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The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability.A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group.Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

BACKGROUND Prognostication of myeloproliferative neoplasm (MPN) has always been challenging, even with the advent of Janus kinase 2 (JAK2 V617F) molecular studies. The survival pattern of patients diagnosed with MPN in developing countries is still undetermined. MATERIALS AND METHODS The national MPN registry conducted from 2009 to 2015 in Malaysia provided a comprehensive insight into the demographics, clinical characteristics and laboratory parameters of patients diagnosed with MPN nationwide. The study analysed the survival patterns and mortality outcomes and risk among 671 patients diagnosed with essential thrombocythaemia (ET), polycythaemia vera (PV), primary myelofibrosis (PMF) and unclassified MPN (MPN-U). Mortality status was traced and confirmed until the end of December 2018, with right censoring applied to patients alive beyond that. RESULTS The analysed cohort consisted of 283 (42.2%) ET, 269 (40.1%) PV, 62 (9.2%) PMF and 57 (8.5%) MPN-U incident cases with diagnosis made between 2007 and 2015. The majority of patients were male (52.3%) and Malay (48.9%), except for ET, in which the majority of patients were female (60.1%) and of Chinese origin (47.0%). Female patients were found to have significantly better overall survival (OS) rates in ET (p = 0.0285) and MPN-U (p = 0.0070). Patients with JAK2 V617F mutation were found to have marginally inferior OS over time. Multivariable Cox regression identified patients with increased age [hazard ratio (HR) 1.055, 95% CI 1.031; 1.064], reduced haemoglobin (HB) level (HR 0.886, 95% CI 0.831; 0.945, p = 0.0002), being male (HR 1.545, 95% CI 1.077; 2.217, p = 0.0182), and having MPN-U (HR 2.383, 95% CI 1.261; 4.503, p = 0.0075) and PMF (HR 1.975, 95% CI 1.054; 3.701, p = 0.0335) at increased risk for worse mortality outcomes. CONCLUSION Myeloproliferative neoplasm reduces patient survival. The degree of impact on survival varies according to sub-type, sex, bone marrow fibrosis and HB levels. The JAK2 V617F mutation was not found to affect the survival pattern or mortality outcome significantly.

Aim: Patients with relapsing–remitting multiple sclerosis (RRMS) treated with natalizumab have anecdotally reported a ‘feel-good experience’ (FGE). The authors characterized the FGE using survey data from patients with RRMS treated with natalizumab or other disease-modifying therapies (other-DMT). Methods: Questionnaire data from RRMS patients who use MyMSTeam, an online patient social network, were analyzed. Results: The survey included 347 patients (95 natalizumab; 252 other-DMT). More natalizumab than other-DMT patients self-reported having an FGE (62.1 vs 44.8%; p = 0.001) as well as other physical, emotional and cognitive benefits. Conclusion: This study demonstrates that physical, emotional and cognitive benefits were more commonly reported by patients treated with natalizumab than those treated with other disease-modifying therapies and helps characterize patient-reported factors associated with the FGE.

IntroductionA major site of secondhand smoke exposure for children and adults is the home. Few studies have evaluated the impact of e-cigarette or hookah use on home air quality, despite evidence finding toxic chemicals in secondhand e-cigarette aerosols and hookah smoke. We assessed the effect of e-cigarette and hookah use on home air quality and compared it with air quality in homes where cigarettes were smoked and where no smoking or e-cigarette use occurred.MethodsNon-smoking homes and homes where e-cigarettes, hookah or cigarettes were used were recruited in the New York City area (n=57) from 2015 to 2019. Particulate matter with diameter less than 2.5 µm (PM2.5), black carbon and carbon monoxide (CO) were measured during a smoking or vaping session, both in a ‘primary’ smoking room and in an adjacent ‘secondary’ room where no smoking or vaping occurred. Log transformed data were compared with postanalysis of variance Tukey simultaneous tests.ResultsUse of hookah significantly increased PM2.5levels compared with non-smoking homes, in both the primary and secondary rooms, while use of e-cigarettes increased PM2.5levels only in primary rooms. Additionally, in-home use of hookah resulted in greater CO concentrations than the use of cigarettes in primary rooms.ConclusionsUse of e-cigarettes or hookah increases air pollution in homes. For hookah, increases in PM2.5penetrated even into rooms adjacent to where smoking occurs. Extending smoke-free rules inside homes to include e-cigarette and hookah products is needed to protect household members and visitors from passive exposure to harmful aerosols and gases.

Introduction STRIVE was a 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative (JCV-negative) relapsing-remitting multiple sclerosis (RRMS) patients with disease duration ≤ 3 years. The objective of STRIVE was to examine no evidence of disease activity (NEDA) status and predictors of NEDA in natalizumab-treated patients with early RRMS. Methods Proportions of patients with NEDA were evaluated along with baseline predictors of NEDA, annualized relapse rate, 24-week confirmed disability worsening (CDW), magnetic resonance imaging assessments (T2 and gadolinium-enhancing lesions), and serious adverse events. Results In years 1 and 2, 56.1% (95% confidence interval [CI] 48.7–63.4%) and 73.6% (95% CI 66.2–80.2%) of patients (intent-to-treat population [N = 222]), respectively, achieved NEDA. In years 3 and 4, 84.6% (95% CI 78.0–89.9%) and 91.9% (95% CI 86.4–95.8%) of patients, respectively, achieved Clinical NEDA (no relapses or 24-week CDW). Baseline predictors of NEDA in year 4 were Expanded Disability Status Scale score ≤ 2.0 (odds ratio [OR] = 3.85 [95% CI 1.54–9.63]; p = 0.004) and T2 lesion volume > 4 cc (OR = 0.39 [95% CI 0.15–0.98]; p = 0.046), with the latter also predicting Clinical NEDA in year 4 (OR = 0.21 [95% CI 0.05–0.92]; p = 0.038). The cumulative probability of CDW at year 4 was 19.3%. Serious adverse events were reported in 11.3% of patients. Conclusion These results support the long-term safety and effectiveness of natalizumab. Baseline predictors of NEDA help to inform benefit-risk assessments of natalizumab treatment in JCV-negative patients with early RRMS. Trial Registration ClinicalTrials.gov identifier NCT01485003. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01722-w.

Aims Nocturia has been increasingly recognized as a potential manifestation of cardiovascular disease. However, the relationship between nocturia and electrocardiographic (ECG) abnormalities has not been studied. This study aims to characterize the diagnostic utility of nocturia in identifying left ventricular hypertrophy (LVH), left atrial enlargement (LAE), and prolonged QTc on ECG. Methods Retrospective analysis of nocturnal voiding frequency and contemporaneous ECG data from consecutive patients evaluated at a university-based outpatient cardiology clinic. Three sets of three incremental binary multiple logistic regression models controlling for (1) age, (2) sex and race, and (3) body mass index, hypertension, diabetes mellitus, and diuretic utilization were performed to determine whether nocturia was predictive of LVH, LAE, and prolonged QTc. Results Included patients (n = 143, 77.6% nocturia) were predominantly African-American (89.5%), female (74.1%), and obese (61.5%), of whom 44.1%, 41.3%, and 27.3% had LVH, LAE, and prolonged QTc, respectively. Older age, African-American race, obesity, hypertension, diuretic use, LVH, and LAE were significantly associated with nocturia on univariate analysis. No significant differences were observed in the strength of associations between nocturia and LVH, LAE, or QTc prolongation based on age. Nocturia independently predicted LVH in Models I-III (odds ratios [ORs], 2.99-3.20; relative risks [RRs], 1.18 for all, p ≤ .046) and LAE in Models I-III (ORs, 4.24-4.72; RRs, 1.21 for all, p ≤ .015). No significant associations were observed between nocturia and prolonged QTc. Conclusions Nocturia may be a risk marker for underlying structural cardiac abnormalities.

BACKGROUND: Groin pain is a common long-term complication of total hip arthroplasty (THA). Femoral head size has been proposed as one of the primary causes. The implants used in dual mobility (DM) THA have large outer-bearing articulations, which could increase the risk of post-operative groin pain. Hip resurfacing (HR), too, has been shown to be associated with a risk of groin pain. QUESTIONS/PURPOSES: The goals of this study were to compare the incidence of groin pain at 1 year after hip arthroplasty in patients with different femoral head diameters and in patients undergoing conventional THA, DM THA, and HR. METHODS: After combing an institutional registry for all patients who had undergone THA or HR for primary hip osteoarthritis, we included 3193 patients in the analysis; 2008 underwent conventional THA, 416 underwent DM THA, and 769 underwent HR. We used logistic regression modeling to analyze the relation of groin pain at 1 year after surgery to patient demographics and clinical characteristics, including age, sex, body mass index (BMI), University of California at Los Angeles activity score at 1 year after surgery, bearing couple, and the ratio of acetabular diameter to femoral head diameter. We also measured cup inclination and anteversion in a subset of patients with and without groin pain at 1 year to assess whether pain could be related to implant position. RESULTS: Overall, 8.7% of patients reported groin pain at 1 year. Patients with groin pain were younger and had lower BMIs. There were increased odds of groin pain with a greater cup-to-head ratio, although DM implants, interestingly, were not significantly associated with groin pain; this may be attributable to so much of their movement taking place inside the implant. Subgroup analysis measuring cup inclination and anteversion showed no difference in cup position between patients with and without pain. CONCLUSION: In this population of hip arthroplasty patients, the incidence of groin pain 1 year after surgery did not differ among patients undergoing DM and conventional THA; DM THA in particular was not associated with a higher risk of groin pain, despite its comparatively larger femoral head sizes. HR, on the other hand, was associated with a higher risk of pain. Appropriate implant sizing and bearing couple choice may optimize the functional benefit of THA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11420-020-09764-6) contains supplementary material, which is available to authorized users.

Objective To identify the extent of hospital-to-hospital variation in use of obstetrical blood transfusion. Design Population-based cohort study linking provincial perinatal and blood transfusion registries. Setting British Columbia, Canada, 2004-2015. Population All pregnant women delivering at or beyond 20 weeks' gestation at any British Columbia hospital. Methods Mixed-effects regression models were used to estimate hospital-specific transfusion rates after sequentially accounting for (1) the role of random variation, (2) maternal medical and obstetrical characteristics (i.e. patient case mix) and (3) institutional and delivery factors (such as use of instrumental or caesarean delivery). Main outcome measures Hospital-specific use of obstetrical red blood cell transfusion. Results Among 44 hospitals, crude institutional transfusion rates across the study period ranged from 3.7 to 23.6 per 1000, with an average of 8.3 per 1000. After adjusting for maternal characteristics, institution and delivery risk factors, a nearly three-fold difference in rates between the 10th and 90th percentile remained (5.4-14.5 per 1000). Twelve sites had rates significantly higher or lower than the provincial average. Women residing in remote areas were 2.5-fold (95% CI 1.8-3.5] more likely to receive a blood transfusion than were women residing in metropolitan areas. Conclusions Meaningful variation between hospitals in use of blood transfusion during pregnancy was not explained by differences in patient case-mix or institutional factors, suggesting that over- or under-utilisation of this resource may be occurring in obstetrical care. Tweetable abstract Use of blood transfusion in pregnant women varied broadly between hospitals in British Columbia, Canada.

Smart grids integrate power system engineering with information and communication technology to form a complex system. In this study, a framework is proposed to model the smart grid as interdependent complex networks and investigate the topology vulnerabilities subject to targeted attacks. As a serious targeted cyber-physical threat, the load redistribution attack is a type of false data injection attack. Adversaries can intentionally intercept communication traffic flows or cooperatively manipulate data transmitted over the communication network to mislead the control centre to perform incorrect actions, thereby tripping off lines or breakers, and even triggering cascading failures. Based on the intelligent attack mechanism, a new approach is introduced to identify sequential attack targets according to the node importance, which can in turn collapse the entire power system. Based on the particular characteristics of power systems, the components require achieving a power balance through the redistribution or shedding of loads in each attack. Compared to random removal and block removal, the effectiveness of the proposed strategy was validated on the IEEE 39-bus and the actual provincial backbone network. From the analysis of the experimental results, we find that the topology vulnerability is closely related to the critical node types and locations.

Background: There is much advancement in treatment of chronic myeloid leukemia (CML) since the approval of first tyrosine kinase inhibitor (TKI), imatinib, by US FDA in 2001. One of them is definitely the concept of stopping TKI, starting at the CML patients who have achieved deep molecular response (MR) of MR4.5 for a reasonable long period of at least two years, pioneered by the researchers from French and Australia. Meanwhile, interferon, the standard treatment of CML before the era of TKI, showed that interferon-responded patients may indeed retain the response once interferon was withdrawn via interferon-induced immunity towards the leukemic clone. This is further supported by stop trial in Japan, in which after stopping TKI, interferon was given for 2 years and it showed a higher drug-free rate compared to stop trial from French and Australia. Hence, it is logical to postulate the use of interferon after TKI was stopped when patients have attained deep MR for more than two years will increase the percentage of patients remain TKI-free on follow-up. Materials and Methods: This is a multi-center randomized controlled trial. Adult CML patients, diagnosed in chronic phase, treated with ongoing TKI for at least 3 years without previous history of TKI failure and have achieved stable deep MR on International Scale for ≥2 years with at least 2 readings of MR4.5 (including the latest before study entry), were randomized into 2 arms: (1) peginterferon-α-2a, subcutaneous weekly, starting at 180 mcg, or (2) observation. Disease is monitored by PCR (centralized in Ampang Hospital) at monthly for the first year, 2 monthly for the second year and 3 monthly for the third year. Relapse is defined as either (i) one reading of loss of major MR, i.e. reading of >0.1% IS and confirmed by second analysis taken 1 month later if the first analysis point reading is ≤1% IS, or (ii) positivity of BCR-ABL1 transcripts, as confirmed by a second analysis point, indicating the increase (at least 1 log) in relation to the first analysis point at two successive assessments. Quality of Life is assessed using EORTC QLO-C30. Results: At the time of writing, total of 8 patients were randomized, 5 into peginterferon arm, 3 into observation arm, all were on imatinib, M:F = 4:4, Malay: Chinese:Indian = 3:4:1, median age 49.5 (range 25-58), median follow-up 4 months (range 1-6) and none of them relapse. Two patients developed imatinib withdrawal syndrome, both female on observation arm, one was mild and resolved after 2 months but one was severe and needed termination after 2 months and restarted on imatinib. Two patients in peginterferon arm developed mild hepatitis with liver enzymes

The archaic definition and registration processes for stillbirth currently prevalent in Canada impede both clinical care and public health. The situation is fraught because of definitional problems related to the inclusion of induced abortions at ≥20 weeks' gestation as stillbirths: widespread uptake of prenatal diagnosis and induced abortion for serious congenital anomalies has resulted in an artefactual temporal increase in stillbirth rates in Canada and placed the country in an unfavourable position in international (stillbirth) rankings. Other problems with the Canadian stillbirth definition and registration processes extend to the inclusion of fetal reductions (for multi-fetal pregnancy) as stillbirths, and the use of inconsistent viability criteria for reporting stillbirth. This paper reviews the history of stillbirth registration in Canada, provides a rationale for updating the definition of fetal death and recommends a new definition and improved processes for fetal death registration. The recommendations proposed are intended to serve as a starting point for reformulating issues related to stillbirth, with the hope that building a consensus regarding a definition and registration procedures will facilitate clinical care and public health.RéSUMé: La définition et les méthodes d’enregistrement archaïques des mortinaissances qui prévalent actuellement au Canada entravent à la fois les soins cliniques et la santé publique. La situation est délicate à cause des problèmes de définition que pose l’inclusion des avortements provoqués à ≥ 20 semaines de gestation parmi les mortinaissances : le recours généralisé au diagnostic prénatal et les avortements provoqués en cas d’anomalies congénitales graves ont entraîné une augmentation temporelle artéfactuelle des taux de mortinatalité au Canada et placé le pays dans une position défavorable dans les classements internationaux (de la mortinatalité). Les autres problèmes dans la définition et les méthodes d’enregistrement canadiennes des mortinaissances sont l’inclusion de la réduction fœtale (pour les grossesses multifœtales) parmi les mortinaissances et l’emploi de critères de viabilité inconsistants pour déclarer les mortinaissances. Nous examinons ici l’histoire de l’enregistrement des mortinaissances au Canada, nous justifions une révision possible de la définition de la mort fœtale et nous recommandons une nouvelle définition et des méthodes d’enregistrement améliorées des morts fœtales. Les recommandations proposées se veulent un point de départ à une reformulation des questions liées à la mortinatalité, dans l’espoir que l’établissement d’un consensus sur une définition et sur les méthodes d’enregistrement facilitera les soins cliniques et la santé publique.

Background Patient-reported outcome measures (PROMs) are being used increasingly to determine the success of total knee arthroplasty (TKA). Our goal is to investigate whether advanced age is associated with lower PROM scores. Methods We used our hospital’s TKA registry to examine the relationship between age and PROMs in all patients 50-90 years of age who underwent unilateral or simultaneous bilateral primary TKA between 2007 and 2011 with a primary diagnosis of osteoarthritis. All 5 domains of the Knee Injury and Arthritis Outcomes Score (KOOS) and the Lower Extremity Activity Scale (LEAS) at baseline, 2 years, and 5 years were collected. The association between age and PROM score was assessed by piecewise linear regression using generalized estimating equations, adjusting for demographics, comorbidity, and baseline score. Results Significant nonlinear relationships among age, KOOS subdomains, and LEAS were found. The placement of the age spline knot was at 70 years for KOOS Symptom and 68 years for KOOS Pain, KOOS Activities of Daily Living (ADL), and LEAS. The KOOS Symptom domain showed a significant worsening between 2-year and 5-year follow-up (P Conclusion We found an age-related decline in KOOS Pain, KOOS Symptom, KOOS ADL, and LEAS scores. The best fitting spline knots were at 68 (KOOS Pain, KOOS ADL, and LEAS) and 70 years (KOOS Symptoms), respectively. This demonstrates that there is a critical age at which functional decline begins regardless of the quality of the TKA surgery. Our findings will help surgeons accurately guide patient expectations after TKA based on age. Level of Evidence Level II, prognostic study.

Background: Clinical significance of germinal center B-cell (GCB) and non-GCB sub-categorization, expression of MYC, BCL2, BCL6, CD5 proteins and Epstein Barr virus encoded RNA (EBER) positivity in diffuse large B-cell lymphoma (DLBCL) remain controversial. Could these biomarkers accurately identify high risk DLBCL patients? Are MYC, BCL2 and BCL6 proteins expression feasible as baseline testing to predict c-Myc, BCL2 or BCL6 gene rearrangements? Aims: To investigate prognostic values of GCB/non-GCB sub-categorization, Double Protein Expression Lymphoma (DPL), Triple Protein Expression Lymphoma (TPL), positivity of CD5 protein and EBER in patients with DLBCL disease. To evaluate correlation between BCL2 , c-Myc and BCL6 gene rearrangements with BCL2, MYC and BCL6 proteins expression. Methods: Diagnostic tissue samples of 120 DLBCL patients between January 2012 to December 2013 from four major hospitals in Malaysia were selected. Samples were subjected to immunohistochemical staining, fluorescent in-situ hybridization (FISH) testing, and central pathological review. Pathological data were correlated with clinical characteristics and treatment outcome. Results: A total of 120 cases were analysed. Mean age of diagnosis was 54.1 years ± 14.6, 64 were males, 56 were females, mean follow up period was 25 months (ranged from 1 to 36 months). Of the 120 cases, 74.2% were non-GCB whereas 25.8% were GCB, 6.7% were EBER positive, 6.7% expressed CD5 protein, 13.3% were DPL and 40% were TPL. The prevalence of c-Myc, BCL2, BCL6 gene rearrangements were 5.8%, 5.8%, and 14.2%, respectively; and 1.6% were Double Hit Lymphoma (DHL). EBER positivity, DPL, TPL, c-Myc gene rearrangement, BCL2 gene rearrangement, extra copies of BCL2 gene and BCL6 gene rearrangement were associated with shorter median overall survival (P 0.05). Overall, c-Myc, BCL2 and BCL6 gene rearrangements showed weak correlation with expression of MYC, BCL2 and BCL6 proteins (P>0.05). Fluorescent in situ hybridization is the preferred technique for prediction of treatment outcome in DLBCL patients. Conclusion: c-Myc, BCL2, and BCL6 gene rearrangements, EBER expression, DHL, TPL and IPI score are reliable risk stratification tools. MYC, BCL2 and BCL6 proteins expression are not applicable as baseline biomarkers to predict c-Myc, BCL2, and BCL6 gene rearrangements.

BACKGROUND Blood transfusion is frequently used as an indicator of severe maternal morbidity during pregnancy. However, few studies have examined its validity in population perinatal databases. METHODS We linked a perinatal database from British Columbia, Canada, with the province's Central Transfusion Registry for 2004-2015 deliveries. Using the Central Transfusion Registry records for red blood cell transfusion as the gold standard, we calculated the sensitivity, specificity, positive predictive value, and negative predictive value of the perinatal database variable for red blood cell transfusion, overall and by transfusion risk factor status. We used multivariable logistic regression to examine whether outcome misclassification altered the odds ratios for different transfusion risk factors. RESULTS Among 473,688 deliveries, 4,033 (8.5 per 1,000) had a red blood cell transfusion according to the Central Transfusion Registry. The sensitivity of the perinatal database transfusion variable was 72.3 [95% confidence interval (CI) = 72.2, 72.4]. Sensitivity differed according to the presence of many transfusion risk factors (e.g., 84.9% vs. 72.2% in deliveries with versus without uterine rupture). Odds ratios associated with some transfusion risk factors were exaggerated when the perinatal database transfusion variable was used to define the outcome instead of the Central Transfusion Registry variable, but 95% confidence intervals for these estimates overlapped. CONCLUSION Blood transfusion was documented with reasonable sensitivity in this large population perinatal database. However, validity varied according to risk factor status. Our findings enable researchers to better account for outcome misclassification in studies of obstetrical transfusion risk factors.

INTRODUCTION Socioeconomic factors such as poverty may mediate racial disparities in health outcomes after total hip arthroplasty (THA) and confound analyses of differences between blacks and whites. METHODS Using a large institutional THA registry, we built models incorporating individual and census tract data and analyzed interactions between race and percent of population with Medicaid coverage and its association with 2-year patient-reported outcomes. RESULTS Black patients undergoing THA had worse baseline and 2-year pain and function scores compared with whites. We observed strong positive correlations between census tract Medicaid coverage and percent living below poverty (rho = 0.69; P < 0.001). Disparities in 2-year Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function were magnified in communities with high census tract Medicaid coverage. For blacks in these communities, 2-year WOMAC function scores were predicted to be -5.54 points lower (80.42 versus 85.96) compared with blacks in less deprived communities, a difference not observed among whites. CONCLUSION WOMAC pain and function 2 years after THA are similar among blacks and whites in communities with little deprivation (low percent census tract Medicaid coverage). WOMAC function at 2 years is worse among blacks in areas of higher deprivation but is not seen among whites. LEVEL OF EVIDENCE Level II - Cohort Study.

Background Cognitive impairment affects many patients with multiple sclerosis (MS). NeuroTrax, a computerized cognitive screen that can be administered during routine clinical care, provides a consistent, validated, objective cognitive profile measure with a global cognitive score (GCS) and seven individual domain scores. Natalizumab is an efficacious therapy for relapsing MS, demonstrating reductions in disability worsening and MS disease activity measured by magnetic resonance imaging. Objective The aim of this study was to assess cognitive function as measured by NeuroTrax in MS patients treated with natalizumab for ≥ 2 years. Methods This retrospective observational study included adult MS patients in the United States who received 300 mg intravenous natalizumab every 4 weeks for ≥ 2 years. NeuroTrax data were evaluated at baseline and yearly thereafter. Changes in GCS and the seven individual cognitive domain scores from baseline to after 24 infusions of natalizumab were analyzed. Results In the study population at baseline (N = 52), 22 patients (42.3%) had disease duration of 0–5 years; 12 patients (23.1%) were treatment naive. GCS score improved significantly from baseline [mean 95.5, standard deviation (SD) 12.9] to year 2 (mean 98.9, SD 13.2; change from baseline 3.4; p = 0.003). After 2 years on natalizumab, 17 patients (32.7%) demonstrated clinically significant improvement (increase from baseline > 1 SD) in GCS. Results were similar regardless of whether patients had previously received MS therapy. Conclusions Patients treated with natalizumab demonstrated significant improvement in cognitive function, measured by NeuroTrax GCS, over 2 years of treatment.

ObjectivesTo estimate and compare the salivary cotinine levels using a semiquantitative method, called NicAlert, between three groups: non-smokers, daily smokers of cigarettes and daily smokers of midwakh, and to compare the carbon monoxide (CO) levels among these groups.Materials and methodsA total of 159 adult male volunteers aged 20 and above were included, with 54 current cigarette smokers, 52 current midwakh smokers and 53 non-smokers. Estimate of breath carbon monoxide and salivary cotinine were collected, as well as sociodemographic characteristics and details of smoking habits and second-hand smoke exposure among participants. Institutional review board approval was obtained and data were analysed using SPSS V.21 with the Kruskal-Wallis test used to obtain differences in the distribution.ResultsThere was no significant difference in the median breath CO and salivary cotinine levels between cigarette and midwakh smokers. Levels of breath CO were significantly higher in cigarette and midwakh smokers as compared with non-smokers (19.5, 17.5 and 6.0, respectively, pConclusionThese are the first data that we are aware of that demonstrate that in terms of at least two key biomarkers of tobacco use, there are comparable levels of exposure between cigarettes and midwakh users, demonstrating a need for intensified attention to the use of midwakh.

STRIVE was a 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative (JCV-negative) relapsing-remitting multiple sclerosis (RRMS) patients with disease duration ≤ 3 years. The objective of STRIVE was to examine no evidence of disease activity (NEDA) status and predictors of NEDA in natalizumab-treated patients with early RRMS.Proportions of patients with NEDA were evaluated along with baseline predictors of NEDA, annualized relapse rate, 24-week confirmed disability worsening (CDW), magnetic resonance imaging assessments (T2 and gadolinium-enhancing lesions), and serious adverse events.In years 1 and 2, 56.1% (95% confidence interval [CI] 48.7-63.4%) and 73.6% (95% CI 66.2-80.2%) of patients (intent-to-treat population [N = 222]), respectively, achieved NEDA. In years 3 and 4, 84.6% (95% CI 78.0-89.9%) and 91.9% (95% CI 86.4-95.8%) of patients, respectively, achieved Clinical NEDA (no relapses or 24-week CDW). Baseline predictors of NEDA in year 4 were Expanded Disability Status Scale score ≤ 2.0 (odds ratio [OR] = 3.85 [95% CI 1.54-9.63]; p = 0.004) and T2 lesion volume 4 cc (OR = 0.39 [95% CI 0.15-0.98]; p = 0.046), with the latter also predicting Clinical NEDA in year 4 (OR = 0.21 [95% CI 0.05-0.92]; p = 0.038). The cumulative probability of CDW at year 4 was 19.3%. Serious adverse events were reported in 11.3% of patients.These results support the long-term safety and effectiveness of natalizumab. Baseline predictors of NEDA help to inform benefit-risk assessments of natalizumab treatment in JCV-negative patients with early RRMS.ClinicalTrials.gov identifier NCT01485003.

Objective To link the INTERGROWTH-21st gestational weight gain standard with the risks of excess maternal postpartum weight retention, approximated by women's weight change between successive pregnancies. Methods A population-based retrospective cohort study of 58,534 women delivering successive pregnancies in British Columbia, Canada (2000-2015) was conducted. Pregnancy weight gain (kg) in the index pregnancy was converted into a gestational age-standardized z-score using the INTERGROWTH-21st standard. Excess interpregnancy weight gain was defined as weight increases of 5 kg, 10 kg, or obesity (≥30 kg/m2) at the next pregnancy. Weight gain z-scores and excess interpregnancy weight change were associated using logistic regression. Results For all definitions of excess interpregnancy weight gain, risks remained low and stable below a weight gain z-score of 0 (50th percentile) but rose sharply with increasing z-scores above zero. Compared with women gaining −1 to 0 SD (16th to 50th percentiles), women gaining > 0 to +1 SD (51st to 84th percentiles) were 55% to 84% more likely to retain excess weight between pregnancies. Risks were three- to sixfold higher in women gaining >+1 SD. Conclusions A large range of the INTERGROWTH-21st percentiles were associated with increased risks of excess interpregnancy weight gain. The standard may normalize high weight gains of women at increased risk of excess weight retention.

Background Natalizumab is an effective treatment for multiple sclerosis (MS) and has a well-characterized safety profile, with more than 10 years of postmarketing experience. TYGRIS was a 5-year observational cohort study designed to obtain long-term safety data in natalizumab-treated MS patients. We examined the incidence and pattern of serious adverse events (SAEs) in this large postmarketing sample of natalizumab-treated patients. Methods Investigators reported SAEs in natalizumab-treated patients. Malignancy incidence rates were compared with rates in the general population using external databases. Results Of 6508 enrolled patients, 4938 (75.9%) completed the study. SAEs occurring in more than 0.5% of patients included urinary tract infection (n = 50; 0.8%), pneumonia (n = 46; 0.7%), progressive multifocal leukoencephalopathy (PML; n = 44; 0.7%), and immune reconstitution inflammatory syndrome (n = 44; 0.7%). Fifty-five patients (0.9%) experienced treatment-emergent serious opportunistic infections, 44 of which were PML. Two patients with PML died. The overall malignancy incidence rate was 449.0 per 100,000 patient-years (95% confidence interval [CI], 375.1–533.1). With few exceptions, incidence rates for individual malignancies had 95% CIs encompassing incidence rates in the general population. Hepatotoxic events occurred in 6 patients; 4 patients had evidence of alternative cause or confounders. Of 96 fatal events, investigators considered 81 unrelated or unlikely to be related to treatment and 5 related or possibly related; causality was not provided for 10. Conclusion Data from this large, long-term study indicate that the nature, character, and frequency of SAEs in real-world settings are consistent with natalizumab's known safety profile. (Funded by Biogen; ClinicalTrials.gov identifiers: NCT00477113 and NCT00483847.)

Purpose The purpose of this paper is to assess perceptions of organizational readiness to integrate clinic-based community health workers (cCHWs) between traditional CHWs and potential cCHW employers and their staff in order to inform training and implementation models. Design/methodology/approach A cross-sectional mixed-methods approach evaluated readiness to change perceptions of traditional CHWs and potential employers and their staff. Quantitative methods included a printed survey for CHWs and online surveys in Qualtrics for employers/staff. Data were analyzed using SPSS software. Qualitative data were collected via focus groups and key informant interviews. Data were analyzed with NVIVO 11 Plus software. Findings CHWs and employers and staff were statistically different in their perceptions on appropriateness, management support and change efficacy (p Originality/value Community health workers serve to fill the gaps in the social and health care systems. They are an innovation as an emerging workforce in health care settings. Health care organizations need to learn how to integrate paraprofessionals such as cCHWs. Understanding readiness to adopt the integration of cCHWs into clinical settings will help prepare systems through trainings and adapting organizational processes that help build capacity for successful and sustainable integration.

Background Successful clinical outcomes following unicompartmental knee arthroplasty (UKA) depend on lower limb alignment, soft tissue balance and component positioning, which can be difficult to control using manual instrumentation. Although robotic-assisted surgery more reliably controls these surgical factors, studies assessing outcomes of robotic-assisted UKA are lacking. Therefore, a prospective multicenter study was performed to assess outcomes of robotic-assisted UKA. Methods A total of 1007 consecutive patients (1135 knees) underwent robotic-assisted medial UKA surgery from six surgeons at separate institutions between March 2009 and December 2011. All patients received a fixed-bearing metal-backed onlay implant as tibial component. Each patient was contacted at minimum two-year follow-up and asked a series of five questions to determine survivorship and patient satisfaction. Worst-case scenario analysis was performed whereby all patients were considered as revision when they declined participation in the study. Results Data was collected for 797 patients (909 knees) with average follow-up of 29.6 months (range: 22–52 months). At 2.5-years of follow-up, 11 knees were reported as revised, which resulted in a survivorship of 98.8%. Thirty-five patients declined participation in the study yielding a worst-case survivorship of 96.0%. Of all patients without revision, 92% was either very satisfied or satisfied with their knee function. Conclusion In this multicenter study, robotic-assisted UKA was found to have high survivorship and satisfaction rate at short-term follow-up. Prospective comparison studies with longer follow-up are necessary in order to compare survivorship and satisfaction rates of robotic-assisted UKA to conventional UKA and total knee arthroplasty.

BACKGROUND: In recent decades, many smaller hospitals in British Columbia, Canada, have stopped providing planned obstetric services. We examined the effect of these service closures on the labour and delivery outcomes of pregnant women living in affected communities. METHODS: We used maternal postal codes to identify delivery records (1998–2014) of women residing in a community affected by service closure. The records were obtained from the British Columbia Perinatal Data Registry. We examined the effect of the closures using a within-communities fixed-effects framework and included similar-sized communities without service closures to control for underlying time trends. The primary outcome was a previously published composite measure of labour and delivery safety, the Adverse Outcome Index, which includes adverse events such as birth injury and unanticipated operative procedures, and includes weights for severity of adverse events. Secondary outcomes included maternal or newborn transfer, and use of obstetric interventions. RESULTS: We found little evidence that closure of planned obstetric services affected the risk of composite adverse maternal–newborn outcome (−0.4 excess adverse events per 100 deliveries, 95% confidence interval [CI] −2.0 to 1.1), or most other secondary outcomes. The severity of composite outcome events decreased following the closures (rate ratio 0.58, 95% CI 0.36 to 0.89). Closures were associated with increases in use of epidural analgesia (3.4 excess events per 100 deliveries, 95% CI 0.4 to 6.3) and length of antepartum stay (0.6 h, 95% CI 0.1 to 1.0 h). INTERPRETATION: Closure of planned obstetric services in low-volume hospitals was not associated with an increase or decrease in frequency of adverse events during labour and delivery.

Introduction Hookahs (water pipes) are rapidly increasing in popularity worldwide. Evidence suggests that although perceived as safer than cigarette smoke, hookah smoke may be as, or even more, dangerous as cigarette smoke. Methods Air samples from 33 homes—11 where only hookah-smoking occurred, 12 with only cigarettes and 10 with no smoking—were collected to analyse concentrations of particulate matter (PM 2.5 ), black carbon, elemental and organic carbon and carbon monoxide (CO). Air quality was assessed in rooms where smoking occurred and in an adjacent room. Results Hookah and cigarette smoking impaired home air quality. The rooms in which hookahs were smoked showed the highest concentrations for all pollutants. CO was significantly greater in the rooms where hookahs were smoked than in the cigarette-smoking rooms and the non-smoking households (p 2.5 levels were also elevated in hookah homes compared to cigarette and non-smoking homes, although not significantly different. Conclusions This study, the first of its kind, demonstrates potentially hazardous levels of home air pollution in rooms where hookahs are being smoked as well as in adjacent rooms. These levels were greater than those in cigarette smoking homes, raising concerns about potential negative health effects on all individuals living in homes where hookahs are smoked.

Resume Objectif La presente directive vise a fournir des conseils concernant la prise en charge du travail spontane intrapartum, normal ou anormal, a terme, chez les femmes en sante, ainsi que des conseils relatifs a la prise en charge de la dystocie lors du premier et du deuxieme stade du travail, pour favoriser l'accouchement vaginal et optimiser les issues de la grossesse. Donnees probantes Des documents publies ont ete recuperes au moyen de recherches effectuees dans PubMed et la Cochrane Library, en octobre 2011, a partir d'une terminologie appropriee et controlee (p. ex., labour pain; labour, obstetric; dystocia) et de mots-cles (p. ex., obstetric labor, perineal care, dysfunctional labor). Lorsque cela convenait, on n'a tenu compte que des resultats qui proviennent de revues systematiques, d'essais controles aleatoires ou d'essais cliniques controles et d'etudes d'observation. Seuls les resultats des 10 dernieres annees ont ete pris en consideration; les recherches ont ete regulierement mises a jour jusqu'au 15 juin 2015 et integrees a la directive. Valeurs La qualite des donnees probantes a ete evaluee en fonction des criteres decrits dans le Rapport du Groupe d'etude canadien sur les soins de sante preventifs (tableau 1). Declarations sommaires 1.La duree du premier stade du travail augmente avec l'âge et l'indice de masse corporelle de la mere. (II-2) 2.Chez les femmes nullipares a faible risque qui sont en phase active du travail (c.-a-d. que le col est dilate d'au moins 4 cm), un rythme de dilatation du col superieur ou egal a 0,5 cm/heure est considere comme normal. (II-2) 3.Chaque unite d'obstetrique devrait mettre en place une directive concernant l'utilisation des opioides pendant le travail, notamment en ce qui concerne le mode d'action, les doses moyennes et maximales, les voies d'administration, les effets secondaires potentiels pour la mere et le fœtus, les precautions d'emploi, les antagonistes des opioides et les techniques de reanimation pour chaque medicament. (III) 4.L'analgesie peridurale procure le soulagement de la douleur le plus efficace pour les femmes en travail. Ces dernieres decident du moment de l'injection, une fois que le diagnostic du travail a ete etabli. (I) Recommandations 1.Les prestataires de soins de sante devraient repousser l'admission a l'unite des naissances des femmes a terme qui sont en travail jusqu'a ce qu'elles atteignent la phase active du travail (c.-a-d., lorsque le col est dilate d'au moins 4 cm). (II-2A) 2.La consignation d'informations et la communication concernant la progression du travail sont des aspects importants de la prise en charge du travail. Les unites d'obstetrique et des naissances devraient mettre en place des politiques locales en matiere de consignation d'informations sur le travail, notamment en ce qui a trait a l'utilisation des partogrammes et a leur application dans la prise en charge du travail. (III-A) 3.Les femmes devraient etre informees des avantages de la position verticale pendant le travail. Par ailleurs, on devrait les encourager a trouver les positions qu'elles pensent etre les plus confortables et les aider a les adopter. (I-B) 4.On devrait laisser aux femmes peu susceptibles d'avoir besoin d'une anesthesie generale le choix de manger ou de boire comme elles le souhaitent ou selon ce que permet la phase de travail. (I-A) 5.Le soutien continu pendant le travail est recommande pour toutes les femmes en phase de travail actif. Toutes les unites d'obstetrique devraient offrir a chaque femme la possibilite de beneficier d'un soutien continu et individuel pendant le travail. (I-A) 6.On ne doit envisager l'amniotomie et l'oxytocine, entre autres mesures, qu'une fois le diagnostic de dystocie pose, soit au cours du premier ou du deuxieme stade du travail. (I-B) 7.Les femmes et les prestataires de soins de sante devraient recevoir de l'information sur les strategies de prise en charge du travail precoce et sur les mecanismes d'obtention d'aide aupres des prestataires de soins. (III-A) 8.Lorsque cela est approprie, les prestataires de soins de sante devraient soutenir les femmes dans leur choix concernant les methodes analgesiques a utiliser pendant le travail, qui pourraient comprendre des mesures pharmacologiques et non pharmacologiques. (III-A) 9.Chaque femme devrait recevoir, avant le debut du travail, des renseignements fondes sur des donnees probantes concernant les options d'analgesie pendant le travail. Par ailleurs, on devrait lui laisser tout le temps necessaire pour discuter des risques et des avantages de chaque option disponible a l'unite ou elle doit accoucher. (III-A) 10.Il faudrait eviter de recourir a l'analgesie par la meperidine pendant le travail, compte tenu de la longue duree des effets de ses metabolites actifs et des effets indesirables sur le comportement du nouveau-ne. (II-2B) 11.Pendant le travail, on devrait privilegier la peridurale a faible dose, lorsqu'elle est offerte, plutot que celle a forte dose, notamment pour favoriser la mobilite. (I-A) 12.On devrait encourager les femmes qui recoivent une peridurale a adopter des positions confortables et a maintenir leur mobilite et leur flexibilite tout au long du travail. (I-B) 13.Une fois la peridurale en place, on devrait poursuivre la perfusion jusqu'a la fin de la troisieme phase du travail. (I-A) 14.La poussee, en tant qu'element de progression du deuxieme stade, peut commencer une fois que le col est completement dilate, qu'on a confirme que la presentation est bien engagee et que la femme ressent le besoin de pousser. (III-A) 15.Il vaut mieux retarder la poussee lorsque la femme ne ressent pas le besoin de pousser, en particulier si la presentation est a une hauteur superieure a +2 cm ou n'est pas occipito-pubienne, en supposant que la surveillance du fœtus ne montre rien d'anormal et que l'etat de la parturiente est satisfaisant. (I-A) 16.Si l'on retarde la poussee en fonction de la parite et de l'administration ou non d'une peridurale, il faut le faire en conformite avec les delais decrits dans le present texte, a moins de circonstances attenuantes. (II-2B) 17.Il vaut mieux laisser la femme choisir la methode de poussee, spontanee ou dirigee avec la manœuvre de Valsalva. La poussee dirigee peut etre utile pour l'expulsion finale de la tete. (II-2B) 18.Il faut eviter le recours systematique a l'episiotomie lors des accouchements vaginaux spontanes. (I-A) 19.On devrait administrer des oxytocines a titre prophylactique, apres la naissance des bebes. (I-A) 20.Dans le cas d'accouchements a terme et prematures de bebes qui n'ont pas besoin d'etre reanimes, il est recommande de retarder le clampage du cordon de 60 secondes, quelle que soit la methode d'accouchement. (I-B) 21.La dystocie ne devrait pas etre diagnostiquee avant le debut de la phase active du premier stade du travail ou avant que le col ne soit dilate d'au moins 4 cm. (II-2D) 22.On devrait adapter l'augmentation de l'oxytocine pour eviter la tachysystolie ou une activite excessive de l'uterus et pour provoquer quatre ou cinq contractions par periode de 10 minutes (200 unites Montevideo). Un minimum de quatre a six heures d'activite uterine suffisante pourrait s'averer necessaire pour obtenir la reaction souhaitee. (I-A) Il est recommande que chaque unite d'obstetrique se dote d'un protocole connu et accessible qui indique la dose initiale, les paliers d'augmentation et la dose maximale. Toute unite d'obstetrique devrait envisager de mettre en place une methode standard d'administration de l'oxytocine. (III-A) 23.Il n'est pas recommande de proceder a un accouchement operatoire moins de deux heures apres le debut de la poussee si l'etat de la mere et la surveillance fœtale sont normaux. (III-D) 24.Lorsque le deuxieme stade depasse les delais recommandes (voir le present texte), il faudrait envisager d'accelerer l'accouchement. La prolongation de ces delais peut s'averer appropriee s'il y a descente continue de la tete, si l'etat de la mere et du fœtus sont satisfaisants et si l'accouchement vaginal est imminent. (II-2B) 25.Il a ete demontre que les schemas posologiques de l'oxytocine a forte dose permettent de reduire la duree du travail, comparativement aux schemas a faible dose. Il est recommande d'utiliser la plus faible dose necessaire qui permet d'assurer une progression normale, dans le but de reduire le risque de provoquer une tachysystolie ou une activite uterine excessive tout en provoquant de trois a cinq contractions (200 unites Montevideo) par periode de 10 minutes. (I-A)

1. Nan Jiang, PhD* 2. Lily Lee†,§ 3. Judith T. Zelikoff, PhD‡ 4. Michael Weitzman, MD†,‡,¶,** 1. *Department of Population Health, 2. †Department of Pediatrics, 3. ‡Department of Environmental Medicine, School of Medicine, New York University, New York, NY 4. ¶College of Global Public Health, New York University, New York, NY 5. §Brooklyn College, Brooklyn, NY 6. **NYU Abu Dhabi Public Health Research Center, Abu Dhabi, United Arab Emirates 1. 1. Lauterstein D, 2. Hoshino R, 3. Gordon T, 4. Watkins BX, 5. Weitzman M, 6. Zelikoff J The Changing Face of Tobacco Use Among United States Youth. Lauterstein D, Hoshino R, Gordon T, Watkins BX, Weitzman M, Zelikoff J. Curr Drug Abuse Rev. 2014;7(1):29–43 [OpenUrl][1][CrossRef][2][PubMed][3] 2. 1. Nguyen KH, 2. Tong VT, 3. Marynak KL, 4. King BA US Adults' Perceptions of the Harmful Effects during Pregnancy of Using Electronic Vapor Products Versus Smoking Cigarettes, Styles Survey, 2015. Nguyen KH, Tong VT, Marynak KL, King BA. Prev Chronic Dis. 2016;13:E175 [OpenUrl][4] 3. 1. McGrath-Morrow SA, 2. Hayashi M, 3. Aherrera A, 4. et al. The Effects of Electronic Cigarette Emissions on Systemic Cotinine Levels, Weight and Postnatal Lung Growth in Neonatal Mice. McGrath-Morrow SA, Hayashi M, Aherrera A, et al. PLoS One. 2015;10(2):e0118344 [OpenUrl][5][CrossRef][6][PubMed][7] The emergence of electronic cigarettes (e-cigarettes) as devices touted to be helpful in the cessation or reduction of smoking has prompted many concerns about the prevalence and consequences of their use during pregnancy. Both pregnant women and health-care providers are poorly informed or misinformed about the potential health risks associated with e-cigarettes, which has profound consequences on clinical conversations about the product. Unfortunately, the scientific literature has not yet caught up with the rise in e-cigarette use. The safety of e-cigarettes to the mother and fetus is largely unknown, with a handful of human studies finding minimal health effects. In large part, concerns about e-cigarettes have been the result of the adverse health effects associated with nicotine during pregnancy, which include low birthweight, abnormal corpus callosum, and alterations in appetite, attention, and cognition. Although the health consequences of e-cigarette use during pregnancy remain poorly understood, it is imperative that health-care providers are well equipped to initiate conversations about e-cigarette use with pregnant women and women of childbearing age to discourage use during pregnancy as an aid to quitting smoking. E-cigarettes are the most commonly used, newly developed electronic nicotine delivery systems. They are battery-powered vaporizers that heat a liquid solution (typically containing nicotine, glycerol, propylene glycol, flavorings, and other additives) to deliver an aerosol for user inhalation with the intention of imitating conventional cigarettes. Since their introduction to the US market in 2007, e-cigarette use has increased rapidly among youths and adults. E-cigarettes are widely advertised and often are promoted as less harmful alternatives to cigarettes and also as effective smoking cessation tools, which has considerable … [1]: {openurl}?query=rft.jtitle%253DCurr%2BDrug%2BAbuse%2BRev%26rft.volume%253D7%26rft.spage%253D29%26rft_id%253Dinfo%253Adoi%252F10.2174%252F1874473707666141015220110%26rft_id%253Dinfo%253Apmid%252F25323124%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.2174/1874473707666141015220110&link_type=DOI [3]: /lookup/external-ref?access_num=25323124&link_type=MED&atom=%2Fpedsinreview%2F39%2F3%2F156.atom [4]: {openurl}?query=rft.jtitle%253DPrev%2BChronic%2BDis%26rft.volume%253D13%26rft.spage%253DE175%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [5]: {openurl}?query=rft.jtitle%253DPLoS%2BOne%26rft.volume%253D10%26rft.spage%253De0118344%26rft_id%253Dinfo%253Adoi%252F10.1371%252Fjournal.pone.0118344%26rft_id%253Dinfo%253Apmid%252F25706869%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [6]: /lookup/external-ref?access_num=10.1371/journal.pone.0118344&link_type=DOI [7]: /lookup/external-ref?access_num=25706869&link_type=MED&atom=%2Fpedsinreview%2F39%2F3%2F156.atom

Resume Objectif Aider les fournisseurs de soins de maternite a reconnaitre les problemes lies a la sante et a la maladie pendant la grossesse et leurs relations avec les prestations de maternite, et a en discuter. Resultats La litterature publiee a ete recuperee par l'intermediaire de recherches menees dans PubMed ou Medline, CINAHL et The Cochrane Library en 2009, au moyen d'un vocabulaire controle (p. ex, « maternity benefits ») et de mots cles (p. ex, « maternity », « benefits », « pregnancy ») appropries. Les resultats ont ete restreints aux analyses systematiques, aux essais comparatifs randomises / essais cliniques comparatifs et aux etudes observationnelles. Aucune restriction n'a ete imposee en matiere de langue ou de date. Les recherches ont ete mises a jour de facon reguliere et integrees a la directive clinique jusqu'en decembre 2009. La litterature grise (non publiee) a ete identifiee par l'intermediaire de recherches menees dans les sites Web d'organismes s'interessant a l'evaluation des technologies dans le domaine de la sante et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques et aupres de societes de specialite medicale nationales et internationales.

BACKGROUND While mobile technologies have addressed health care access and affordability gaps, billions of emerging mobile users have yet to benefit from the health information available on their mobile phones. OBJECTIVE • To understand data-enabled mobile phone ownership and behaviors among low-income young urban Indian families, who represent the next billion mobile users. • To identify the barriers to usage and how these barriers can be overcome in the design of mHealth interventions. METHODS We used a two-step process, starting with research on mobile adoption behaviors and then testing several versions of a mobile health application. We interviewed 257 young people in diverse low-income communities in Mumbai and Delhi who were expecting a child or had an infant. We used the hypotheses generated by our research for iterative, rapid prototype development and qualitative and quantitative testing over two rounds with users in Mumbai. The mobile application included health information presented in audio, text, images and videos, and we studied users as they navigated the mobile journey. Prototype development was informed by learnings from commercial apps used by emerging mobile users that address patchy connectivity, low data speeds and cost-conscious consumers. Our design team included experts in IT, economic development, health, and behavioral science. RESULTS We found rapidly increasing and recent ownership of internet-enabled phones (83%). More than half (56%) of users had acquired their smartphone in the last year. Smartphone ownership rose from 47% in households earning less than INR 20,000 (US$308) per month to 81% in households earning INR 20,000–40,000 per month (US$308–US$615). Phone ownership across the same income segments increased dramatically in neighborhoods that had better infrastructure and connectivity. Internet users sought primarily entertainment (95%), social networking (82%), and online gaming (74%). The 18% of respondents who used the internet to seek health care information reported that, among all sources of health care information, they felt that digital information was the least reliable. The 20% of the sample who did not use the internet cited lack of knowledge (80%), high cost (57%), lack of local language content (39%), and lack of motivation (35%). In our prototype testing, our users were more likely to respond to the test mobile app when it was data light, transparent, and allowed for offline viewing and sharing. Limiting screen choices allowed users to make confident decisions. Visual and video content was preferred to written text. CONCLUSIONS Serving the unique needs of emerging mobile users will require socioculturally appropriate health applications designed by multidisciplinary teams. The user journey should be linear and nudge users toward useful information with both reward and loss-aversion techniques. The app alone will not be successful in improving health unless it is part of a holistic, systemic approach that includes technology companies, local government officials, health clinics, community businesses, and other stakeholders.

The heat shock response is an important cytoprotective mechanism for protein homeostasis and is an essential protective response to cellular stress and injury. Studies on changes in the heat shock response with aging have been mixed with regard to whether it is inhibited, and this, at least in part, reflects different tissues and different models. Cellular senescence is a key feature in aging, but work on the heat shock response in cultured senescent (SEN) cells has largely been limited to fibroblasts. Given the prevalence of oxidative injury in the aging cardiovascular system, we investigated whether SEN primary human coronary artery endothelial cells have a diminished heat shock response and impaired proteostasis. In addition, we tested whether this downregulation of heat shock response can be mitigated by 17β-estradiol (E2), which has a critical cardioprotective role in women, as we have previously reported that E2improves the heat shock response in endothelial cells (Hamilton KL, Mbai FN, Gupta S, Knowlton AA. Arterioscler Thromb Vasc Biol 24: 1628–1633, 2004). We found that SEN endothelial cells, despite their unexpectedly increased proteasome activity, had a diminished heat shock response and had more protein aggregation than early passage cells. SEN cells had increased oxidative stress, which promoted protein aggregation. E2treatment did not decrease protein aggregation or improve the heat shock response in either early passage or SEN cells. In summary, cellular senescence in adult human endothelial cells is accompanied by increased oxidative stress and a blunting of proteostasis, and E2did not mitigate these changes.NEW & NOTEWORTHY Senescent human endothelial cells have a diminished heat shock response and increased protein aggregates. Senescent human endothelial cells have increased basal oxidative stress, which increases protein aggregates. Physiological level of 17β-estradiol did not improve proteostasis in endothelial cells.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/proteostasis-in-senescent-endothelial-cells/ .

BACKGROUND While mobile technologies have unlocked opportunities to address health care access and affordability gaps, billions of emerging mobile users are yet to reap the benefits of connected health. OBJECTIVE We studied data enabled mobile phone ownership and behaviors amongst low income young Indian families. Our goal was to study the barriers to usage in this rapidly growing segment and how these barriers can be overcome to design meaningful health interventions. METHODS Starting with secondary research, our team conducted primary research interviews in a group of 250 young families (pregnancy or an infant in the family) within six diverse low income communities in Mumbai and Delhi. The surveyed population represents the global segment of the next billion emerging mobile users. The hypotheses generated from our research were used for rapid prototype development, testing and iteration over two rounds with similar users in Mumbai. Prototype development was informed by learnings from commercial apps used by emerging mobile users that address patchy connectivity, low data speeds and cost conscious consumers. The prototype testing included qualitative and quantitative methods. RESULTS Our primary research showed rapidly increasing and recent ownership of internet enabled phones (83%) in our surveyed population. 56% of users had acquired their smartphone in the last year and only 10% had owned a smartphone for more than 2 years. Phone ownership had a strong gender bias with only 39% women owned phones compared with 85% in men. Smartphone ownership was linked to monthly house income, rising from 35% ownership in households earning less than 20,000 INR to 90% in households earning 20,000-40,000 INR. Phone ownership across the same income segments increased dramatically in digitally ready neighborhoods that had a superior infrastructure and connectivity. The main reasons for not using the internet were lack of knowledge (80%), cost (57%), lack of local language content (39%) and lack of motivation (35%). Emerging mobile users were drawn to the internet primarily for entertainment (95%), social networking (82%), and online gaming (74%). Only 18% of the population was using internet to seek health care related information, and when they did, digital health information was reported as least reliable, with close to 90% of respondents ranking them lowest on the reliability scale. Our users were more likely to respond to the test mobile app when it was data light, transparent, and allowed for offline viewing and sharing. Behaviorally, reducing cognitive load significantly allowed users to make confident decisions. This meant creating linear user journeys, minimizing screen choices and nudging users towards specific messages using a combination of rewards and loss aversion techniques. Even though literate, our users responded overwhelmingly to visual and video content than to written text. Finally, activating the user journey on the app was much more powerful when done through a trusted community resource. CONCLUSIONS Slimming down existing health apps won’t address the unique needs of emerging mobile users. Designing connected health interventions for the next billion mobile users requires multi-disciplinary teams to design content experiences and user journeys rooted in local ecosystems and tailored to the users’ unique sensibilities.

Background Community characteristics such as poverty affect total knee arthroplasty (TKA) outcomes. However, it is unknown whether other community factors such as immigrant proportion (IP) also affect outcomes. Our objective was to determine the association of neighborhood IP on preoperative (pre-op) and 2-year postoperative (post-op) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function after elective TKA. Methods Patients in a high volume institutional TKA registry between May 2007 and February 2011 were retrospectively analyzed. Demographics, pre-op and 2-year post-op WOMAC pain and function scores, and geocodable addresses were obtained. Patient-level variables were linked to US Census Bureau census tract data. The effect of patient and neighborhood-level factors on WOMAC scores were analyzed using linear mixed effects models. Results 3898 TKA patients were analyzed. Pre-op and 2-year post-op WOMAC pain and function scores were between 2.75–4.88 WOMAC points worse in neighborhoods with a high IP (≥ 40%) compared to low IP (

Introduction Since the 2012 identification of 3 risk factors for natalizumab-associated progressive multifocal leucoencephalopathy (PML) changes in the PML incidence rate have been of interest. Objectives Determine the natalizumab-associated PML incidence in the global postmarketing setting since introduction of the anti-JCV antibody assay and evaluate the relationship of PML incidence with natalizumab exposure. Patients and methods The incidence of confirmed PML cases in Biogen's global safety database from 2009 to 2017 was evaluated retrospectively. Overall incidence in all exposed patients was determined by the estimated total number of patients ever exposed to natalizumab and the number of confirmed PML cases. Changes in natalizumab exposure patterns over time were evaluated by 12-infusion epochs. Results As of 30 November 2017, 180,656 patients worldwide had received ≥ 1 natalizumab dose (total exposure: 625,451 patient-years); overall natalizumab-associated PML incidence was 4.19/1000 patients. The increase in overall monthly incidence reported from 2012 onward appears to level off in mid-2016; overall incidence remained between 4.18–4.24/1000 over the last 21 months. Discussion NA. Conclusion Overall PML incidence has been stable since mid-2016. This stabilisation coincides with the introduction and publication of the new PML risk algorithm.

1. Lily Lee*,† 2. Jenni A. Shearston‡,§ 3. Michael Weitzman, MD*,‡ 1. *Department of Pediatrics, New York University School of Medicine, New York, NY. 2. ‡College of Global Public Health, New York University, New York, NY. 3. †Brooklyn College, City University of New York, New York, NY. 4. §Department of Population Health, New York University School of Medicine, New York, NY. 1. 1. Drummond MB, 2. Upson D Electronic Cigarettes: Potential Harms and Benefits. Drummond MB, Upson D. Ann Am Thorac Soc. 2014;11(2):236–242. doi: 10.1513/AnnalsATS.201311-391FR. [OpenUrl][1][CrossRef][2][PubMed][3] 2. 1. Lauterstein D, 2. Hoshino R, 3. Gordon T, 4. Watkins B, 5. Weitzman M, 6. Zelikoff J The Changing Face of Tobacco Use Among United States Youth. Lauterstein D, Hoshino R, Gordon T, Watkins B, Weitzman M, Zelikoff J. Curr Drug Abuse Rev. 2014;7(1): 29–43. [OpenUrl][4][CrossRef][5][PubMed][6] 3. 1. Maziak W, 2. Jawad M, 3. Jawad S, 4. Ward KD, 5. Eissenberg T, 6. Asfar T Interventions for Waterpipe Smoking Cessation. Maziak W, Jawad M, Jawad S, Ward KD, Eissenberg T, Asfar T. Cochrane Database Syst Rev. 2015 Jul 31;7:CD005549. doi: 0.1002/14651858.CD005549.pub3. Almost all cigarette use in the United States begins during adolescence, and about 3 of every 4 adolescent smokers continue to smoke into adulthood. Although overall cigarette consumption in the United States has decreased by 33% in the last decade, overall tobacco use among middle and high school students has demonstrated little to no decline. The United States has witnessed an increase in the use of new, so-called alternative tobacco products (ATPs). The many types of ATPs vary from the more popular smoked products such as electronic cigarettes (e-cigarettes) and hookahs (also known as water-pipes or narghile) to smokeless products such as snus. These ATPs are believed by the public and adolescents to be less harmful, less addictive, and more stylish than cigarettes. They are being promoted as and perceived by adolescents, the general public, and health care clinicians as safer alternatives to traditional cigarettes. Many in the public health community fear that, in the absence of widespread awareness and regulatory policies, ATPs will encourage adolescents to start smoking and, thus, undermine a decades-long campaign to “denormalize” smoking. Rates of past 30-day use of e-cigarettes among middle and high school students tripled from 2013 to 2014, after doubling the year before. From 2010 to 2014, the percentage of high school seniors who used hookahs in the last year increased from 17% to 23%. In 2014, for the first time, e-cigarettes were reported to be the most commonly used tobacco product by high school students (13.4%), ahead of both hookahs … [1]: {openurl}?query=rft.jtitle%253DAnn%2BAm%2BThorac%2BSoc%26rft.volume%253D11%26rft.spage%253D236%26rft_id%253Dinfo%253Adoi%252F10.1513%252FAnnalsATS.201311-391FR%26rft_id%253Dinfo%253Apmid%252F24575993%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1513/AnnalsATS.201311-391FR&link_type=DOI [3]: /lookup/external-ref?access_num=24575993&link_type=MED&atom=%2Fpedsinreview%2F37%2F7%2F310.atom [4]: {openurl}?query=rft.jtitle%253DCurr%2BDrug%2BAbuse%2BRev%26rft.volume%253D7%26rft.spage%253D29%26rft_id%253Dinfo%253Adoi%252F10.2174%252F1874473707666141015220110%26rft_id%253Dinfo%253Apmid%252F25323124%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [5]: /lookup/external-ref?access_num=10.2174/1874473707666141015220110&link_type=DOI [6]: /lookup/external-ref?access_num=25323124&link_type=MED&atom=%2Fpedsinreview%2F37%2F7%2F310.atom

Aims and objectives To describe Chinese women's experiences with "zuo yue zi" in British Columbia, Canada. Background Women born in China and Taiwan are increasingly immigrating to westernised countries. Many women choose to follow traditional Chinese postpartum practices, also called "zuo yue zi." Few studies have examined women's use of traditional practices in western countries. Design The study used a qualitative descriptive design. Methods We recruited 13 mothers who were: aged 19 or older, immigrants from mainland China, Hong Kong or Taiwan in the last 5 years, and caring for infants born in the previous 6 weeks. Semistructured interviews were conducted in Mandarin, translated into English, transcribed and analysed using inductive content analysis. Results The core theme was Chinese women's novel encounters with "zuo yue zi." The women's expectations of "zuo yue zi" were acquired through birth experiences or interactions with family and friends. The participants struggled with implementing traditional practices because social support and formal institutional structures were lacking. They modified their expectations about "zuo yue zi." Factors affecting their practices were catalysts and deterrents. Catalysts included help from Chinese family members, friends and informed healthcare providers. Deterrents included unregulated paid helpers, uninformed care providers, financial constraints and structural limitations in their new environments. Conclusions Chinese immigrant women struggled to modify and implement traditional practices in their adopted country when they encountered financial constraints, unregulated paid helpers and varying support from health care providers. Relevance to clinical practice Some postpartum women following "zuo yue zi" believed that the practice would prevent chronic illness and strengthen their intrafamily relationships. Immigrant mothers require nursing support to follow traditional postpartum practices. Nurses can advocate on patients' behalf to increase care providers' knowledge about "zuo yue zi" and public awareness for necessary regulated institutional structures.

OBJECTIVES: The side population (SP) contains cells with stem cell/progenitor properties. Previously, we observed that the mouse pancreas SP expanded after pancreatic injury. We aimed to characterize the SP in human pancreas as a potential source of stem cells. METHODS: Human organ donor pancreata were fractionated into islets and exocrine tissue, enriched by tissue culture and dispersed into single cells. Cells were phenotyped by flow cytometry, and the SP was defined by efflux of fluorescent dye Hoechst 33342 visualized by ultraviolet excitation. Cells were flow sorted, and their colony-forming potential measured on feeder cells in culture. RESULTS: An SP was identified in islet and exocrine cells from human organ donors: 2 with type 1 diabetes, 3 with type 2 diabetes, and 28 without diabetes. Phenotyping revealed that exocrine SP cells had an epithelial origin, were enriched for carbohydrate antigen 19-9 ductal cells expressing stem cell markers CD133 and CD26, and had greater colony-forming potential than non-SP cells. The exocrine SP was increased in a young adult with type 1 diabetes and ongoing islet autoimmunity. CONCLUSIONS: The pancreatic exocrine SP is a potential reservoir of adult stem/progenitor cells, consistent with previous evidence that such cells are duct-derived and express CD133.

The increased focus on stillbirth related issues in recent years has brought several previously neglected issues ‘out of the shadows’ [1] and highlighted the need for greater preventive efforts and better care for bereaved mothers and families. Some issues (such as the option of cesarean delivery for fetal death at late gestation [2], viewing the fetus following pregnancy termination for a fetal anomaly [3,4] and acknowledgement of paternal grief and anxiety [5]) reflect a substantial shift from previous traditions in clinical practice. At a conceptual level as well, there are challenges that may lead to a break with tradition. These include definitional aspects related to fetal death and stillbirth, and considerations related to the surveillance of pregnancy outcomes. Is fetal death or (still)birth following fetal demise the central event of medical concern? Should fetal deaths due to iatrogenic pregnancy termination be excluded from the definition of fetal death? What viability criteria should be used to distinguish between early pregnancy loss and fetal death at later gestation? Should surveillance of pregnancy outcomes be restricted to viable fetuses or should surveillance be more comprehensive? Do fetal deaths resulting from iatrogenic pregnancy termination constitute private events to be recorded in medical charts or do they require registration and publicly accessible documentation? In this commentary, we briefly review such concerns [6,7], with the hope of initiating an international discussion and consensus. This article is protected by copyright. All rights reserved.

To estimate the probability of spontaneous onset of labour (SOL) among women with uncomplicated pregnancies who have reached 41+0 weeks and to examine the influence of maternal characteristics on this event.We conducted a population-based retrospective cohort study of women with uncomplicated singleton pregnancies in cephalic presentation between 41+0 and 42+0 weeks' gestation. Detailed clinical information was obtained from the British Columbia Perinatal Data Registry. We determined the time from 41+0 weeks to the exact day and time of SOL, pre-labour Caesarean section, or onset of labour following induction. A Kaplan-Meier curve was created to estimate the probability of SOL. A Cox regression model was used to assess the independent influence of maternal age, parity, BMI, and pregnancy weight gain on the SOL, and to assess the extent to which prediction of SOL could be individualized according to a woman's characteristics.Among 15 253 women undelivered at 41+0 weeks, there was a 67.6% (95% CI 66.4% to 68.7%) chance of SOL by 41+6 weeks. Although SOL was statistically more likely in younger women, higher parity, lower BMI, and lower weight gain (P0.01), the multivariable model's predictive ability was poor (c-statistic 0.56).Maternal characteristics were not a strong determinant for successful individualized prediction of SOL in women with uncomplicated pregnancies reaching 41+0 weeks of gestation. Our population-based estimates of the daily occurrence of SOL can be used to inform discussions with women on when to offer induction of labour.

IntroductionSince the identification in 2012 of three risk factors for natalizumab-associated progressive multifocal leukoencephalopathy (PML), changes in the PML incidence rate have been of interest.MethodsThe incidence of confirmed PML cases in Biogen’s postmarketing global safety database from November 2009 to November 2017 was evaluated retrospectively. Overall incidence in natalizumab-exposed patients was determined by the estimated total number of patients exposed and the number of confirmed cases. Changes in exposure patterns over time were evaluated by 12-infusion epochs.ResultsAs of 30 November 2017, 180,656 patients worldwide had received ≥1 dose; overall natalizumab-associated PML incidence was 4.19/1000 patients. Since mid-2016, overall monthly incidence of PML appears to have stabilised, remaining between 4.18 and 4.24/1000. PML incidence was greatest in later, higher risk infusion epochs (≥37 infusions). The relative increase in the proportion of patients in higher-exposure epochs (>24 infusions) has declined from 2013 to 2017.ConclusionsThe stabilisation of overall natalizumab-associated PML incidence beginning mid-2016 coincides with the introduction of a new risk algorithm, suggesting that risk stratification factors are being incorporated into clinical practice and may continue to impact future incidence.Support: Biogen. Disclosures to be included on poster.

To identify maternal, care provider, and institutional-level risk factors for early term (37–38 weeks) elective repeat cesarean delivery in a population-based cohort. Retrospective cohort study of women in the British Columbia (BC) Perinatal Data Registry, BC, Canada, 2008–2011, with an elective repeat cesarean delivery at term. Absolute percent differences (risk differences) in early term delivery rates were calculated according to maternal characteristics, type of care provider, calendar time (day of the week, time of year), and annual institutional obstetrical volume. Of the 7,687 elective repeat cesareans at term in BC, 55 % occurred before 39 + 0 weeks. Early term delivery was significantly more common with multiple previous cesareans [8.2 percentage points (95 % CI 5.5, 10.9) for 2 previous cesareans, 11.3 (95 % CI 5.1, 17.4) for 3 or more previous cesareans], obesity [6.7 percentage points (95 % CI 1.6, 11.7)], and a hospital obstetrical volume

Background: Impairment of apoptosis is a hallmark of cancer and can result in resistance to therapy. Over-expression of the pro-survival protein BCL-2 is common in breast cancer, with elevated levels found in approximately 85% of luminal tumors. Although BCL-2 has been shown to be an important prognostic marker, its role as a therapeutic target has yet to be fully explored. Small molecule inhibitors termed ‘BH3 mimetics’ that mimic the action of pro-apoptotic BH3-only proteins have recently been developed. These bind and neutralize BCL-2 pro-survival proteins. We have previously shown that the BH3 mimetic ABT-737 (which neutralizes BCL-2, BCL-XL and BCL-W) synergizes with docetaxel in BCL-2-positive patient-derived xenograft (PDX) models. Recently, a potent BCL-2-specific inhibitor, ABT-199, has been developed that is showing considerable promise in early phase studies of lymphoid malignancies. Since BCL-2 expression is prominent in the luminal B tumors, we sought to determine whether it might be feasible to target luminal B tumors with combination therapy comprising endocrine therapy (tamoxifen) and a BH3 mimetic (ABT-737 or ABT-199), using novel PDX models of luminal B breast cancer. Methods and Results: A panel of 36 primary breast tumor xenografts (including 15 luminal tumors) was generated in immunocompromised (NOG) mice. Three BCL-2-positive luminal B models (23T, 315T, 50T), as determined by Ki-67 immunostaining and gene expression profiling, and a control BCL-2-positive, ER-negative model (838T) were selected for further study. Cohorts of mice bearing tumor xenografts were treated with either ABT-737 (50 mg/kg i.p. d1-10), tamoxifen or both agents in q21d cycles. Tumor response and overall survival were significantly improved by combination therapy in all three ER-positive xenograft models, when compared to tamoxifen alone (p Discussion: Patient derived xenograft models of luminal B breast cancer have been derived that recapitulate the phenotype of the primary tumor. Here we have demonstrated that concomitant targeting of BCL-2 confers marked benefit above tamoxifen alone. Moreover, synergy between BH3 mimetics and PI3K/mTOR inhibitors could be exploited by targeting of both survival pathways, a strategy that appeared both safe and effective. Collectively, our findings provide a rationale for clinical evaluation of BH3 mimetics in early phase studies in breast cancer. Here, BCL-2 protein or mRNA expression (as determined by immunohistochemistry or RT-PCR, respectively) could provide a suitable companion biomarker for patient selection. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-01.

Objective To review the most current literature in order to provide evidence-based recommendations to obstetrical care providers on induction of labour. Options Intervention in a pregnancy with induction of labour. Outcomes Appropriate timing and method of induction, appropriate mode of delivery, and optimal maternal and perinatal outcomes. Evidence Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library in 2010 using appropriate controlled vocabulary (e.g., labour, induced, labour induction, cervical ripening) and key words (e.g., induce, induction, augmentation). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to the end of 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values The evidence in this document was rated using criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1).

Resume Objectif Analyser la litterature la plus recente afin de formuler des recommandations factuelles a l'intention des fournisseurs de soins obstetricaux au sujet du declenchement du travail. Options Mise en œuvre d'un declenchement du travail dans le cadre d'une grossesse. Issues Chronologie et methode appropriees pour ce qui est du declenchement, mode d'accouchement approprie et issues maternelles et perinatales optimales. Resultats La litterature publiee a ete recuperee par l'intermediaire de recherches menees dans PubMed, CINAHL et The Cochrane Library en 2010, au moyen d'un vocabulaire controle (p. ex. « labour », « induced », « labour induction », « cervical ripening ») et de mots cles (p. ex. « induce », « induction », « augmentation ») appropries. Les resultats ont ete restreints aux analyses systematiques, aux essais comparatifs randomises / essais cliniques comparatifs et aux etudes observationnelles. Aucune restriction n'a ete appliquee en matiere de date ou de langue. Les recherches ont ete mises a jour de facon reguliere et integrees a la directive clinique jusqu'a la fin de 2010. La litterature grise (non publiee) a ete identifiee par l'intermediaire de recherches menees dans les sites Web d'organismes s'interessant a l'evaluation des technologies dans le domaine de la sante et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques et aupres de societes de specialite medicale nationales et internationales. Valeurs La qualite des resultats est evaluee au moyen des criteres decrits dans le rapport du Groupe d'etude canadien sur les soins de sante preventifs (Tableau 1).

SummaryThe prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer.