periosteal perimeter in the femur, and improved bone density in the distal femur and proximal tibia. Further, we report changes to the metaphyseal periosteum with increased presence of adipocyte and fat mass in the periosteum of SCI animals, which was not present in naive animals. The layer of fat increased markedly in HU308-treated animals compared with SCI-vehicle-treated animals. Overall, these data show that CB2 agonism targets a number of cell types that can influence overall bone quality.

We investigated whether more advanced climacteric stage in the mid-40s is associated with thyroid autoimmunity and dysfunction.This cross-sectional cohort study included 2,569 46-year-old women. Thyroid hormone, thyroid peroxidase antibodies, and follicle-stimulating hormone levels were determined. Using menstrual history and follicle-stimulating hormone levels, the participants were divided into climacteric (n = 340) and preclimacteric (n = 2,229) groups. Women diagnosed with premature ovarian insufficiency (menopause by 40 y of age) were excluded. The use of thyroid medication was evaluated from the medication reimbursement register. The prevalence of thyroid medication use, laboratory-based thyroid dysfunction, and thyroid peroxidase antibody positivity was compared between the two groups. The association between climacteric status and thyroid disorders was investigated using a logistic regression model including smoking and thyroid antibody status.At 46 years old, climacteric women used thyroid medication more often than preclimacteric women (9.1% vs 6.1%; P = 0.04). There was no difference in the prevalence of subclinical or clinical hypothyroidism and hyperthyroidism in nonmedicated participants (5.5% vs 5.0%; P = 0.7) or thyroid peroxidase antibody positivity (14.0% vs 15.0%, P = 0.7). In the regression model, being climacteric (OR = 1.6; 95% CI 1.1-2.3; P = 0.02) and antibody positivity (OR 4.9; 95% CI 3.6-6.6; P 0.001) were associated with a higher prevalence of thyroid dysfunction.More advanced climacteric stage in the mid-40s was slightly associated with thyroid dysfunction but not thyroid autoimmunity.Video Summary:http://links.lww.com/MENO/A771.

Background:Mortality from COVID-19 has been associated with older age, black race, and comorbidities including obesity, Understanding the clinical risk factors and laboratory biomarkers associated with severe and fatal COVID-19 will allow early interventions to help mitigate adverse outcomes. Our study identified risk factors for in-hospital mortality among patients with COVID-19 infection at a tertiary care center, in Detroit, Michigan.Methods:We conducted a single-center, retrospective cohort study at a 776-bed tertiary care urban academic medical center. Adult inpatients with confirmed COVID-19 (nasopharyngeal swab testing positive by real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay) from March 8, 2020, to June 14, 2020, were included. Clinical information including the presence of comorbid conditions (according to the Charlson Weighted Index of Comorbidity (CWIC)), initial vital signs, admission laboratory markers and management data were collected. The primary outcome was in-hospital mortality.Results:Among 565 hospitalized patients, 172 patients died for a case fatality rate of 30.4%. The mean (SD) age of the cohort was 64.4 (16.2) years, and 294 (52.0%) were male. The patients who died were significantly older (mean [SD] age, 70.4 [14.1] years vs 61.7 [16.1] years; P < 0.0001), more likely to have congestive heart failure (35 [20.3%] vs 47 [12.0%]; P = 0.009), dementia (47 [27.3%] vs 48 [12.2%]; P < 0.0001), hemiplegia (18 [10.5%] vs 18 [4.8%]; P = 0.01) and a diagnosis of malignancy (16 [9.3%] vs 18 [4.6%]; P = 0.03).From multivariable analysis, factors associated with an increased odds of death were age greater than 60 years (OR = 2.2, P = 0.003), CWIC score (OR = 1.1, P = 0.023), qSOFA (OR = 1.7, P < 0.0001), WBC counts (OR = 1.1 , P = 0.002), lymphocytopenia (OR = 2.0, P = 0.003), thrombocytopenia (OR = 1.9, P = 0.019), albumin (OR = 0.6 , P = 0.014), and AST levels (OR = 2.0, P = 0.004) on admission.Conclusions:This study identified risk factor for in-hospital mortality among patients admitted with COVID-19 in a tertiary care hospital at the onset of U.S. Covid-19 pandemic. After adjusting for age, CWIC score, and laboratory data, qSOFA remained an independent predictor of mortality. Knowing these risk factors may help identify patients who would benefit from close observations and early interventions.

The medical needs of the transgender population are increasingly recognized within the US health care system. Hormone therapy and gender-affirming surgery present distinct anatomic, hormonal, infectious, and psychosocial issues among transgender kidney transplant donors and recipients. We present the first reported experience with kidney transplantation and donation in transgender patients. A single-center case series (January 2014-December 2018) comprising 4 transgender kidney transplant recipients and 2 transgender living donors was constructed and analyzed. Experts in transplant surgery, transplant psychiatry, transplant infectious disease, pharmacy, and endocrinology were consulted to discuss aspects of care for these patients. Four transgender patients identified as male-to-female and 2 as female-to-male. Three of 6 had gender-affirming surgeries prior to transplant surgery, 1 of whom had further procedures posttransplant. Additionally, 4 patients were on hormone therapy. All 6 had psychiatric comorbidities. The 4 grafts have done well, with an average serum creatinine of 1.45 mg/dL at 2 years (range 1.01-1.85 mg/dL). However, patients encountered various postoperative complications, 1 of which was attributable to modified anatomy. Thus, transgender kidney transplant patients can present novel challenges in regard to surgical considerations as well as pre- and posttransplant care. Dedicated expertise is needed to optimize outcomes for this population.

BACKGROUND: Racial disparities are central in the national conversation about Covid-19. Black/African Americans are contracting and dying from COVID-19 disproportionately. We assessed risk factors for death from COVID-19 among black inpatients at an urban center in Detroit, MI. METHODS: This was a retrospective, single-center cohort study. We reviewed the electronic medical records of patients positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the virus that causes COVID-19) on qualitative polymerase-chain-reaction assay, who were admitted between 3/8-5/6/2020. The primary outcome was in-hospital mortality. RESULTS: The case fatality rate was 29.1% (122/419). The mean duration of symptoms prior to hospitalization was 5.3 (3.9) days. Patients who died were older (mean [SD] age, 68.7 [14.8] years vs 60.3 [16.0] years; p

Background: This study quantifies the number of potentially “avoided”cancer deaths due to differences in 10-year relative survival between three time periods, reflecting temporal improvements in cancer diagnostic and/or treatment practices in Australia. Methods: National population-based cohort of 2,307,565 Australians ages 15 to 89 years, diagnosed with a primary invasive cancer from 1985 to 2014 with mortality follow-up to December 31, 2015. Excess mortality rates and crude probabilities of cancer deaths were estimated using flexible parametric relative survival models. Crude probabilities were then used to calculate “avoided cancer deaths” (reduced number of cancer deaths within 10 years of diagnosis due to survival changes since 1985–1994) for all cancers and 13 leading cancer types. Results: For each cancer type, excess mortality (in the cancer cohort vs. the expected population mortality) was significantly lower for more recently diagnosed persons. For all cancers combined, the number of “avoided cancer deaths” (vs. 1985–1994) was 4,877 (1995–2004) and 11,385 (2005–2014) among males. Prostate (1995–2004: 2,144; 2005–2014: 5,099) and female breast cancer (1,127 and 2,048) had the highest number of such deaths, whereas Conclusions: Screening and early detection likely contributed to the high number of “avoided cancer deaths” for prostate and female breast cancer, whereas early detection remains difficult for lung and pancreatic cancers, highlighting the need for improved preventive and screening measures. Impact: Absolute measures such as “avoided cancer deaths” can provide a more tangible estimate of the improvements in cancer survival than standard net survival measures.

Colloidal quantum dot (CQD) solar cells have benefited from rapidly rising single-junction efficiencies in recent years and have shown promise in multijunction and color-tuned applications. However...

Background According to previous studies, older patients frequently have serum concentrations of antidepressant medication above the recommended reference range. Objective The aim of this study was to investigate whether prescribed doses of antidepressants and the proportion of individuals with serum concentrations above the recommended reference range in older individuals (≥ 65 years) have changed over a 10-year period in Norway. Methods Serum concentration measurements and prescribed daily doses of antidepressants in 2007 and 2017 were extracted from a therapeutic drug monitoring (TDM) database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. The database contains routine follow-up serum concentration measurements of psychotropic drugs for patients from all parts of the country. For citalopram, escitalopram, sertraline, mirtazapine and venlafaxine, the differences between 2007 and 2017 in mean prescribed doses and the proportion of patients with at least one serum concentration above the reference range, according to the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) guidelines, were compared. For the proportion of patients with serum concentrations above the recommended reference range, differences between individuals aged 65–79 and ≥ 80 years were also examined. Results The analyses of prescribed doses included 806 patients from 2007 and 1932 patients from 2017, with 972 and 2441 TDM samples, respectively. Between 2007 and 2017, modest reductions in prescribed daily doses were observed for citalopram (20 vs. 17 mg/day) and escitalopram (11 vs. 10 mg/day), but the proportion of patients with serum concentrations above the recommended reference range was unchanged for both drugs, i.e. 11.5% vs. 12.4% for citalopram and 3.6% vs. 2.9% for escitalopram. For mirtazapine and venlafaxine, prescribed doses were reduced from 28 to 25 mg/day and 150 to 125 mg/day, respectively. A significant reduction in the proportion of individuals with serum concentrations above the recommended reference range was observed for mirtazapine (27.1% vs. 11.5%) and for individuals aged ≥ 80 years using venlafaxine (60.0% vs. 30.0%). For sertraline, no differences in prescribed doses or serum concentrations above the recommended reference range were observed. Conclusions Over a 10-year period, prescribed doses of antidepressants have been slightly reduced in older Norwegian patients, but a considerable proportion is still exposed to high serum concentrations of antidepressants. Electronic supplementary material The online version of this article (10.1007/s40266-020-00784-9) contains supplementary material, which is available to authorized users.

Adequate knowledge in pharmacology is crucial in many professions but a non-negligible proportion of students fail the exams and knowledge of underlying factors is largely lacking. This study was performed to evaluate to what extent various factors are related to student performance in pharmacology-related courses in higher education, linking administrative data to attendance at non-mandatory teaching sessions and questionnaire replies. A total of 596 students (median age: 22 years; 70% female) were included from eight courses which are part of either the medical, pharmacy, dentistry, nursing, or biomedical analyst degree programs at the Sahlgrenska Academy, Gothenburg, Sweden. In all, 380 (64%) students passed the regular program- and course-specific exam. Multivariate logistic regression analysis revealed that a high participation rate in non-mandatory teaching sessions, as well as a perceived great interest in pharmacology, was associated with students’ passing of the exam; adjusted odds ratio (95% confidence interval): 1.30 (1.19 to 1.42; per 10 percentage unit increase in attendance) and 3.38 (1.86 to 6.12), respectively. Working for wages during the course weeks and pre-university grades used in the program application were significant factors in subgroups of students, negatively and positively associated with the exam results, respectively. Age, having Swedish as a second language, and time spent studying were only associated with the exam result in the univariate analyses. To conclude, both students and teachers can contribute significantly to successful education within pharmacology, students by participating in the teaching sessions and teachers by encouraging students to find the subject interesting. Electronic supplementary material The online version of this article (10.1007/s40670-020-01026-8) contains supplementary material, which is available to authorized users.

Purpose To assess the evidence for decision making, at the health care and the patient levels, regarding the use of gene expression assays to inform chemotherapy decisions in breast cancer patients with intermediate clinical risk of recurrence. Methods Systematic literature searches were performed (January 2002–April 2020) in Medline, Embase, PubMed, Cochrane Library, PsycINFO and HTA databases. Inclusion criteria: patients (P) were individuals with post-surgical breast cancer at intermediate clinical risk of recurrence; intervention (I)/comparison (C) was (i) use of, versus no use of, a gene expression assay and (ii) withholding versus providing chemotherapy; outcomes (O) were overall survival (OS), health-related quality of life (HRQL), and recurrence. Randomised controlled trials (RCTs) and non-RCTs were included. Random-effects meta-analyses were performed where possible. Results Three inconclusive non-RCTs, respectively, compared OS and recurrence with and without a gene expression assay. No studies investigated HRQL. Regarding the comparison withholding versus providing chemotherapy based on a gene expression assay, one RCT and four non-RCTs evaluated OS. In the RCT, 93.9% (I) versus 93.8% (C) were alive at 9 years. Three RCTs and seven non-RCTs evaluated recurrence. Three RCTs could be pooled regarding distant recurrence; 4.29% versus 3.88% had such an event (risk ratio: 1.12 (95% confidence interval: 0.90 to 1.39). Conclusion Regarding the use of gene expression assays in breast cancer, evidence on patient effects, informing patient-level chemotherapy decision making, is available. However, evidence for prioritisation at the overall health care level, i.e. use of, versus no use of, such assays, is largely lacking.

Background: With the improvements in cancer diagnosis and treatment, more patients with cancer are surviving for longer periods than before. This study aims to quantify the proportion cured and median survival time for those who are not cured for major cancers in Australia. Methods: Australian population-based cohort of 2,164,172 cases, ages 15 to 89 years, whose first cancer diagnosis between 1982 and 2014 was one of 22 leading cancers, were followed up to December 2014. Flexible parametric cure models were used to estimate the proportion cured and median survival time for those uncured by age, sex, and spread of disease, and temporal trends in these measures. Results: Cure estimates could be generated for 19 of the 22 cancer types. The unadjusted proportion cured ranged from 5.0% for pancreatic cancer to 90.0% for melanoma. Median survival time for those uncured ranged from 0.35 years for pancreatic cancer to 6.05 years for prostate cancer. Cancers were divided into four groups according to their proportion cured in the 1980s and the degree of improvement over 28 years. Esophageal, stomach, pancreatic, liver, gallbladder, lung, and brain cancer had lower proportion cured and smaller improvements over time. Conclusions: For cancers with poor survival in which little has changed over time either in prolonging life or achieving statistical cure, efforts should be focused on reducing the prevalence of known risk factors and earlier detection, thereby enabling more effective treatment. Impact: Cure models provide unique insights into whether survival improvements are due to prolonging life or through curing the disease.

BackgroundPatients with primary intracerebral haemorrhage (ICH) are at increased long-term risks of recurrent stroke and other comorbidities. However, available estimates come predominantly from hospital-based studies with relatively short follow-up. Moreover, there are also uncertainties about the influence of ICH location on risks of recurrent stroke, disability, dementia and quality of life.MethodsIn a population-based study (Oxford Vascular Study/2002–2018) of patients with a first ICH with follow-up to 10 years, we determined the long-term risks of recurrent stroke, disability, quality of life, dementia and hospital care costs stratified by haematoma location.ResultsOf 255 cases with primary ICH (mean/SD age 75.5/13.1), 109 (42.7%) had lobar ICH, 144 (56.5%) non-lobar ICH and 2 (0.8%) had uncertain location. Annual rates of recurrent ICH were higher after lobar versus non-lobar ICH (lobar=4.0%, 2.7–7.2 vs 1.1%, 0.3–2.8; p=0.02). Moreover, cumulative rate of dementia was also higher for lobar versus non-lobar ICH (n/% lobar=20/36.4% vs 16/20.8%, p=0.047), and there was a higher proportion of disability at 5 years in survivors (15/60.0% vs 9/31.0%, p=0.03). The 10-year quality-adjusted life years (QALYs) were also lower after lobar versus non-lobar ICH (2.9 vs 3.8 for non-lobar, p=0.04). Overall, the mean 10-year censor-adjusted costs were £19 292, with over 80% of costs due to inpatient hospital admission costs, which did not vary by haematoma location (p=0.90).ConclusionCompared with non-lobar ICH, the substantially higher 10-year risks of recurrent stroke, dementia and lower QALYs after lobar ICH highlight the need for more effective prevention for this patient group.

Background. Patients with juvenile idiopathic arthritis (JIA) can have low levels of antibodies to vaccine antigens due to immunologic features of the main disease, disruptions in vaccination schedule and immunosuppressive drugs administration Objective. The aim of the study was to examine the status of postvaccinal immunity and determine the factors associated with preservation of protective level of antibodies in patients with JIA. Methods. This cross-sectional study included patients with JIA at the age from 2 to 17 years old vaccinated under the age of two (before JIA) against measles, rubella, parotitis, hepatitis B and diphtheria. Levels of IgG to vaccine antigens were measured by enzyme immunoassay. The minimum protective level of anti-measles IgG was esteemed as 0.18 IU/ml, antibodies to rubella — 10 IU/ml, for parotitis — COI > 1.0, for hepatitis B — 10 mIU/ml, antibodies to diphtheria — 0.09 IU/ml. Results. The study included 90 patients with JIA (71% of girls) at the age (median) 11.3 (7.5; 14.9) years. The age of JIA manifestation was 6.0 (4.0; 8.0) years, disease duration — 4.0 (2.0; 7.3) years. Glucocorticosteroids administration in anamnesis or at study entry was recorded in 24/88 (27%) patients, methotrexate — 81/88 (92%), genetically engineered biologic drugs — 54/89 (61%). Protective level of antibodies to measles virus was revealed in 45 (50%) children with JIA, to rubella virus — in 88 (98%), to parotitis — in 68 (76%), to hepatitis B — in 49 (54%), to diphtherial anatoxin — in 45 (50%). The decrease of postvaccinal immunity level was associated with JIA duration and glucocorticosteroids administration (against diphtheria) duration, as well as drop-out immunization (against measles). Conclusion. Major part of children with JIA have no protection against measles, parotitis, hepatitis B or diphtheria. High risk of progression of such vaccine-preventable diseases in these children demands development of individual programs of immunization.

Background We aim to compare the clinical outcomes of patients with early-stage HER2+ breast cancer treated with adjuvant chemotherapy (AC) and neoadjuvant chemotherapy (NAC). Methods Patients with non-metastatic HER2+ breast cancer treated from 2009 to 2018 at our institution comprised our study cohort (n = 1254). Pathologic complete response (pCR) was defined as the absence of invasive disease in the breast and axilla after NAC. Log-rank, Kaplan-Meier, and inverse probability of treatment weighting were used to assess differences in disease-free and overall survival between groups stratified by AC vs. NAC and pCR vs. non-pCR. Results The majority received AC (n = 787 or 62.8%) while 467 (37.2%) patients received NAC. Median follow up for AC and NAC groups was 46 and 28 months, respectively. The crude disease-free survival and overall survival of our study cohort were 92.2% and 89.1% for AC, 89.1% and 82.2% for NAC pCR, and 68.1% and 60.0% for NAC non-pCR, respectively. For clinical stage ≥IIB patients, NAC conferred a positive but statistically nonsignificant treatment effect over AC in multivariate analysis. Conclusions After adjusting for imbalances in our subgroups, we found that, regardless of the sequence of chemotherapy (AC vs. NAC), patients with early-stage HER2+ breast cancer had excellent outcomes.

© 2020 British Journal of AnaesthesiaBackground: Accidental dural puncture is an uncommon complication of epidural analgesia and can cause postdural puncture headache (PDPH). We aimed to describe management practices and outcomes after PDPH treated by epidural blood patch (EBP) or no EBP. Methods: Following ethics committee approval, patients who developed PDPH after accidental dural puncture were recruited from participating countries and divided into two groups, those receiving EBP or no EBP. Data registered included patient and procedure characteristics, headache symptoms and intensity, management practices, and complications. Follow-up was at 3 months. Results: A total of 1001 patients from 24 countries were included, of which 647 (64.6%) received an EBP and 354 (35.4%) did not receive an EBP (no-EBP). Higher initial headache intensity was associated with greater use of EBP, odds ratio 1.29 (95% confidence interval 1.19–1.41) per pain intensity unit increase. Headache intensity declined sharply at 4 h after EBP and 127 (19.3%) patients received a second EBP. On average, no or mild headache (numeric rating score≤3) was observed 7 days after diagnosis. Intracranial bleeding was diagnosed in three patients (0.46%), and backache, headache, and analgesic use were more common at 3 months in the EBP group. Conclusions: Management practices vary between countries, but EBP was more often used in patients with greater initial headache intensity. EBP reduced headache intensity quickly, but about 20% of patients needed a second EBP. After 7 days, most patients had no or mild headache. Backache, headache, and analgesic use were more common at 3 months in patients receiving an EBP.

Refereed/Peer-reviewed Objective: To investigate vitamin D status in women with the onset of the climacteric phase by age 46 as both early menopause and inadequate vitamin D status may increase the risk of adverse health outcomes. Methods: A cross-sectional study included 2,544, 46-year-old women from a birth cohort. Women were divided into the following two groups according to their menstrual history and follicle-stimulating hormone (FSH) concentration: 1) climacteric (FSH ≥25 IU/L and amenorrhea ≥4 mo, n = 351) and 2) preclimacteric women (FSH

Dual-agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPAR𝛼/𝛾) have shown beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to unfavorable cardiovascular and/or renal effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPAR𝛼/𝛾 dual-agonist Tesaglitazar to GLP-1 to allow for the GLP-1 receptor-dependent delivery of Tesaglitazar. GLP-1/Tesaglitazar does not differ from matched GLP-1 in GLP-1R signaling, but shows GLP-1R-dependent PPAR𝛾-RXR heterodimerization with enhanced efficacy to improve body weight, food intake, and glucose metabolism relative to GLP-1 or Tesaglitazar in mice with diet- and genetically-induced obesity. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout (ko) mice and shows preserved effects in DIO mice at doses subthreshold for GLP-1 and Tesaglitazar to improve metabolism. Consistent with the GLP-1R expression pattern, LC/MS-based proteomics identified a series of novel PPAR protein targets in the hypothalamus that are acutely upregulated by Tesaglitazar and by GLP-1/Tesaglitazar, but not by treatment with GLP-1. Collectively, our data show that GLP-1/Tesaglitazar improves energy and glucose metabolism with superior efficacy to GLP-1 or Tesaglitazar alone and suggest that this conjugate holds therapeutic value to treat hyperglycemia and insulin resistance.

Varicella (chickenpox) is a common, highly contagious disease caused by primary infection with varicella zoster virus (VZV), which can result in bacterial superinfection, central nervous system complications, and hospitalization. Stage 2 of this Phase 3 open-label study (ClinicalTrials.gov identifier: NCT03843632) enrolled 100 healthy infants, children, and adolescents (12 months-6 years, n = 37; 7-12 years, n = 33; 13-17 years, n = 30) without a clinical history of varicella. Participants aged 12 months-12 years were administered 1 dose of VARIVAX™ 0.5 mL (Varicella Virus Vaccine Live [Oka/Merck]) and adolescents aged 13-17 years were administered 2 doses 6 weeks apart. For participants seronegative at baseline (VZV antibody titer1.25 glycoprotein enzyme-linked immunosorbent assay [gpELISA] units/mL), immunogenicity was assessed by seroconversion (VZV antibody titer ≥5 gpELISA units/mL) and VZV antibody geometric mean titers 6 weeks after the final dose. For participants who were VZV seropositive at baseline (VZV antibody titer ≥1.25 gpELISA units/mL), immunogenicity was assessed by antibody titer geometric mean fold rise and percentage of participants with ≥4-fold rise in antibody titer 6 weeks after the final dose. A Vaccine Report Card was used to report solicited and unsolicited adverse events through 42 days post-vaccination. After series completion among seronegative participants across age groups (n = 74), 98.6% demonstrated seroconversion 6 weeks post-vaccination; among seropositive participants (n = 26), 65.4% had ≥4-fold rise in antibody titer 6 weeks post-vaccination. No new safety signals were observed. Administering VARIVAX to infants, children, and adolescents resulted in an acceptable immune response with a safety profile consistent with the licensed product.

Diabetes-related foot ulcers (DFUs) affect around 20 million people annually and are a leading cause of the global disability burden (1). DFUs are complex to treat, take months to heal, result in poorer quality of life, and place patients at high risk of hospitalization and amputation. Thus, understanding the influence that different factors have on healing of DFUs is vital. Various demographic, comorbidity, limb, ulcer, and treatment-related factors associated with healing of DFUs have been identified from cohorts attending mostly metropolitan tertiary centers (2–4). However, very few studies have prospectively investigated the influence that these and other factors have on healing in more real-world DFU cohorts attending geographically diverse secondary and tertiary centers. Therefore, we aimed to investigate the influence of 34 factors on healing in a large real-world DFU cohort. We prospectively examined 4,832 consecutive patients with DFU(s) that presented for their first visit to 1 of 65 secondary or tertiary diabetic foot services, across 15 of 17 regions in Queensland (Australia), between July 2011 and December 2017. A DFU was defined as a full-thickness wound below the ankle on a person with diabetes. For DFU clinical and research purposes, foot-related health professionals using the Queensland High Risk Foot Form (QHRFF) directly examined each patient clinically at their first (and subsequent) visit for 4 demographic, 9 comorbidity, 6 limb, 3 ulcer, and 12 treatment factors (5). For those with multiple DFUs, we used the most severe score for each factor and the combined ulcer size from all DFUs (5). Factors from the first visit were used as the baseline. Subsequent visit examinations determined if the DFU(s) healed, …

© 2020 American Academy of Neurology, Objective: To identify characteristics, predictors, and outcomes of acute symptomatic seizures (ASS) in cerebral venous thrombosis (CVT), we investigated 1,281 consecutive adult patients with CVT included from 12 hospitals within the International CVT Consortium. Methods: We defined ASS as any seizure between symptom onset and 7 days after diagnosis of CVT. We stratified ASS into prediagnosis and solely postdiagnosis ASS. Status epilepticus (SE) was also analyzed separately. We analyzed predictors for ASS and the association between ASS and clinical outcome (modified Rankin Scale) with multivariable logistic regression. Results: Of 1,281 eligible patients, 441 (34%) had ASS. Baseline predictors for ASS were intracerebral hemorrhage (ICH; adjusted odds ratio [aOR] 4.1, 95% confidence interval [CI] 3.0-5.5), cerebral edema/infarction without ICH (aOR 2.8, 95% CI 2.0-4.0), cortical vein thrombosis (aOR 2.1, 95% CI 1.5-2.9), superior sagittal sinus thrombosis (aOR 2.0, 95% CI 1.5-2.6), focal neurologic deficit (aOR 1.9, 95% CI 1.4-2.6), sulcal subarachnoid hemorrhage (aOR 1.6, 95% CI 1.1-2.5), and female-specific risk factors (aOR 1.5, 95% CI 1.1-2.1). Ninety-three (7%) patients had solely postdiagnosis ASS, best predicted by cortical vein thrombosis (positive/negative predictive value 22%/92%). Eighty (6%) patients had SE, independently predicted by ICH, focal neurologic deficits, and cerebral edema/infarction. Neither ASS nor SE was independently associated with outcome. Conclusion: ASS occurred in one-third of patients with CVT and was associated with brain parenchymal lesions and thrombosis of the superficial system. In the absence of prediagnosis ASS, no subgroup was identified with sufficient risk of postdiagnosis ASS to justify prophylactic antiepileptic drug treatment. We found no association between ASS and outcome.

Background Diabetes-related foot ulcers (DFU) take months to heal, reduce patient’s quality-of-life, and induce large healthcare expenditure. Various factors have been identified to influence DFU healing at fixed periods, however, data on factors associated with time-to-healing is scarce. Methods Patients presenting with DFU to Diabetic Foot Services across Queensland, Australia between July 2011 and December 2017 were included and had their demographics, disease history and treatments examined at baseline. Outcome of interest was healing of all ulcers within two-year follow-up time. Time-to-healing and associated factors were examined using flexible parametric survival models, which easily enabled including time-varying coefficients and predicting proportions healed. Results Of 4,709 included patients (median age 63 years, 69.5% male, 10.5% Indigenous), median time-to-healing was 112 days, and 68% healed within two years. Younger age ( Conclusions This study identified novel and confirmatory factors influencing time-to-healing over 24 months in a large real-world cohort of people with diabetes-related foot ulcers. Visualizing the adjusted predicted proportion healed revealed the influence each factor had on healing rates over time. Key messages Flexible parametric survival model provided flexibility in investigating time-varying effects and outcome prediction in those with diabetes-related foot ulcer healing.

Background Implementation of guideline-based care for diabetes-related foot ulcers (DFU) in clinical practice is typically sub-optimal. We aimed to evaluate the cost-effectiveness of implementing different incremental increases in guideline-based care scenarios, compared with current practice, using discrete event simulation models. Methods The costs and effectiveness of current practice (identified as 30% receiving guideline-based care, remainder (70%) non-guideline-based care) were compared with seven hypothetical scenarios of implementing incremental increases in guideline-based care (40%, 50%, 60%, 70%, 80%, 90%, 100%) and evaluated using discrete event simulation models, including important events of disease history and parameterised by a large DFU cohort. Incremental cost-effectiveness ratio for each scenario was calculated and compared to willingness-to-pay of AUD28,000 per quality-adjusted life-years (QALY). Probability sensitivity analysis was conducted to incorporate parameter uncertainty by 2,000 random simulations. Results Under a three-year time-horizon, the seven scenarios (40%-100% guideline-based care) were estimated to incrementally save $901-$1843 (AUD 2020) and provide 0.017-0.056 more QALY per person, with all scenarios being cost-saving & more effective than current practice (30% guideline-based care). From probability sensitivity analyses we were increasingly confident (69.7%-89.8% confident) that implementing increased incremental scenarios (40%-100% guideline-based care) would be cost-effective compared with current practice (59.8%-73.4% confident). Conclusions All scenarios incrementally increasing guideline-based care were evaluated to be cost-saving and more effective than current practice according to this discrete event simulation modelling based on a large real-world cohort. Key messages Our findings support the cost-effectiveness of implementing any incremental increase in guideline-based care compared to current practice.

Background While relative survival is commonly used to describe cancer prognosis, its interpretation remains confusing. Alternative measures provide additional insights into the survival experience of Australian cancer patients. Methods Population-based cohort of over 2 million Australians diagnosed with 19 types of primary invasive cancer from 1982 to 2014 with mortality follow-up to 31 December 2015. Flexible parametric survival models were used to estimate loss of life expectancy, avoidable cancer deaths, crude survival, probability of cure and survival of uncured population for cancers diagnosed in Australia. Results There has been an overall decrease in the loss of life expectancy caused by a cancer diagnosis. Australians diagnosed in 2014 will gain an extra 432,588 life years due to the improvement in relative survival since 1982. Similarly, 29% (females) and 40% (males) of expected cancer deaths among the 2005-2014 cohort will be avoided compared to the 1985-1994 cohort. While the 10- year crude probability of cancer deaths decreased over time, patterns varied by cancer type. The crude probability of competing deaths increased with age. Between 1982 and 2009, the cure proportion increased significantly for all cancers. Conclusion Alternative measures of survival may help communicate the reducing impact that a cancer diagnosis has on average life expectancy. Key messages The growing number of Australian cancer survivors can pose emerging challenges to these patients, their caregivers, medical professionals and health-care systems in accessing or providing evidence-based survivorship and psychosocial care after a cancer diagnosis.

Background Diabetes-related foot disease is the leading cause of lower limb amputations in Queensland. Amputations can be either minor (below the ankle joint) or major (above the ankle joint). Minor amputations may be performed to prevent major amputations prophylactically, but how these forms of amputations interrelate, and where their interrelationships are weakest and strongest, is unknown. Knowledge of small-area variation in interrelations between minor and major amputations is relevant to prevention and improved management of foot disease. Methods Data on lower limb amputations performed between 2014 and 2018 on patients aged 20+ years with diabetes were obtained from the Queensland Hospital Admitted Patient Data Collection. Rates were calculated using the number of people, rather than the number of amputation procedures. A Bayesian hierarchical spatial multivariate model was used to examine patterns over 516 populated statistical areas 2 in Queensland. Results During 2014 to 2018, 3,548 Queenslanders had at least one minor amputation, and 1,114 had at least one major amputation. Modelled amputation rates varied markedly across the State (standardised morbidity ratio (SMR) IQR: 0.67 to 1.22), with areas in far north Queensland having extremely high rates. There was consistently high area-level correlation between minor and major amputation rates. The highest SMRs for both minor and major amputations were in the Northern Peninsula. Conclusions Elevated rates of minor and major amputations in areas in Queensland, most noticeably the far north, indicate an urgent need for greater support for people with diabetes-related foot disease. Key messages Text: Large differences in minor and major amputation rates across Queensland indicate that certain regions require greater assistance in managing diabetes-related foot disease.

Objective Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. Methods A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. Results In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 x 10(-24); odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 x 10(-16)). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 x 10(-16)) increased risk of CVT compared with individuals with blood group O. Interpretation We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021

Chemicals associated with health problems can migrate from packaging into food matrices. Therefore, consumers need to be aware of health concerns associated with incorrectly used plastic food packaging. However, little is known about consumers’ knowledge and their plastics usage practices. This study assessed this knowledge and practices among young South African adult consumers. Our online survey of 293 participants focused on their objective (actual) and subjective (self-perceived) knowledge about plastic food packaging care and safety, their utilization practices, and their sources of information about safe use of plastics. Participants’ utilization practices showed broad misuse. Their subjective knowledge about the correct use of plastic packaging was in most respects contradicted by their limited objective knowledge. We found that plastic identification codes on packaging largely failed in their informative purpose, instead, participants mainly consulted informal information sources about plastics. The knowledge gaps, unsafe plastic use practices, and information source deficiencies identified here can help to guide future improvements. We call for consumer education, across all demographics, about plastic utilization practices and associated health concerns about plastic chemicals. We also highlight the need for the government, food and plastics industries to join forces in ensuring that consumers are informed about safe plastic packaging usage.

Background and Purpose: The PROGRESS trial (Perindopril Protection Against Recurrent Stroke Study) conducted in the early 1990s showed that blood pressure (BP) lowering therapy reduced the risks of recurrent stroke by about 50% after spontaneous intracerebral hemorrhage (ICH). However, the ICH subgroup was a minority, and trial cohorts are invariably selective. Therefore, it is unclear whether the impact of BP control on risk of recurrent stroke in ICH observed in PROGRESS would be as great in real-world practice. Methods: We compared BP control (mean BP during study follow-up) and risks of recurrent stroke after first-ever primary ICH in 2 colocated population-based studies before and after the PROGRESS trial (1995–2001) in Oxfordshire: Oxfordshire Community Stroke Project (OCSP; 1981–1986) and OXVASC (Oxford Vascular Study; 2002–2018). Results: Two hundred seventy-seven patients (753 patient-years of follow-up) with first-ever primary ICH were ascertained in OXVASC and OCSP. Baseline systolic BP was comparable between the 2 studies (mean/SD=183.8/36.5 in OXVASC versus 178.1/38.2 in OCSP, P =0.30) but among one hundred thirty-seven 90-day survivors, mean BP during follow-up was substantially lower in OXVASC versus OCSP (135.2/16.4 versus 157.3/17.8, P P =0.006), predominantly driven by a reduction at younger ages (5-year risk at age P =0.001; hazard ratio, 0.14 [0.04–0.54]). Conclusions: Risks of recurrent stroke after primary ICH have fallen significantly in Oxfordshire over the past 4 decades, coinciding with substantial improvements in BP control during follow-up.

The increasing worldwide prevalence of obesity, fatty liver diseases and the emerging understanding of the important roles lipids play in various other diseases is generating significant interest in lipid research. Lipid visualization in particular can play a critical role in understanding functional relations in lipid metabolism. We investigated the potential of multispectral optoacoustic tomography (MSOT) as a novel modality to non‐invasively visualize lipids in laboratory mice around the 930nm spectral range. Using an obesity‐induced non‐alcoholic fatty liver disease (NAFLD) mouse model, we examined whether MSOT could detect and differentiate different grades of hepatic steatosis and monitor the accumulation of lipids in the liver quantitatively over time, without the use of contrast agents, i.e. in label‐free mode. Moreover, we demonstrate the efficacy of using the real‐time clearance kinetics of indocyanine green (ICG) in the liver, monitored by MSOT, as a biomarker to evaluate the organ’s function and assess the severity of NAFLD. This study establishes MSOT as an efficient imaging tool for lipid visualization in preclinical studies, particularly for the assessment of NAFLD., Multispectral optoacoustic tomography (MSOT) is demonstrated for the first time as an efficient imaging tool for the non‐invasive assessment of hepatic steatosis in a non‐alcoholic fatty liver disease (NAFLD) mouse model.

Aim To investigate methodological aspects potentially related to the diverging scientific literature on the prevalence of drug-related hospitalisations, focusing on causality assessments. Methods Original studies contributing data to a recent meta-analysis were reviewed. Methodological aspects, in particular those related to causality assessments, were extracted and compiled. Results Thirteen studies provided data on the prevalence of drug-related admissions. Seven studies focused on adverse drug reactions (prevalences 1.3-10%), and six studies used the broader concept of drug-related problems (prevalences 4.5-41%). In 10 out of 13 studies, causality between the drug and the specified problem was assessed. One study required a probable causal relationship; the remaining studies merely required a possible causal relationship. Five studies assessed the association between the problem assumed to be related to drug therapy and the admission, at one end requiring the former to be demonstrated as the underlying cause and, at the other, merely requiring a temporal relationship between drug intake and admission. Three out of eight studies involving multiple assessors for all/some cases reported the inter-rater agreement, ranging from none to almost perfect. Physicians were involved in the assessments in five studies, reporting prevalences of 3.2% to 4.5%, while studies without such medical input reported prevalences of 8.8% to 41%. Conclusions This review illustrates that methodological issues contribute to the diverse literature on drug-related admissions. We provide suggestions for harmonisation of research, including explicitly assessing the drug-problem-admission relationships from a medical perspective, focusing on problems where the drug treatment is the probable culprit. Funding Agencies|Swedish Network for Pharmacoepidemiology; Swedish government [ALFGBG-716941]; county councils (the ALF-agreement) [ALFGBG-716941]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2013-02639]

Background Immunosuppressive drugs, incomplete vaccine coverage, immune system dysregulation might be factors of a low level of anti-vaccine antibodies in JIA patients. The study aimed to evaluate vaccine coverage, post-vaccine immunity, and risk factors of non-protective levels of antibodies against measles, mumps, rubella, hepatitis B, and diphtheria in JIA patients. Methods A cross-sectional study included 170 children diagnosed with JIA aged 2 to 17 years who received routine vaccinations against measles, rubella, mumps (MMR), diphtheria, and hepatitis B national vaccine schedule. In all patients, the levels of post-vaccination antibodies (IgG) for measles, rubella, mumps, hepatitis B, and diphtheria were measured with ELISA. Results Protective level of antibodies were 50% against hepatitis B, 52% - diphtheria, 58% - measles, 80% - mumps, 98% rubella. MMR’s best coverage had patients with enthesitis-related arthritis-85%, compared to oligoarthritis-70%, polyarthritis-69%, systemic arthritis-63%. Diphtheria coverage was 50, 51, 46, 63%, respectively. Incomplete MMR vaccination had 39% patients, treated with biologics, 22% with methotrexate and 14% with NSAID (p = 0.025), and 61, 46, 36% for diphtheria (p = 0.021). Incomplete vaccination was a risk factor of non-protective level of antibodies against measles (HR = 2.03 [95%CI: 1.02; 4.0], p = 0.042), mumps (HR = 6.25 [95%CI: 2.13; 17.9], p = 0.0008) and diphtheria (HR = 2.39 [95%CI: 1.18; 4.85], p = 0.016) vaccines, as well as JIA category, biologics, corticosteroids and long-term methotrexate treatment for distinct vaccines. One-third part of JIA patients continued vaccination against MMR and diphtheria without serious adverse events and JIA flare. There were no differences between patients who continued MMR vaccination or denied in the means of JIA category and treatment options. Patients, continued diphtheria vaccination rare received methotrexate (p = 0.02), biologics (p = 0.004), but had higher levels of anti-diphtheria antibodies (p = 0.024) compare who omitted vaccination. Methotrexate (OR = 9.5 [95%CI: 1.004; 90.3]) and biologics (OR = 4.4 [95%CI: 1.6; 12.1]) were predictors of omitted diphtheria revaccination. Conclusion Children with JIA may have lower anti-vaccine antibody levels and required routine checks, especially in children with incomplete vaccination, biologics, systemic arthritis, and long-term methotrexate treatment. Revaccination of JIA patients was safe and effective.

ObjectiveTo assess effects of treatment against a hypothesized neuroinflammation in children with symptoms corresponding to the research condition Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) which is not included in current diagnostic systems.MethodsSystematic literature searches were performed (1998 to June 2020) in PubMed, Embase, the Cochrane Library, CINAHL, PsycInfo, and HTA databases. Inclusion criteria: patients (P) were children (ResultsFour randomised controlled trials (RCTs) and three non-RCTs, including 23 to 98 patients, fulfilled the PICO. HRQL was not investigated in any study. Regarding level of functioning, two RCTs investigated antibiotics (penicillin V, azithromycin) and one RCT investigated immunomodulating treatments (intravenous immunoglobulins (IVIG), plasma exchange). Regarding symptoms, two non-RCTs investigated anti-inflammatory treatment (cyclooxygenase (COX) inhibitors, corticosteroids), two RCTs and one non-RCT investigated antibiotics (penicillin V, azithromycin), and two RCTs investigated immunomodulating treatments (IVIG, plasma exchange). Complications, reported in five studies, were consistent with those listed in the summary of products characteristics (SPC). All studies were assessed to have some or major problems regarding directness, the absence of an established diagnosis contributing to clinical diversity in the studied populations. All studies were assessed to have major risk of bias, including selection and detection biases. Due to clinical and methodological diversity, meta-analyses were not performed.ConclusionThis systematic review reveals very low certainty of evidence of beneficial effects, and moderate certainty of evidence of adverse effects, of anti-inflammatory, antibacterial or immunomodulating treatments in patients with symptoms corresponding to the research condition PANS. Available evidence neither supports nor excludes potential beneficial effects, but supports that such treatment can result in adverse effects.RegistrationPROSPERO (CRD42020155714).

Purpose To describe methodological and reporting issues in non-randomised comparative drug safety studies pooled in meta-analyses, with focus on confounding by indication. Methods All studies included in statistically significant meta-analyses in a recent publication investigating fall risk properties of cardiovascular drugs were reviewed. Study characteristics were extracted and assessed. Results Nine studies, including between 498 and 321,995 individuals, contributed data to the significant meta-analyses in which loop diuretics and beta-blockers were associated with falls, five published in 2015. Five individual studies reported a statistically significant association. In the five cohort studies, characteristics of exposed vs unexposed individuals were either not reported (n = 3) or differed substantially regarding morbidity (n = 2). Drug treatment was determined at baseline, and data on falls were collected for up to 2 years thereafter. Out of the four case-control studies, the cases and controls in only one study were matched for morbidity. Morbidity characteristics of fallers compared with non-fallers were either not reported (n = 2) or they differed (n = 1) or were reported according to the matched-for diseases (n = 1). Confounding by indication was explicitly discussed in two studies. None of the abstract conclusions considered causality issues or the possibility of confounding by indication. Conclusions Confounding by indication is a major issue in non-randomised comparative drug safety studies, a problem which may be concealed in meta-analyses. To enhance such research, compared groups need to be balanced regarding relevant factors including morbidities and characteristics adequately reported. Confounding by indication needs to be explicitly discussed and highlighted in the abstract conclusion.

Background: China contributes to almost half of the esophageal cancer cases diagnosed globally each year. However, the prognosis information of this disease in this large population is scarce. Methods: Data on a population-based cohort consisting of residents of Shandong Province, China who were diagnosed with esophageal cancer during the period from 2005 to 2014 were analyzed. The cancer-specific survival rates were estimated using Kaplan–Meier analysis. Discrete-time multilevel mixed-effects survival models were used to investigate socioeconomic status (SES) disparities on esophageal cancer survival. Results: The unadjusted 1-, 3-, and 5-year cause-specific survival rates were 59.6% [95% confidence interval (CI), 59.2%–59.9%], 31.9% (95% CI, 31.5%–32.3%), and 23.6% (95% CI, 23.1%–24.0%), respectively. Patients of blue-collar occupations had higher risk of esophageal cancer–related death than those of white-collar occupations in the first 2 years after diagnosis. Rural patients had higher risk of death than urban patients in the first 3 years after diagnosis. The risks of esophageal cancer–related death among patients living in low/middle/high SES index counties were not different in the first 2 years after diagnosis. However, patients living in high SES index counties had better long-term survival (3–5 years postdiagnosis) than those living in middle or low SES index counties. Conclusions: Socioeconomic inequalities in esophageal cancer survival exist in this Chinese population. Higher individual- or area-level SES is associated with better short-term or long-term cancer survival. Impact: Elucidation of the relative roles of the SES factors on survival could guide interventions to reduce disparities in the prognosis of esophageal cancer.

To evaluate clinical outcomes over a 1-year period in patients affected by symptomatic focal chondral lesions of the knee treated with micro-fragmented stromal-vascular fraction plus microfractures compared to microfractures alone. Two groups of 20 patients were arthroscopically treated with microfractures for a symptomatic focal chondral defect of the knee. At the end of surgery, in the experimental group, micro-fragmented stromal-vascular fraction was injected into the joint. Primary end point was WOMAC score at 12 months. Secondary end points were any adverse events, Oxford Knee Score, EQ-5D score, VAS for pain, analgesic and anti-inflammatory consumption. All the patients were evaluated at 12-month follow-up. No adverse reactions were noted. Analgesic and anti-inflammatory consumption was similar in both groups. At 1-month follow-up, no differences were noted between groups when compared to pre-operative scores. At 3-month follow-up, patients in both groups improved from the baseline in all variables. Significantly lower VAS scores were found in the experimental group (4.2 ± 3.2 vs. 5.9 ± 1.7, p = 0.04). At 6- and 12-month follow-ups, patients in the experimental group scored better in all outcomes with a moderate effect size; in particular, better WOMAC scores were obtained at 12 months, achieving the primary end-point of the study (17.7 ± 11.1 vs. 25.5 ± 12.7; p = 0.03). Injection of micro-fragmented stromal-vascular fraction is safe and, when associated with microfractures, is more effective in clinical terms than microfractures alone in patients affected by symptomatic focal chondral lesions of the knee. Results of the current study provide information that could help physicians to improve their counseling for patients concerning ADMSCs. Level 1—therapeutic study.

ObjectiveThe aim of this study was to assess nutrient patterns and their relation to anemia and iron status of school children using pooled data from three study populations in South Africa.MethodsData from 5- to 12-y-old children (N = 578) from three independent studies conducted in two provinces in South Africa were pooled. Data used in the analysis were dietary intake, hemoglobin, and plasma ferritin concentrations. Nutrient patterns were determined using factor analysis. Logistic regression analysis was performed to determine relationships of nutrient patterns with anemia and iron deficiency.ResultsIn the pooled group, 13.8% of the children were anemic and 27.7% were iron deficient (ID). More than half of children did not meet the Estimated Average Requirement for various nutrients, including vitamins A, C, B12, folate, and zinc, although only 17.7% of children had an iron intake below the requirements. Median intakes for vitamins A and C were lower for anemic than non-anemic children (P = 0.03 and 0.02, respectively) and for ID versus non-ID children (P = 0.03 and 0.046, respectively). Four nutrient patterns were identified: plant protein, carbohydrate, iron, and B vitamins; animal protein and saturated fat; vitamins A and B12; and calcium and fiber. The vitamin A and B12 nutrient pattern was associated with lower odds of being anemic (odds ratio, 0.63; 95% confidence interval, 0.49–0.91; P = 0.035).ConclusionThe present results highlighted the potential role of the combination of dietary vitamin A and B12 in the etiology of nutritional anemia in school-age children in South Africa. Nutrient pattern analysis may improve the understanding of the synergistic role of nutrients related to anemia and may assist in planning intervention strategies.

Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.

ObjectiveWe sought to develop the first Damage Index (DI) in systemic sclerosis (SSc).MethodsThe conceptual definition of ‘damage’ in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic literature review and consultation with patient partners and non-rheumatologist experts produced a list of potential items for inclusion in the DI. These steps were used to reduce the items: (1) Expert members of the SCTC (n=331) were invited to rate the appropriateness of each item for inclusion, using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1568 patients, the univariable relationships between the remaining items and the endpoints of mortality and morbidity (Physical Component Summary score of the Short Form 36) were analysed, and items with pResultsNinety-three (28.1%) complete survey responses were analysed; 58 of 83 items were retained. The univariable relationships with death and/or morbidity endpoints were statistically significant for 22 items, with one additional item forced into the multivariable model by experts due to clinical importance, to create a 23-item weighted SCTC DI (SCTC-DI). The SCTC-DI was predictive of morbidity and mortality in the external cohort.ConclusionsThrough the combined use of consensus and data-driven methods, a 23-item SCTC-DI was developed and retrospectively validated.

Summary Background Antithrombotic (anticoagulant or antiplatelet) therapy is withheld from some patients with cerebral cavernous malformations, because of uncertainty around the safety of these drugs in such patients. We aimed to establish whether antithrombotic therapy is associated with an increased risk of intracranial haemorrhage in adults with cerebral cavernous malformations. Methods In this population-based, cohort study, we used data from the Scottish Audit of Intracranial Vascular Malformations, which prospectively identified individuals aged 16 years and older living in Scotland who were first diagnosed with a cerebral cavernous malformation during 1999–2003 or 2006–10. We compared the association between use of antithrombotic therapy after first presentation and the occurrence of intracranial haemorrhage or persistent or progressive focal neurological deficit due to the cerebral cavernous malformations during up to 15 years of prospective follow-up with multivariable Cox proportional hazards regression assessed in all individuals identified in the database. We also did a systematic review and meta-analysis, in which we searched Ovid MEDLINE and Embase from database inception to Feb 1, 2019, to identify comparative studies to calculate the intracranial haemorrhage incidence rate ratio according to antithrombotic therapy use. We then generated a pooled estimate using the inverse variance method and a random effects model. Findings We assessed 300 of 306 individuals with a cerebral cavernous malformation who were eligible for study. 61 used antithrombotic therapy (ten [16%] of 61 used anticoagulation) for a mean duration of 7·4 years (SD 5·4) during follow-up. Antithrombotic therapy use was associated with a lower risk of subsequent intracranial haemorrhage or focal neurological deficit (one [2%] of 61 vs 29 [12%] of 239, adjusted hazard ratio [HR] 0·12, 95% CI 0·02–0·88; p=0·037). In a meta-analysis of six cohort studies including 1342 patients, antithrombotic therapy use was associated with a lower risk of intracranial haemorrhage (eight [3%] of 253 vs 152 [14%] of 1089; incidence rate ratio 0·25, 95% CI 0·13–0·51; p Interpretation Antithrombotic therapy use is associated with a lower risk of intracranial haemorrhage or focal neurological deficit from cerebral cavernous malformations than avoidance of antithrombotic therapy. These findings provide reassurance about safety for clinical practice and require further investigation in a randomised controlled trial. Funding UK Medical Research Council, Chief Scientist Office of the Scottish Government, The Stroke Association, Cavernoma Alliance UK, and the Remmert Adriaan Laan Foundation.