Association between early treatment of multiple sclerosis and patient-reported outcomes: a nationwide observational cohort study

Background Timing of disease-modifying therapy affects clinical disability in multiple sclerosis, but it is not known whether patient reported outcomes are also affected. This study investigates the relationship between treatment timing and patient-reported symptoms and health-related quality of life. Methods This was a nationwide observational cohort study of adults with relapsing multiple sclerosis, with disease onset between 2001 and 2016, and commenced on disease-modifying treatment within 4 years from disease onset. Patients commencing treatment within 0–2 years were compared with patients commencing treatment at 2–4 years. Indication bias was mitigated by propensity matching. Outcomes were patient-reported symptoms and health-related quality of life as measured by the Multiple Sclerosis Impact Scale (MSIS-29) and EuroQol-5 Dimensions-3 Level (EQ-5D). The follow-up period was 4–10 years from disease onset. Results There were 2648 patients (69% female, median age 32.8) eligible for matching. Mean follow-up time was 3.7 years. Based on 780 matched patients, each year of treatment delay was associated with a worse MSIS physical score by 2.75 points (95% CI 1.29 to 4.20), and worse MSIS psychological score by 2.02 points (95% CI 0.03 to 3.78), in the adjusted models. Among 690 matched patients, earlier treatment start was not associated with EQ-5D score during the follow-up. Conclusions Earlier commencement of disease-modifying treatment was associated with better patient-reported physical symptoms when measured using a disease-specific metric; however, general quality of life was not affected. This indicates that other factors may inform patients’ overall quality of life

Similar mortality and reduced loss to follow-up in integrated compared with vertical programs providing antiretroviral treatment in sub-saharan Africa.

BACKGROUND: Vertical HIV programs have achieved good results but may not be feasible or appropriate in many resource-limited settings. Médecins sans Frontières has treated HIV in vertical programs since 2000 and over time integrated HIV treatment into general health care services using simplified protocols. We analyzed the survival probability among patients receiving antiretroviral therapy (ART) from 2003 to 2010 in integrated versus vertical programs in 9 countries in sub-Saharan Africa. METHODS AND FINDINGS: Cox regression assessed mortality and program design association, adjusting for baseline age, body mass index, clinical WHO stage, tuberculosis, program age and setting. The analysis included 15,403 HIV-positive adults on ART in 7 vertical (14,124 patients) and 10 integrated (1279 patients) programs. Cox regression including 14,523 patients followed for up to 30 months ART showed similar outcomes for mortality (adjusted hazard ratio (aHR) 1.02; 95% confidence interval (CI): 0.83 to 1.24) and lower risk of loss to follow-up (aHR: 0.71; 95% CI: 0.61 to 0.83) in integrated compared with vertical programs. The greatest risk of death was from initiating ART at WHO stage 4 (aHR 1.99, 95% CI: 1.74 to 2.29), although greater program experience was protective (aHR: 0.77, 95% CI: 0.66 to 0.89). Risk of loss to follow-up was greater in experienced programs (aHR: 3.33; 95% CI: 2.92 to 3.79) and rural settings (aHR: 3.82; 95% CI: 3.49 to 4.20). CONCLUSIONS: ART delivery in integrated general health care programs results in good outcomes. Compared with vertical HIV programs, patients initiated ART in integrated programs at more advanced stages of clinical immunosuppression yet had similar risk of death and lower risk of loss to follow-up

Women With Chronic Hypoparathyroidism Have Low Risk of Adverse Pregnancy Outcomes

Context: There are scarce data on the management of chronic hypoparathyroidism (hypoPT) in pregnant women. Objective: The aim of this study was to evaluate pregnancy outcome and total number of births in maternal chronic hypoPT. Methods: The Swedish National Patient Register, The Swedish Prescribed Drug Register, Swedish Medical Birth Register, and the Total Population Register were used to identify 97 women with chronic hypoPT and 1030 age-matched controls who delivered 139 and 1577 singleton infants, respectively, following diagnosis between 1997 and 2017. Results: Women in the chronic hypoPT group had more frequent diabetes (DM) and chronic kidney disease (CKD) compared with the control group (P = 0.043 and P < 0.001, respectively). After adjusting for DM, CKD, maternal age at delivery, and calendar year of delivery, chronic hypoPT cases were associated with increased risk of induction of labor (OR, 1.82; 95% CI, 1.13-2.94) and birth of infants with lower birth weight (beta-coefficient -188 g; 95% CI, -312.2 to -63.8) compared with controls. No difference was found in infant length, small for gestational age, or head circumference after adjustments. Mean gestational age at delivery after controlling for DM, CKD, and pre-eclampsia was not significantly younger (P = 0.119). There was no difference in congenital malformations or perinatal death and no difference in the total number of infants born between groups (P = 0.518). Conclusion: The majority of women with chronic hypoPT had normal pregnancy outcomes, and the overall risks appear low. Maternal chronic hypoPT is, however, associated with higher risk of induction of labor and slightly lower infant birth weight.Peer reviewe

The Epidemiology of Staphylococcus aureus and Panton-Valentine Leucocidin (pvl) in Central Australia, 2006-2010

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: The Central Australian Indigenous population has a high incidence of Staphylococcus aureus bacteremia (SAB) but little is known about the local molecular epidemiology. Methods: Prospective observational study of bacteremic and nasal colonizing S.aureus isolates between June 2006 to June 2010. All isolates underwent single nucleotide polymorphism (SNP) genotyping and testing for the presence of the Panton-Valentine Leucocidin (pvl) gene. Results: Invasive isolates (n = 97) were predominantly ST93 (26.6 %) and pvl positive (54.3 %), which was associated with skin and soft tissue infections (OR 4.35, 95 % CI 1.16, 16.31). Non-multiresistant MRSA accounted for 31.9 % of bacteremic samples and showed a trend to being healthcare associated (OR 2.16, 95 % CI 0.86, 5.40). Non-invasive isolates (n = 54) were rarely ST93 (1.9 %) or pvl positive (7.4 %). Conclusions: In Central Australia, ST93 was the dominant S.aureus clone, and was frequently pvl positive and associated with an aggressive clinical phenotype. Whether non-nasal carriage is more important with invasive clones or whether colonization occurs only transiently remains to be elucidated

Early Adherence to Antiretroviral Medication as a Predictor of Long-Term HIV Virological Suppression: Five-Year Follow Up of an Observational Cohort

OBJECTIVE: Previous studies have demonstrated a cross-sectional relationship between antiretroviral adherence and HIV virological suppression. We assessed the predictive value of baseline adherence in determining long-term virological failure. DESIGN: We assessed baseline adherence via an adherence questionnaire between administered to all consenting patients attending antiretroviral clinics in Khayelitsha township, South Africa, between May 2002 and March 2004. Virological status was ascertained after five years of follow up and multivariate analysis used to model associations of baseline variables and medication adherence with time to viral suppression or failure. RESULTS: Our adherence cohort comprised 207 patients, among whom 72% were female. Median age was 30 years and median CD4 count at initiation was 55 cells/mm(3). We found no statistically significant differences between baseline characteristics and early adherence groups. Multivariate analysis adjusting for baseline CD4 and age found that patients with suboptimal baseline adherence had a hazard ratio of 2.82 (95% CI 1.19-6.66, p = 0.018) for progression to virological failure compared to those whose baseline adherence was considered optimal. CONCLUSIONS: Our longitudinal study provides further confirmation of adherence as a primary determinant of subsequent confirmed virological failure, and serves as a reminder of the importance of initial early investments in adherence counseling and support as an effective way to maximize long-term treatment success

Description of social contacts among student cases of pandemic influenza during the containment phase, Melbourne, Australia, 2009

Introduction: Students comprised the majority of early cases of influenza A(H1N1)pdm09 in Melbourne, Australia. Students and school settings were targeted for public health interventions following the emergence of pH1N1. This study was conducted to describe changes in social contacts among the earliest confirmed student cases of pH1N1 in Melbourne, Australia, to inform future pandemic control policy and explore transmission model assumptions. Methods: A retrospective cross-sectional behavioural study of student cases with laboratory-confirmed pH1N1 between 28 April and 3 June 2009 was conducted in 2009. Demographics, symptom onset dates and detailed information on regular and additional extracurricular activities were collected. Summary measures for activities were calculated, including median group size and median number of close contacts and attendance during the students' exposure and infectious periods or during school closures. A multivariable model was used to assess associations between rates of participation in extracurricular activities and both school closures and students' infectious periods. Results: Among 162 eligible cases, 99 students participated. Students reported social contact in both curricular and extra-curricular activities. Group size and total number of close contacts varied. While participation in activities decreased during the students' infectious periods and during school closures, social contact was common during periods when isolation was advised and during school closures. Discussion: This study demonstrates the potential central role of young people in pandemic disease transmission given the level of non-adherence to prevention and control measures. These finding have public health implications for both informing modelling estimates of future pandemics and targeting prevention and control strategies to young people

Pregnancy Outcomes in Men and Women Treated With Teriflunomide. A Population-Based Nationwide Danish Register Study

Background: The majority of persons diagnosed with multiple sclerosis (MS) experience their first MS symptoms in the reproductive age. Teriflunomide (TFL, Aubagio), was first released in Denmark for relapsing-remitting MS in December 2013. TFL treatment is contraindicated in women of childbearing potential who are not using reliable contraception. TFL can be transmitted via semen and a low risk of male-mediated embryo-fetal toxicity is described.Objective: To report pregnancy outcomes of TFL-treated women and partners to TFL-treated men: gestation week.Methods: Prospective cohort study comparing pregnancy outcomes of TFL-treated men and women, matched on age at conception, 1:4 with controls from the general population. Data on TFL-treated patients treated 1st of January 2014–31st of December 2016 for at least 30 consecutive days prior to conception, and with conception occurring latest 2 years after treatment discontinuation were extracted from The Danish Multiple Sclerosis Registry and merged with several national reproductive registries. Logistic regression was used to analyse the association between TFL exposure and any adverse event.Results: A total of 31 pregnancies were recorded, 13 women and 18 of partners to a TFL-treated man. All 18 partners of TFL-treated men completed their pregnancies: livebirth (18), gestation time &gt;37 weeks (17), gestation time 33–36 weeks (1), normal birth weight (18), spontaneous and elective abortion (0), congenital malformation (plagiocephali) (1), normal delivery (14), induced delivery (2), cesarean section (2), Apgar score ≥7 (18). Among the 13 pregnancies in women exposed to TFL: elective abortion (11), spontaneous abortion (0), livebirth (2), gestation time &gt;37 weeks (2), normal birth weight (2), congenital malformations (0), normal delivery (1), induced delivery (1), Apgar score ≥7 (2). The TFL group was associated with a 22% reduction in the odds of any adverse event relative to controls, although this association was not significant (OR 0.78; 95% CI 0.16–3.72, p = 0.753).Conclusion: Pregnancy outcomes were consistent with those of the general population. The malformation reported of the partner to a TFL-treated man is comparable to the rate of plagiocephaly reported in Denmark

Causes of Multiple Sclerosis: a functional genomics approach

Multiple Sclerosis (MS) is the most common disabling neurological disease affecting young adults in Western Society. To date, 55 strongly associated single nucleotide polymorphisms have been discovered. We now need to identify causal genes. While T-cells as targets for therapeutic intervention have rarely proven useful, there is strong clinical and in-vitro data identifying NK cell deficiencies in patients, and key roles for monocytes in myelin and axon destruction and autoantigen presentation. RNA extracted from magnetic bead sorted monocytes and NK cells, of healthy controls (HC) and untreated patients with relapsing remitting MS (RRMS), was labelled and hybridised to Affymetrix Human Gene 1.0 ST arrays. Expression values were standardized across chips using RMA and quantile normalization as implemented in GenePattern. Genes were ranked by expression difference significance by Mann Whitney U test and ANOVA. To date, we have analysed monocytes of 30 patients and 39 HC, and NK cells from 25 patients and 32 HC. Expression differences of those genes adjacent to MS associated risk SNPs lying between 110kb upstream and 40kb downstream of a candidate gene were considered. We have identified three genes worthy of further analysis on this basis: RGS1, HHEX and THEMIS. To test the relevance of these candidates to central nervous system (CNS) autoimmunity, we aim to mimic phenotypes associated with these expression quantitative trait loci (eQTL) in in-vitro cultures of purified NK cells and monocytes, and in-vivo in a mouse model of MS - experimental autoimmune encephalomyelitis (EAE)

Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP)

ObjectiveThe Tysabri Observational Programme (TOP), which began >10 years ago, is an open-label, multinational, prospective observational study evaluating the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients.MethodsThese data provide a 10-year interim analysis of safety and effectiveness in TOP. Annualised relapse rates (ARRs) and disability progression/improvement were analysed using the Poisson model and the Kaplan-Meier method, respectively. Analyses included patients on natalizumab and those who discontinued natalizumab but remained in TOP.ResultsAs of November 2017, TOP included 6148 patients. Overall, 829 patients (13.5%) experienced ≥1 serious adverse event (SAE), with infection the most common (4.1%). Fifty-three patients (0.9%) had confirmed progressive multifocal leukoencephalopathy. SAE data were consistent with natalizumab's known safety profile; no new safety signals were identified. A total of 3210 patients (52.2%) discontinued natalizumab; 2117 (34.4%) withdrew from TOP. Median time on natalizumab was 3.3 (range 0–11.6) years; median follow-up time was 5.2 (range 0–10.8) years. The on-natalizumab ARR was 0.15, a 92.5% reduction from the year before initiation. Ten-year cumulative probabilities of disability worsening and improvement were 27.8% and 33.1%, respectively. On-natalizumab ARRs were similar between patients who discontinued or remained on natalizumab, suggesting limited attrition bias.ConclusionsSince the TOP 5-year interim analysis (December 2012), cohort size (6148 vs 4821), median exposure (3.3 vs 1.8 years) and median follow-up time (62 vs 26 months) have increased. This 10-year interim analysis further supports the robust real-world effectiveness and well-established safety profile of natalizumab.Trial registration numberNCT00493298