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Background: The Hajj is an annual religious mass gathering event held in Makkah, Saudi Arabia. With millions of participants from across the globe attending the Hajj, the risk of importation, transmission, and global spread of infectious diseases is high. The emergence of antimicrobial resistant (AMR) bacteria is of worldwide concern and the Hajj poses a serious risk to its dissemination. This review aims to synthesize published literature on AMR bacteria acquisition and transmission associated with the Hajj. Methods: We searched electronic databases to identify literature published between January 1990 and December 2021. The search strategy included medical subject headings and keyword terms related to AMR bacteria and the Hajj. Results: After screening 2214 search results, 51 studies were included in the analysis. The review found 6455 AMR bacteria transmissions related to the Hajj. Thirty predominantly enteric or respiratory disease-causing AMR bacterial species were reported with isolates identified in cases on five continents. Most were male, aged above 50 years and were diagnosed in Makkah. Most cases were identified through hospital-based research; few cases were detected in community or primary health care settings. Conclusions: This review provides a contemporary account of knowledge related to AMR transmission at the Hajj. It emphasizes the need for the enhancement of surveillance for AMR bacteria globally.

OBJECTIVES: It is important to understand relationships of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension, given their high baseline risk of adverse outcomes. We assessed associations of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension by pre-pregnancy body mass index categories. STUDY DESIGN: We identified 14,369 women with chronic hypertension using electronic health records from 3 integrated health care delivery systems (2005-2014). Gestational weight gain-for-gestational age charts were used to calculate gestational weight gain z-scores, which account for gestational age. Modified Poisson regression models using generalized estimating equations were used to calculate relative risks and 95% confidence intervals, adjusted for sociodemographic and medical characteristics. MAIN OUTCOME MEASUREMENTS: Preeclampsia, preterm delivery, cesarean delivery, neonatal intensive care unit admission, birthweight (extracted from the electronic health record) RESULTS: In women with normal weight or overweight, low gestational weight gain (z-score1) was associated with 40-90% greater risk of preeclampsia and 59-113% greater risk of LGA. In women with obesity, low GWG was associated with 27-54% lower risk of several adverse pregnancy outcomes, including preeclampsia and cesarean delivery. CONCLUSIONS: In women with chronic hypertension and normal weight or overweight, moderate gestational weight gain may confer the lowest risk of adverse outcomes. In women with chronic hypertension and obesity, low gestational weight gain may be necessary for the lowest risk of adverse pregnancy outcomes.

Key Points Question How does the prevalence of hypertension in pregnant women change when using the 2017 American College of Cardiology/American Heart Association definition, which is lower than the American College of Obstetricians and Gynecologists threshold, and is there an association with maternal or fetal outcomes? Findings In this cohort study that included 137 389 pregnancies, the prevalence of hypertension increased from 10.3% to 28.1% and resulted in a net reclassification index of 20.8% for the identification of future preeclampsia and 3.8% for the identification of fetal/neonatal adverse events. Meaning These findings suggest that applying the lower diagnostic thresholds to pregnant women may better identify women at risk of adverse events., This cohort study estimates the prevalence of hypertension among pregnant women using the 2017 American College of Cardiology/American Heart Association (ACC/AHA) definition of hypertension instead of the American College of Obstetricians and Gynecologists threshold and assesses identification of adverse maternal or fetal outcomes associated with use of the ACC/AHA guidelines., Importance Hypertensive disorders of pregnancy are a leading cause of maternal morbidity and mortality. The impact of applying recent guideline definitions for nonpregnant adults to pregnant women is unclear. Objective To determine whether reclassification of hypertensive status using the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline definition better identifies women at risk for preeclampsia or eclampsia and adverse fetal/neonatal events compared with the current American College of Obstetricians and Gynecologists (ACOG) definition of hypertension. Design, Setting, and Participants This cohort study used electronic medical record data of women who delivered singleton infants between 2009 and 2014 at a large US regional health system. Data analysis was performed from July 2020 to September 2020. Exposure Application of ACC/AHA and ACOG guidelines for the definition of chronic and gestational hypertension. Main Outcomes and Measures The primary maternal end point was the development of preeclampsia or eclampsia, and the primary fetal/neonatal end point was a composite of preterm birth, small for gestational age, and neonatal intensive care unit admission within 28 days of delivery. Net reclassification indices were calculated to examine how well the lower ACC/AHA diagnostic threshold reclassifies outcomes of pregnancy compared with the current ACOG definition of hypertension. Results Applying the ACC/AHA criteria to 137 389 pregnancies of women (mean [SD] age at time of delivery, 30.1 [5.8] years) resulted in a 14.3% prevalence of chronic hypertension (19 621 pregnancies) and a 13.8% prevalence of gestational hypertension (18 998 pregnancies). A 17.8% absolute increase was found in the overall prevalence of hypertension from 10.3% to 28.1%. The 2.1% of women who were reclassified with chronic rather than gestational hypertension had the highest risk of developing preeclampsia compared with women without hypertension by either criterion (adjusted risk ratio, 13.58; 95% CI, 12.49-14.77). Overall, the use of the ACC/AHA criteria to diagnose hypertension resulted in a 20.8% improvement in the appropriate identification of future preeclampsia, but only a 3.8% improvement of appropriate fetal/neonatal risk classification. Conclusions and Relevance Using the lower diagnostic threshold for hypertension recommended in the 2017 ACC/AHA guideline increased the prevalence of chronic and gestational hypertension, markedly improved the appropriate identification of women who would go on to develop preeclampsia, and was associated with the identification of adverse fetal/neonatal risk.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of 98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. Conclusion: The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease.

ObjectiveTo employ diffusion imaging connectome methods to explore network development in the contralesional hemisphere of children with perinatal stroke and its relationship to clinical function. We hypothesized alterations in global efficiency of the intact hemisphere would correlate with clinical disability.MethodsChildren with unilateral perinatal arterial (n = 26) or venous (n = 27) stroke and typically developing controls (n = 32) underwent 3T diffusion and T1 anatomical MRI and completed established motor assessments. A validated atlas coregistered to whole-brain tractography for each individual was used to estimate connectivity between 47 regions. Graph theory metrics (assortativity, hierarchical coefficient of regression, global and local efficiency, and small worldness) were calculated for the left hemisphere of controls and the intact contralesioned hemisphere of both stroke groups. Validated clinical motor assessments were then correlated with connectivity outcomes.ResultsGlobal efficiency was higher in arterial strokes compared to venous strokes (p < 0.001) and controls (p < 0.001) and was inversely associated with all motor assessments (all p < 0.012). Additional graph theory metrics including assortativity, hierarchical coefficient of regression, and local efficiency also demonstrated consistent differences in the intact hemisphere associated with clinical function.ConclusionsThe structural connectome of the contralesional hemisphere is altered after perinatal stroke and correlates with clinical function. Connectomics represents a powerful tool to understand whole brain developmental plasticity in children with disease-specific cerebral palsy.

Objective: To identify gender differences in opioid prescribing from ambulatory care settings and identify factors associated with prescribing of opioids for men and women. Design and participants: Retrospective analysis of data from The National Ambulatory Medical Care Survey from January 1, 2006 to December 31, 2015. Eligible patients were at least 18 years old on the date of the physician office visit. Data were collected on patient demographics and clinical factors. Data were analyzed using bivariate and multivariate logistic regression models to explore differences in opioid prescribing among men and women. Due to the large sample size, the significance level was set to p < 0.001. Main outcome measure: Opioid prescribing during an office visit. Results: A total of 322 957 ambulatory care visits for adults were included in the analysis representing 7.8 billion weighted visits nationally. In 771 601 088 (9.8 percent) visits, an opioid was prescribed. Women received an opioid prescription at 9.4 percent of visits compared to 10.4 percent of visits for men. Gender differences for factors including age, region, payment method, and pain diagnosis were observed (p < 0.001). Women had a higher number of visits with an opioid (449 277 925 vs 322 323 163), but men had higher odds of being prescribed an opioid (OR: 1.214; CI: 1.214-1.214). Conclusion: Men are more likely to be prescribed an opioid as compared to women, but women are being prescribed more opioids overall. Gender differences should be further explored to develop gender-specific interventions to reduce opioid prescribing.

Perinatal stroke affects ∼1 in 1000 births and concomitant cognitive impairments are common but poorly understood. Rates of Attention Deficit/Hyperactivity Disorder (ADHD) are increased 5–10× and executive dysfunction can be disabling. We used diffusion imaging to investigate whether stroke‐related differences in frontal white matter (WM) relate to cognitive impairments. Anterior forceps were isolated using tractography and sampled along the tract. Resulting metrics quantified frontal WM microstructure. Associations between WM metrics and parent ratings of ADHD symptoms (ADHD‐5 rating scale) and executive functioning (Behavior Rating Inventory of Executive Function (BRIEF)) were explored. Eighty‐three children were recruited (arterial ischemic stroke [AIS] n = 26; periventricular venous infarction [PVI] n = 26; controls n = 31). WM metrics were altered for stroke groups compared to controls. Along‐tract analyses showed differences in WM metrics in areas approximating the lesion as well as more remote differences at midline and in the nonlesioned hemisphere. WM metrics correlated with parental ratings of ADHD and executive function such that higher diffusivity values were associated with poorer function. These findings suggest that underlying microstructure of frontal white matter quantified via tractography may provide a relevant biomarker associated with cognition and behavior in children with perinatal stroke., Perinatal stroke affects ∼1 in 1000 births and concomitant cognitive impairments such as Attention Deficit/Hyperactivity Disorder (ADHD) and executive dysfunction can be disabling. We used diffusion tensor imaging (DTI) to investigate whether stroke‐related differences in frontal white matter (WM) relate to cognitive impairments. WM metrics correlated with parental ratings of ADHD and executive function suggesting that underlying microstructure of frontal white matter quantified via tractography may provide a relevant biomarker associated with cognition and behavior in children with perinatal stroke.

Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

In this study, we examined the degree to which children's level of anxiety sensitivity (AS) was a precursor to both internalizing problems and peer victimization experiences. Participants were 581 fourth-grade children (M age = 9.31; 51.8% girls; 42.3% Hispanic/Latinx) and their teachers. Measures of AS, internalizing problems, and peer victimization were collected across a single academic year (Fall, Spring). Structural equation modeling and logistic regression analyses indicated AS predicted future internalizing symptoms as well as self- and teacher-reports of peer victimization. Also, children with heightened AS were 2.70 times more likely to reach elevated levels of self-rated peer victimization and 11.53 times more likely to have clinically elevated internalizing problems. This is the first study to examine prospectively the link between AS and children's peer victimization experiences. We discuss implications of the findings for developing preventative interventions for children at risk for peer victimization and internalizing difficulties.

Anticyclic citrullinated peptide (anti-CCP) positivity may be a strong predictor of joint erosion and a potential biomarker for guiding treatment decisions for rheumatoid arthritis (RA). However, limited studies are currently available on the effect of anti-CCP positivity on health care utilization and/or medical costs of RA patients.To investigate short-term and long-term direct health care expenditures associated with anti-CCP positivity in newly diagnosed RA patients.A retrospective cohort study was conducted in adult RA patients within a U.S. integrated health care delivery system (January 1, 2007-June 30, 2015). Patients were required to have 2 RA diagnoses and treatment with a conventional or biologic disease-modifying antirheumatic drug (DMARD) within 12 months. The first RA diagnosis date was labeled as the index date, and patients were followed until they left the health plan, died, or reached the end of the study period. Patient demographics, anti-CCP results, comorbid conditions, and health care resource utilization during baseline (12 months before the index date) and follow-up periods were collected. Nationally recognized direct medical costs were assigned to health care utilization to calculate health care costs in 2015 U.S. dollars. The baseline differences between anti-CCP positivity and negativity and differences in censoring during follow-up were addressed using propensity scores. The mean differences in costs were estimated using recycled prediction methods.2,448 newly diagnosed RA patients were identified and followed for a median of 3.7 years (range = 1-8 years). At baseline, 65.8% of patients were anti-CCP positive. Anti-CCP-positive patients had fewer comorbid conditions at baseline. During the first 12 months of follow-up, median (interquartile range) total health care expenditures for anti-CCP-positive and anti-CCP-negative patients were $6,200 ($3,563-$13,260) and $7,022 ($3,885-$12,995), respectively. After adjusting for baseline differences, total incremental mean cost associated with anti-CCP positivity during the first 12 months was estimated to be $2,163 per patient (P = 0.001). The annual incremental costs in anti-CCP-positive patients became progressively larger over time, from $2,163 during the first year to $5,062 during the fourth year. Anti-CCP positivity was associated with higher prescription, laboratory testing, and rheumatologist utilization. A higher percentage of anti-CCP-positive patients received 1 or more biologic DMARDs (11.6% for anti-CCP-positive vs. 5.7% for anti-CCP negative; P0.001) compared with anti-CCP-negative patients during the 12-month follow-up, which resulted in $2,499 in incremental prescription costs (P0.001). Total additional burden associated with anti-CCP positivity during the first 4 years was estimated to be $14,089 per patient.In newly diagnosed RA patients, higher economic burden associated with anti-CCP positivity was mainly driven by prescription costs.This research and manuscript were funded by Bristol-Myers Squibb (BMS). Alemao and Connolly are employees and shareholders of BMS and participated in the design of the study, interpretation of the data, review/revision of the manuscript, and approval of the final version of the manuscript. An and Cheetham received a grant from BMS for this research. At the time of this study, An was employed by Western University of Health Sciences, and Cheetham was employed by Kaiser Permanente Southern California. Bider-Canfield, Kang, and Lin have nothing to disclose. Some study results were presented as a poster at the American College of Rheumatology Annual Meeting; November 5, 2017; San Diego, CA, and at the International Society for Pharmacoeconomics and Outcomes Research Meeting; May 19, 2018; Baltimore, MD.

Most cases of hemiparetic cerebral palsy are caused by perinatal stroke, resulting in lifelong disability for millions of people. However, our understanding of how the motor system develops following such early unilateral brain injury is increasing. Tools such as neuroimaging and brain stimulation are generating informed maps of the unique motor networks that emerge following perinatal stroke. As a focal injury of defined timing in an otherwise healthy brain, perinatal stroke represents an ideal human model of developmental plasticity. Here, we provide an introduction to perinatal stroke epidemiology and outcomes, before reviewing models of developmental plasticity after perinatal stroke. We then examine existing therapeutic approaches, including constraint, bimanual and other occupational therapies, and their potential synergy with non-invasive neurostimulation. We end by discussing the promise of exciting new therapies, including novel neurostimulation, brain-computer interfaces and robotics, all focused on improving outcomes after perinatal stroke.

Objective To compare maternal and infant outcomes with different antihypertensive medications in pregnancy. Design Retrospective cohort study. Setting Kaiser Permanente, a large healthcare system in the United States. Population Women aged 15–49 years with a singleton birth from 2005–2014 treated for hypertension. Methods We identified medication exposure from automated pharmacy data based on the earliest dispensing after the first prenatal visit. Using logistic regression, we calculated weighted outcome prevalences, adjusted odds ratios (aORs) and 95% confidence intervals, with inverse probability of treatment weighting to address confounding. Main outcome measures Small for gestational age, preterm delivery, neonatal and maternal intensive care unit (ICU) admission, preeclampsia, and stillbirth or termination at > 20 weeks. Results Among 6346 deliveries, 87% with chronic hypertension, the risk of the infant being small for gestational age (birthweight < 10th percentile) was lower with methyldopa than labetalol (prevalence 13.6% vs. 16.6%; aOR 0.77, 95% CI 0.63 to 0.92). For birthweight < 3rd percentile the aOR was 0.57 (0.39 to 0.80). Compared with labetalol (26.0%), risk of preterm delivery was similar for methyldopa (26.5%; aOR 1.10 [0.95 to 1.27]) and slightly higher for nifedipine (28.5%; aOR 1.25 [1.06 to 1.46]) and other β-blockers (31.2%; aOR 1.58 [1.07 to 2.23]). Neonatal ICU admission was more common with nifedipine than labetalol (25.9% vs. 23.3%, aOR 1.21 [1.02 to 1.43]) but not elevated with methyldopa. Risks of other outcomes did not differ by medication. Conclusions Risk of most outcomes was similar comparing labetalol, methyldopa and nifedipine. Risk of the infant being small for gestational age was substantially lower for methyldopa, suggesting this medication may warrant further consideration.

Context: Solomon Islands is a small developing island state located in the south-western Pacific Ocean. A population of approximately 680 000 people live on more than one-third of the 992 islands that make up the country. Approximately 80% of the population reside in rural areas, many in remote, difficult to reach and poorly serviced island settings. Issue: In May 2019, the national surveillance system detected a rumour of a severe diarrhoea outbreak in a very remote and isolated community on Anuta Island, located halfway between the Solomon Islands archipelago and Tuvalu. This communication reports on the investigation and response to the outbreak, which affected 50 people (attack rate of 21.5%) and caused four deaths (case fatality rate of 8%). The authors highlight the system challenges faced in mounting the response and provide suggestions that may help overcome them. Lessons learned: The outbreak highlighted the challenges in detecting and responding to outbreaks in remote and rural areas of the Pacific Islands, and the limitations of rumour surveillance as a relied-upon surveillance strategy. The outbreak emphasises the need to build local capacity to detect, report and respond to outbreaks and the need for policy frameworks that ensure remote communities receive adequate health protection services.

Importance Azithromycin is one of the most commonly prescribed antibiotics in the US. It has been associated with an increased risk of cardiovascular death in some observational studies. Objective To estimate the relative and absolute risks of cardiovascular and sudden cardiac death after an outpatient azithromycin prescription compared with amoxicillin, an antibiotic not known to increase cardiovascular events. Design, Setting, and Participants This retrospective cohort study included 2 large, diverse, community-based integrated care delivery systems with comprehensive capture of encounters and prescriptions from January 1, 1998, to December 31, 2014. The cohort included patients aged 30 to 74 years who had at least 12 months of health-plan enrollment prior to antibiotic exposure. The exclusion criteria were absence of prescription benefits, prescription for more than 1 type of study antibiotic within 10 days, hospitalization or nursing home residence, and serious medical conditions. Risk of cardiovascular death associated with azithromycin vs amoxicillin exposure was calculated after controlling for confounding factors using a propensity score. Data were analyzed from December 1, 2016, to March 30, 2020. Exposures Outpatient prescription of azithromycin or amoxicillin. Main Outcomes and Measures The primary outcomes were cardiovascular death and sudden cardiac death. An a priori subgroup analysis quantified the effects of azithromycin exposure among patients with increased baseline cardiovascular risk. The secondary outcomes were noncardiovascular death and all-cause mortality. Results The study included 7 824 681 antibiotic exposures, including 1 736 976 azithromycin exposures (22.2%) and 6 087 705 amoxicillin exposures (77.8%), among 2 929 008 unique individuals (mean [SD] age, 50.7 [12.3] years; 1 810 127 [61.8%] women). Azithromycin was associated with a significantly increased hazard of cardiovascular death (hazard ratio [HR], 1.82; 95% CI, 1.23-2.67) but not sudden cardiac death (HR, 1.59; 95% CI, 0.90-2.81) within 5 days of exposure. No increases in risk were found 6 to 10 days after exposure. Similar results were observed in patients within the top decile of cardiovascular risk (HR, 1.71; 95% CI, 1.06-2.76). Azithromycin was also associated with an increased risk of noncardiovascular death (HR, 2.17; 95% CI, 1.44-3.26) and all-cause mortality (HR, 2.00; 95% CI, 1.51-2.63) within 5 days of exposure. Conclusions and Relevance These findings suggest that outpatient azithromycin use was associated with an increased risk of cardiovascular death and noncardiovascular death. Causality cannot be established, particularly for noncardiovascular death, owing to the likelihood of residual confounding.

Objectives Physical function is a core outcome in PsA. We examined the construct validity and responsiveness of three commonly used instruments to assess physical function in PsA: HAQ disability index (HAQ-DI), MultiDimensional HAQ (MDHAQ) and the Patient-Reported Outcomes Measurement Information System (PROMIS®) Global-10. Methods Between 2016 and 2019, patients with PsA were enrolled in the Psoriatic Arthritis Research Consortium longitudinal cohort study in the USA. Correlations were calculated at baseline and among change scores using Spearman’s correlation coefficient. Standardized response means were calculated. Agreement with the 20% improvement cut-off was used to determine the potential effect of using MDHAQ or the PROMIS Global-10 physical health (GPH) subscore in place of HAQ-DI when assessing the ACR20. Results A total of 274 patients were included in the analysis. The mean age of patients was 49 years and 51% were male. At baseline, the mean HAQ-DI was 0.6 (s.d. 0.6; range 0–3), the mean MDHAQ was 1.8 (s.d. 1.6; range 0–10) and the mean GPH T-score was 43.4 (s.d. 9.3; range 0–100). All three instruments were strongly correlated at baseline (rho 0.75–0.85). Change scores were moderately correlated (rho 0.42–0.71). Among therapy initiators, the mean change between two visits in HAQ-DI, MDHAQ and GPH was −0.1 (s.d. 0.4), −0.2 (s.d. 1.2) and 2.5 (s.d. 6.1), respectively. The standardized response means were 0.18, 0.16 and 0.41, respectively. Conclusion The three instruments tested are not directly interchangeable but have overall similar levels of responsiveness.

Purpose The use of validated criteria to identify birth defects in electronic healthcare databases can avoid the cost and time-intensive efforts required to conduct chart reviews to confirm outcomes. This study evaluated the validity of various case-finding methodologies to identify neural tube defects (NTDs) in infants using an electronic healthcare database. Methods This analysis used data generated from a study whose primary aim was to evaluate the association between first-trimester maternal prescription opioid use and NTDs. The study was conducted within the Medication Exposure in Pregnancy Risk Evaluation Program. A broad approach was used to identify potential NTDs including diagnosis and procedure codes from inpatient and outpatient settings, death certificates and birth defect flags in birth certificates. Potential NTD cases were chart abstracted and confirmed by clinical experts. Positive predictive values (PPVs) and 95% confidence intervals (95% CI) are reported. Results The cohort included 113 168 singleton live-born infants: 55 960 infants with opioid exposure in pregnancy and 57 208 infants unexposed in pregnancy. Seventy-three potential NTD cases were available for the validation analysis. The overall PPV was 41% using all diagnosis and procedure codes plus birth certificates. Restricting approaches to codes recorded in the infants' medical record or to birth certificate flags increased the PPVs (72% and 80%, respectively) but missed a substantial proportion of confirmed NTDs. Conclusions Codes in electronic healthcare data did not accurately identify confirmed NTDs. These results indicate that chart review with adjudication of outcomes is important when conducting observational studies of NTDs using electronic healthcare data.

Objective To incorporate blood pressure (BP), diagnoses codes, and medication fills from electronic medical records (EMR) to identify pregnant women with hypertension. Study design A retrospective cohort study of singleton pregnancies at three US integrated health delivery systems during 2005–2014. Main outcome measures Women were considered hypertensive if they had any of the following: (1) ≥2 high BPs (≥140/90 mmHg) within 30 days during pregnancy (High BP); (2) an antihypertensive medication fill in the 120 days before pregnancy and a hypertension diagnosis from 1 year prior to pregnancy through 20 weeks gestation (Treated Chronic Hypertension); or (3) a high BP, a hypertension diagnosis, and a prescription fill within 7 days during pregnancy (Rapid Treatment). We described characteristics of these pregnancies and conducted medical record review to understand hypertension presence and severity. Results Of 566,624 pregnancies, 27,049 (4.8%) met our hypertension case definition: 24,140 (89.2%) with High BP, 5,409 (20.0%) with Treated Chronic Hypertension, and 5,363 (19.8%) with Rapid Treatment (not mutually exclusive). Of hypertensive pregnancies, 19,298 (71.3%) received a diagnosis, 9,762 (36.1%) received treatment and 11,226 (41.5%) had a BP ≥ 160/110. In a random sample (n = 55) of the 7,559 pregnancies meeting the High BP criterion with no hypertension diagnosis, clinical statements about hypertension were found in medical records for 58% of them. Conclusion Incorporating EMR BP identified many pregnant women with hypertension who would have been missed by using diagnosis codes alone. Future studies should seek to incorporate BP to study treatment and outcomes of hypertension in pregnancy.

Background Treatment of superficial venous reflux in addition to compression therapy accelerates venous leg ulcer healing and reduces ulcer recurrence. The aim of this study was to evaluate the costs and cost-effectiveness of early versus delayed endovenous treatment of patients with venous leg ulcers. Methods This was a within-trial cost-utility analysis with a 1-year time horizon using data from the EVRA (Early Venous Reflux Ablation) trial. The study compared early versus deferred endovenous ablation for superficial venous truncal reflux in patients with a venous leg ulcer. The outcome measure was the cost per quality-adjusted life-year (QALY) over 1 year. Sensitivity analyses were conducted with alternative methods of handling missing data, alternative preference weights for health-related quality of life, and per protocol. Results After early intervention, the mean(s.e.m.) cost was higher (difference in cost per patient £163(318) (€184(358))) and early intervention was associated with more QALYs at 1 year (mean(s.e.m.) difference 0·041(0·017)). The incremental cost-effectiveness ratio (ICER) was £3976 (€4482) per QALY. There was an 89 per cent probability that early venous intervention is cost-effective at a threshold of £20 000 (€22 546)/QALY. Sensitivity analyses produced similar results, confirming that early treatment of superficial reflux is highly likely to be cost-effective. Conclusion Early treatment of superficial reflux is highly likely to be cost-effective in patients with venous leg ulcers over 1 year. Registration number: ISRCTN02335796 (http://www.isrctn.com).

The emergence of Zika virus has challenged outbreak surveillance systems in many at-risk, low-resource countries. As the virus has been linked with Guillain-Barré syndrome, routine data on the incidence of acute flaccid paralysis (AFP) may provide a useful early warning system for the emergence of Zika virus.We documented all Zika virus outbreaks and cases in 21 Pacific Islands and territories for the years 2007 to 2015. We extracted data from the Global Polio Eradication Initiative database on the reported and expected annual incidence of AFP in children younger than 15 years. Using a Poisson probability test, we tested the significance of unexpected increases in AFP in years correlating with Zika virus emergence. Data were analysed separately for each Pacific Island country and territory.In most Pacific Island countries, early warning surveillance for acute public health threats such as Zika virus is hampered by poor health infrastructure, insufficient human resources and geographical isolation.Only one example was found (Solomon Islands in 2015) of a significant increase in reported AFP cases correlating with Zika virus emergence.We found no conclusive evidence that routinely reported AFP incidence data in children were useful for detecting emergence of Zika virus in this setting. More evidence may be needed from adult populations, who are more likely to be affected by Guillain-Barré syndrome. Reporting of AFP may be deficient in regions certified as polio-free.L'émergence du virus Zika pose un problème pour les systèmes de surveillance des épidémies dans de nombreux pays à faibles ressources et à risque. Étant donné qu'un lien a été établi entre ce virus et le syndrome de Guillain-Barré, les données systématiquement collectées sur l'incidence de la paralysie flasque aiguë (PFA) pourraient peut-être aider à établir un système d'alerte anticipée pour l'émergence du virus Zika.Nous avons documenté toutes les flambées de virus Zika et tous les cas d'infection à virus Zika dans 21 îles et territoires du Pacifique, sur la période 2007 à 2015. À partir de la base de données de l'Initiative mondiale pour l’éradication de la poliomyélite, nous avons extrait des données sur l'incidence annuelle signalée et l'incidence annuelle prévue de la PFA chez les enfants de moins de 15 ans. En utilisant un test de probabilité de Poisson, nous avons testé la significativité de la corrélation entre les augmentations annuelles imprévues des cas de PFA et l’émergence du virus Zika. Les données ont été analysées séparément pour chaque territoire et chaque île du Pacifique.Dans la plupart des îles du Pacifique, les activités de surveillance et d'alerte anticipée des menaces aiguës de santé publique (telles que celle représentée par le virus Zika) sont rendues difficiles par les déficiences des infrastructures de santé, l'insuffisance des ressources humaines et l'isolement géographique des populations.Nous n'avons constaté qu'un seul exemple (Îles Salomon, 2015) d'une augmentation significative des cas signalés de PFA coïncidant avec une émergence du virus Zika.Nous n'avons trouvé aucune preuve concluante permettant d'affirmer que les données systématiquement signalées sur l'incidence de la PFA chez les enfants ont été utiles, dans ces contextes, pour détecter une émergence du virus Zika. Des données complémentaires pourraient être nécessaires en lien avec les populations adultes, qui sont plus susceptibles d'être affectées par le syndrome de Guillain-Barré. Il est également possible que le signalement des PFA soit défaillant dans ces régions certifiées exemptes de poliomyélite.La aparición del virus de Zika ha puesto en peligro los sistemas de control del brote en muchos países en riesgo con escasos recursos. Dado que el virus se ha relacionado con el síndrome de Guillain-Barré, los datos rutinarios sobre la incidencia de parálisis flácida aguda (PFA) pueden proporcionar un sistema de advertencia temprana útil para la aparición del virus de Zika.Se documentaron todos los brotes y casos del virus de Zika en 21 islas y territorios del Pacífico entre los años 2007 y 2015. Se recopiló información de la base de datos de la Iniciativa de Erradicación Mundial de la Poliomielitis sobre la incidencia anual de PFA informada y prevista en niños menores de 15 años. Utilizando una prueba de probabilidad de Poisson, se demostró la importancia de los aumentos inesperados de PFA en los años correlacionados con la aparición del virus de Zika. Se analizaron los datos por separado por cada país y territorio de las Islas del Pacífico.En la mayoría de los países de las Islas del Pacífico, el control de aviso temprano para amenazas sanitarias públicas agudas como el virus de Zika se ve obstaculizado por una infraestructura sanitaria pobre, escasos recursos humanos y aislamiento geográfico.Únicamente se encontró un ejemplo (Islas Salomón en 2015) de un gran aumento en los casos de PFA informada que se correlacionaron con la aparición del virus de Zika.No se encontraron pruebas concluyentes de que los datos de incidencia de PFA informada de forma rutinaria en niños fueran útiles para detectar la aparición del virus de Zika en esta región. Es posible que se necesiten más pruebas de la población adulta, ya que esta tiene más probabilidades de ser afectada por el síndrome de Guillain-Barré. La notificación de casos de PFA puede ser deficiente en algunas regiones sin incidencias de poliomielitis.شكل ظهور فيروس زيكا تحديًا لأنظمة الرصد المنتشرة في العديد من البلدان منخفضة الموارد والمعرضة للخطر. وحيث إن الفيروس يرتبط بمتلازمة غيان-باريه، فقد توفر البيانات الروتينية المتعلقة بالإصابة بشلل الرخو الحاد (AFP) نظام تحذير مفيد ومبكر فيما يتعلق بتفشي فيروس زيكا.لقد قمنا بتوثيق جميع حالات تفشي فيروس زيكا في 21 إقليمًا وجزيرة من جزر المحيط الهادئ للسنوات من 2007 وحتى 2015. وقمنا باستخراج البيانات من قاعدة البيانات الخاصة بالمبادرة العالمية لاستئصال شلل الأطفال فيما يتعلق بحالات الإصابة بالشلل الرخو الحاد (AFP) سنويًا بين الأطفال دون سن 15 عامًا. وباستخدام اختبار بواسون للاحتمالات، قمنا باختبار أهمية الزيادات غير المتوقعة في حالات الإصابة بالشلل الرخو الحاد (AFP) في السنوات المرتبطة بتفشي فيروس زيكا. وتم تحليل البيانات بشكلٍ منفصل لكل إقليم ودولة من دول جزر المحيط الهادئ.في أغلب دول جزر المحيط الهادئ، تتم عرقلة رصد التحذيرات المبكرة لتهديدات الصحة العامة الخطرة مثل زيكا فيروس من قبل البنية الأساسية الصحية السيئة، وعدم كفاية الموارد البشرية، والعزل الجغرافي.لم يتم العثور إلا على مثال واحد (جزر سليمان سنة 2015) من الزيادة الواضحة في حالات الإصابة بالشلل الرخو الحاد (AFP) المبلغ عنها المرتبطة بتفشي فيروس زيكا.لم نعثر على دليل قاطع يشير إلى أن البيانات المتعلقة بحالات الإصابة بالشلل الرخو الحاد (AFP) في الأطفال المبلغ عنها بشكلٍ روتيني كانت مفيدة في الكشف عن تفشي فيروس زيكا في هذه البيئة. قد يلزم وجود المزيد من الأدلة من القطاعات السكانية من البالغين الأكثر عرضة للتأثر بمتلازمة غيان-باريه. قد يكون الإبلاغ عن الإصابة بالشلل الرخو الحاد (AFP) ضعيفًا في المناطق المصنفة على أنها خالية من شلل الأطفال.寨卡病毒的出现对许多存在感染风险且资源匮乏国家的疫情监测系统提出了挑战。 由于该病毒与格林 - 巴利综合征有关，有关急性弛缓性麻痹 (AFP) 发病率的常规数据可提供一个有效的监测寨卡病毒出现的早期预警系统。.我们记录了 2007 年至 2015 年间 21 个太平洋岛屿及地区的所有寨卡病毒疫情和病例，并从全球根除脊髓灰质炎行动数据库中提取了 15 岁以下儿童年 AFP 发病率的报告值和预测值数据。 我们利用泊松概率测试 (Poisson probability test) 对寨卡病毒出现年份里 AFP 发病率的意外增加进行了显著性测试。 每个太平洋岛屿国家和地区的数据进行了独立分析。.在大多数太平洋岛屿国家，对诸如寨卡病毒等突发公共卫生威胁的早期预警监测受到薄弱的卫生基础设施、人力资源不足以及地域隔离的制约。.在报告的寨卡病毒出现相关 AFP 病例中，仅发现一例 AFP 发病率显著增加的病例（2015 年，所罗门群岛）。.我们没有发现明确证据表明定期报告儿童 AFP 发病率数据有助于检测该地区寨卡病毒的出现。 我们可能需要从更有可能感染格林 - 巴利综合征的成年人口那里获得更多证据。 AFP 报告在被证实无脊髓灰质炎的地区可能作用有限。.Появление вируса Зика — важный предмет систем эпидемиологического надзора во многих бедных странах риска. Так как вирус был ассоциирован с синдромом Гийена — Барре, регулярно собираемые данные по заболеваемости остро развивающимся периферическим параличом (ОРПП) могут служить для полезной системы раннего предупреждения по вирусу Зика.Нами задокументированы все вспышки и случаи заражения вирусом Зика на 21 острове и территории Океании в период с 2007 по 2015 год. Сведения были получены из базы данных Глобальной инициативы по ликвидации полиомиелита и касались сообщаемой и прогнозируемой ежегодной заболеваемости ОРПП у несовершеннолетних моложе 15 лет. С помощью критерия Пуассона нами была проверена статистическая значимость неожиданных повышений частоты ОРПП по годам, коррелирующая с заболеваемостью вирусом Зика. Данные были проанализированы отдельно для каждого острова и территории Океании.В большинстве стран Океании ранний предупреждающий надзор по таким важным угрозам для здоровья, как вирус Зика, был осложнен плохой инфраструктурой здравоохранения, недостаточным количеством персонала и географической изоляцией.Был только один пример (Соломоновы острова, 2015) статистически значимого увеличения зарегистрированных случаев ОРПП, коррелирующих с заболеваемостью вирусом Зика.Нами не было найдено доказательств, позволяющих заключить, что регулярно сообщаемые данные об ОРПП у несовершеннолетних могут быть полезны для определения появления вируса Зика в этих условиях. Возможно, требуется больше данных из взрослых групп населения, которые затрагиваются синдромом Гийена — Барре с большей вероятностью. Сообщений об ОРПП может быть также недостаточно в регионах, для которых подтверждено отсутствие полиомиелита.

Introduction Since October 2012, the combined tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine (Tdap) has been recommended in the United States during every pregnancy. Methods In this observational study from the Vaccine Safety Datalink, we describe receipt of Tdap during pregnancy among insured women with live births across seven health systems. Using a retrospective matched cohort, we evaluated risks for selected medically attended adverse events in pregnant women, occurring within 42 days of vaccination. Using a generalized estimating equation, we calculated adjusted incident rate ratios (AIRR). Results Our vaccine coverage cohort included 438,487 live births between January 1, 2007 and November 15, 2013. Across the coverage cohort, 14% received Tdap during pregnancy. By 2013, Tdap was administered during pregnancy in 41.7% of live births, primarily in the 3rd trimester. Our vaccine safety cohort included 53,885 vaccinated and 109,253 matched unvaccinated pregnant women. There was no increased risk for a composite outcome of medically attended acute adverse events within 3 days of vaccination. Similarly, across the safety cohort, over a 42 day window, incident neurologic events, thrombotic events, and new onset proteinuria did not differ by maternal receipt of Tdap. Among women receiving Tdap at 20 weeks gestation or later, as compared to their matched controls, there was no increased risk for gestational diabetes or cardiac events while venous thromboembolic events and thrombocytopenia were diagnosed within 42 days of vaccination at slightly decreased rates. Conclusion Tdap coverage during pregnancy increased from 2007 through 2013, but was still below 50%. No acute maternal safety signals were detected in this large cohort.

Background Perinatal stroke causes most hemiparetic cerebral palsy and leads to lifelong disability. Understanding developmental neuroplasticity following early stroke is increasingly translated into novel therapies. Diaschisis refers to alterations brain structures remote from, but connected to, stroke lesions. Ipsilesional thalamic diaschisis has been described following adult stroke but has not been investigated in perinatal stroke. We hypothesized that thalamic diaschisis occurs in perinatal stroke and its degree would be inversely correlated with clinical motor function. Methods Population-based, controlled cohort study. Participants were children (6 months of age, symptomatic hemiparetic cerebral palsy, and no additional neurologic disorders. Typically developing controls had comparable age and gender proportions. T1-weighted anatomical scans were parcellated into 99 regions of interest followed by generation of regional volumes. The primary outcome was thalamic volume expressed as ipsilesional (ILTV), contralesional (CLTV) and thalamic ratio (CLTV/ILTV). Standardized clinical motor assessments were correlated with thalamic volume metrics. Results Fifty-nine participants (12.9 years old ±4.0 years, 46% female) included 20 AIS, 11 PVI, and 28 controls. ILTV was reduced in both AIS and PVI compared to controls (p, Highlights • We investigated changes to thalamic volume following perinatal stroke. • Ipsilesional thalamic volume is decreased following perinatal stroke. • Contralesional thalamic volume increases following arterial ischemic stroke. • Increased contralesional thalamic volume inversely correlated with motor function.

Computed tomography (CT) has become a standard adjunct in the evaluation of patients with trauma. However, utility of imaging at the referring hospital remains controversial. We study the effect of CT scans at referring hospitals on in-hospital mortality at a receiving trauma center.A retrospective cohort study was performed with adult patients with severe trauma transferred to a level I trauma center from regional nontrauma hospitals between 2012 and 2017. Baseline characteristics were compared with Student's t-test and Pearson's chi-squared testing. The primary endpoint was in-hospital mortality. Cox regression, controlling for transfer time, was used to evaluate the effect of imaging on mortality.Three thousand four hundred and fifteen adult patients with trauma were included: 1135 (33.2%) received a pretransfer CT scan, whereas 2280 (66.8%) did not. Patients who received a pretransfer CT scan were more likely to be older, female, white, have a higher Charlson Comorbidity Index, less severely injured, have a blunt mechanism, and be transferred by ground. There was no difference in distance (58.3 miles versus 57.0 miles, P = 0.34), but transfer times were significantly increased for those who received pretransfer scans (288 versus 213 min, P 0.005). The adjusted model controlling for multiple variables has a hazard ratio of 0.533 (95% confidence interval 0.42-0.68, P 0.005).There is a survival advantage for patients who receive pretransfer CT scans despite having significantly longer transport times. We suggest that this decreased mortality associated with pretransfer imaging may reflect improving trends in referring physician transfer decisions.

The purpose of this study was to test a pharmacist-led intervention to improve gout treatment adherence and outcomes.We conducted a site-randomized trial (n=1463 patients) comparing a 1-year, pharmacist-led intervention to usual care in patients with gout initiating allopurinol. The intervention was delivered primarily through automated telephone technology. Co-primary outcomes were the proportion of patients adherent (proportion of days covered ≥0.8) and achieving a serum urate6.0 mg/dl at 1 year. Outcomes were reassessed at year 2.Patients who underwent intervention were more likely than patients of usual care to be adherent (50% vs 37%; odds ratio [OR] 1.68; 95% confidence interval [CI] 1.30, 2.17) and reach serum urate goal (30% vs 15%; OR 2.37; 95% CI 1.83, 3.05). In the second year (1 year after the intervention ended), differences were attenuated, remaining significant for urate goal but not for adherence. The intervention was associated with a 6%-16% lower gout flare rate during year 2, but the differences did not reach statistical significance.A pharmacist-led intervention incorporating automated telephone technology improved adherence and serum urate goal in patients with gout initiating allopurinol. Although this light-touch, low-tech intervention was efficacious, additional efforts are needed to enhance patient engagement in gout management and ultimately to improve outcomes.

Background Intelligence generated by a surveillance system is dependent on the quality of data that are collected. We investigated the knowledge, attitudes and practices of nurses responsible for outbreak early warning surveillance data collection in Solomon Islands to identify factors that influence their ability to perform surveillance-related tasks with rigour. Methods We interviewed 12 purposively selected surveillance nurses and conducted inductive analysis on resulting data. Results Interviewees were knowledgeable and willing to contribute to the surveillance system. Constraining factors included the perception that surveillance was less important than patient care and could be ‘deferred’ during busy periods and wide variability in the application of case definitions. Motivating factors were frequent in-clinic training, formal recognition for good performance, incentives and designation of a focal point. Nurses held mixed views about the effect of mobile technologies on surveillance practice. Conclusions This study identified several challenges to consistent and accurate data collection and reporting. Engagement of different parts of the health system, including human resources and health facilities’ management, is needed to address these challenges. Electronic supplementary material The online version of this article (10.1186/s12913-018-3508-9) contains supplementary material, which is available to authorized users.

Hereditary angioedema (HAE) with C1 inhibitor deficiency (C1-INH) is characterized by swelling of subcutaneous and/or submucosal tissues.To evaluate efficacy/safety of fixed-dose subcutaneous plasma-derived C1-INH (pdC1-INH) liquid for HAE attack prevention (NCT02584959).Eligible patients were ≥12 years with ≥2 monthly attacks prescreening or pre-long-term prophylaxis. In a partial crossover design, 80% of patients were randomized to placebo or pdC1-INH liquid for 14 weeks and crossed over from active to placebo or vice versa for another 14 weeks. The remainder were randomized to pdC1-INH liquid for 28 weeks. The primary efficacy endpoint was normalized number of attacks (NNA) versus placebo. Key additional endpoints were the proportion of patients achieving NNA reduction ≥50%, attack severity, number of attack-free days, and safety.Seventy-five patients were randomized and 58 (77%) completed the study. Mean age 41 years; 88% HAE type I. Least-squares means of NNA were reduced from 3.9 with placebo to 1.6 with pdC1-INH (from day 1; P.0001). Most patients had ≥50% NNA reduction with pdC1-INH (from day 1, 78%). A total of 8.8% of placebo-treated patients were attack-free and 5.3%, 22.8%, and 63.2% had mild, moderate, and severe attacks, respectively; 37.5% of pdC1-INH-treated patients were attack-free and 8.9%, 26.8%, and 26.8% had mild, moderate, and severe attacks, respectively. Treatment-emergent adverse event rates were similar between groups (52% vs 56% for pdC1-INH crossover vs placebo, respectively).Fixed-dose subcutaneous pdC1-INH liquid was superior to placebo in preventing HAE attacks and demonstrated a favorable safety profile.

Lipid screening determines eligibility for statins and other cardiovascular risk reduction interventions.To examine trends in lipid screening among adults aged ≥20 years in a large, multiethnic, integrated health care delivery system in southern California.Temporal trends in lipid screening were examined from 2009 to 2015 with an index date of September 30 of each year. Lipid screening was defined as the proportion of eligible members each year who (a) had ever been screened among those aged 20-39 years and (b) had been screened in the previous 6 years for those aged ≥ 40 years. Trends were analyzed by age, gender, and the presence of atherosclerotic cardiovascular disease (ASCVD) or diabetes without ASCVD status.More than 2 million individuals were included each year: 5%-6% had ASCVD (includes those with diabetes), 7%-8% had diabetes without ASCVD, and 87% had neither condition. Among the entire population, lipid screening increased from 79.8% in 2009 to 82.6% in 2015 (P0.0001). Among those with ASCVD or diabetes, lipid screening was 99% across all years. Among those without ASCVD or DM, screening increased from 76.9% in 2009 to 80.0% in 2015 (P0.0001), with higher screening among women compared with men and lower screening among individuals younger than 55 years.Consistently high rates of lipid screening were observed among individuals with ASCVD or diabetes. In individuals without these conditions, screening increased over time. However, there is room to further increase screening rates in adults younger than 55 years.This manuscript and research work was supported by a contractual agreement between the Southern California Permanente Medical Group and Regeneron Pharmaceuticals and Sanofi U.S. Researchers from Regeneron and Sanofi collaborated on the study design, interpretation of data, and writing of the manuscript. Ling Grant, Harrison, Chang, Hsu, Cheetham, Wei, and Reynolds are employed by Kaiser Permanente Southern California. Scott is employed by Southern California Permanente Medical Group. Boklage is employed by Regeneron, and Romo-LeTourneau is employed by Sanofi. Preliminary results from this study were presented at the American Heart Association Scientific Sessions; November 12-16, 2016; New Orleans, LA.

Purpose Implementation of the 2013 ACC/AHA cholesterol treatment guideline is likely to vary by statin benefit group. The aim of this study was to document trends in statin use before and after introduction of the ACC/AHA guideline. Methods We conducted a retrospective study with annual cohorts from 2009 to 2015 among members of Kaiser Permanente Southern California aged ≥ 21 years. Members were categorized into four mutually exclusive statin benefit groups: atherosclerotic cardiovascular disease (ASCVD), LDL-C ≥ 190 mg/dL in the last year, diabetes (aged 40–75 years), and 10-year ASCVD risk ≥ 7.5% (aged 40–75 years). Results The cohorts ranged from 1,993,755 members in 2009 to 2,440,429 in 2015. Approximately 5% of patients had ASCVD, 1% had LDL-C ≥ 190 mg/dL, 6% had diabetes, and 10% had a 10-year ASCVD risk ≥ 7.5% each year. Trends in statin use were stable for adults with ASCVD (2009 78%; 2015 80%), recent LDL-C ≥ 190 mg/dL (2009 45%; 2015 44%), and diabetes (2009 74%; 2015 73%), but increased for patients with 10-year ASCVD risk ≥ 7.5% (2009 36%; 2015 47%). High-intensity statin use also increased 142% and 54% among patients with LDL-C ≥ 190 mg/dL and those with ASCVD ≤ 75 years of age, respectively. Moderate-to-high intensity statin utilization increased over 50% among those with a 10-year ASCVD risk ≥ 7.5%. Conclusions Statin use increased substantially among patients with 10-year ASCVD risk ≥ 7.5% and use of appropriate statin dosage increased in each of the four statin benefit groups between 2009 and 2015; however, there is room for improvement.

Between August-2016 and April-2017, Solomon Islands experienced the largest and longest-running dengue outbreak on record in the country, with 12,329 suspected cases, 877 hospitalisations and 16 deaths. We conducted a retrospective review of related data and documents, and conducted key informant interviews to characterise the event and investigate the adaptability of syndromic surveillance for enhanced and expanded data collection during a public health emergency in a low resource country setting. While the outbreak quickly consumed available public and clinical resources, we found that authorities were able to scale up the conventional national syndrome-based early warning surveillance system to support the increased information demands during the event demonstrating the flexibility of the system and syndromic surveillance more broadly. Challenges in scaling up included upskilling and assisting staff with no previous experience of the tasks required; managing large volumes of data; maintaining data quality for the duration of the outbreak; harmonising routine and enhanced surveillance data and maintaining surveillance for other diseases; producing information optimally useful for response planning; and managing staff fatigue. Solomon Islands, along with other countries of the region remains vulnerable to outbreaks of dengue and other communicable diseases. Ensuring surveillance systems are robust and able to adapt to changing demands during emergencies should be a health protection priority.

A substantial percentage of patients report intolerance or side effects of statin treatment leading to treatment changes or discontinuation. The purpose of this study was to examine statin therapy changes and subsequent effects on low-density lipoprotein cholesterol (LDL-C) among patients with statin intolerance (SI). We identified 45,037 adults from Kaiser Permanente Southern California with SI documented between 2006 and 2012. Changes in statin therapy in the year before and after the SI index date were examined. We categorized patients into those who initiated statin therapy, discontinued, up-titrated, down-titrated, or did not switch therapy. We calculated the percentage change in LDL-C from the year before to the year after SI, and the percentage of patients attaining LDL-C

Objective To determine the risks associated with zoster vaccine when administered to patients taking immunosuppressant medications. Patients and Methods Patients enrolled in 1 of 7 managed care organizations affiliated with the Vaccine Safety Datalink between January 1, 2006, and December 31, 2009, were eligible. The exposure of interest was zoster vaccination in patients with current or remote immunosuppressant drug use. The primary outcomes were disseminated varicella zoster virus (VZV) and herpes zoster in the 42 days after vaccination. Automated data were collected on immunosuppressant drugs and baseline medical conditions. A logistic regression model using inverse probability treatment weights was used to estimate the odds of developing VZV or herpes zoster. Results A total of 14,554 individuals had an immunosuppressant medication dispensed around the time of vaccination, including 4826 with current use and 9728 with remote use. Most patients were taking low-dose corticosteroids. No cases of disseminated VZV were found in the current or remote users. The risk of herpes zoster was elevated in the 42 days after vaccination in current vs remote users (adjusted odds ratio, 2.99; 95% CI, 1.58-5.70). Conclusion We found that patients taking immunosuppressant medications at the time of vaccination had a modest increased risk of herpes zoster in the 42 days after vaccination. The development of herpes zoster within 42 days after vaccination suggests that this is more likely due to reactivation of latent zoster virus than dissemination of the vaccine-derived varicella virus. These findings support the current zoster vaccination guidelines.

Gout flares have been challenging to identify in retrospective databases due to gout flares not being well documented by diagnosis codes, making it difficult to conduct accurate database studies. Previous studies have used different algorithms, and in this study, we used a computer-based method to identify gout flares. The objectives of this study were to identify gout flares in gout patients newly initiated on urate-lowering therapy and evaluate factors associated with a patient experiencing gout flares after starting drug treatment. This was a retrospective cohort study identifying gout patients newly initiated on a urate-lowering therapy (ULT) during the study time period of January 1, 2007-December 31, 2010. The index date was the first dispensed ULT prescription during the study time period. Patients had to be ≥18 years of age on index date, have no history of prior ULT prescription during 12 months before index date, and were required to have 12 months of continuous membership with drug benefit during pre-/post-index. Electronic chart notes were reviewed to identify gout flares; these reviews helped create a validated computer-based method to further identify patients with gout flares and were categorized into 0 gout flares, 1-2 gout flares, and ≥3 gout flares during the 12 months post-index period. Multivariable logistic regression was used to examine patient and clinical factors associated with gout flares during the 12-month follow-up period. There were 8905 patients identified as the final cohort and 68 % of these patients had one or more gout flares during the 12-month follow-up: 2797 patients (31 %) had 0 gout flares, 4836 (54 %) had 1-2 gout flares, and 1272 patients (14 %) had ≥3 gout flares. Using a multivariate regression analyses, factors independently associated with 1-2 gout flares and ≥3 gout flares versus no gout flares were similar, however, with slight differences, such as younger patients were more likely to have 1-2 gout flares and patients ≥65 years of age had ≥3 gout flares. Factors such as male gender, not attaining sUA goal, having ≥3 comorbidities, diuretics use, no changes in initial ULT dose, and not adhering to ULT all were associated with gout flares versus no gout flares. Using a new method to identify gout flares, we had the opportunity to compare our findings with the previous studies. Our study findings echo other previous studies where older patients, male, diuretics, having a greater number of comorbidities, and non-adherence are more likely to have more gout flares during the first year of newly initiating ULT. There is an unmet need for patients with gout to be educated and managed more closely, especially during the first year.

Background and purpose — A criticism of total hip arthroplasty (THA) survivorship analysis is that revisions are a late and rare outcome. We investigated whether prolonged opioid use is a possible indicator of early THA failure. Patients and methods — We conducted a cohort study of THAs registered in a total joint replacement registry from January 2008 to December 2011. 12,859 patients were evaluated. The median age was 67 years and 58% were women. Opioid use in the year after surgery was the exposure of interest, and the cumulative daily amounts of oral morphine equivalents (OMEs) were calculated. Post-THA OMEs per 90 day periods were categorized into quartiles. The endpoints were 1- and 5-year revisions. Results — After the first 90 days, 27% continued to use opioids. The revision rate was 0.9% within a year and 1.7% within 5 years. Use of medium-low (100–219 mg), medium-high (220–533 mg), and high (≥ 534 mg) amounts of OMEs in days 91–180 after surgery was associated with a 6 times (95% confidence interval (CI): 3–15), 5 times (CI: 2–13), and 11 times (CI: 2.9–44) higher adjusted risk of 1 year revision, respectively. The use of medium-low and medium-high amounts of OMEs in days 181–270 after surgery was associated with a 17 times (CI: 6–44) and 14 times (95% CI: 4–46) higher adjusted risk of 1-year revision. There was a similar higher risk of 5-year revision. Interpretation — Persistent postoperative use of opioids was associated with revision THA surgery in this cohort, and it may be an early indicator of potential surgical failures. Refereed/Peer-reviewed

Limited safety data are available on inadvertent exposure to quadrivalent human papillomavirus vaccine (4vHPV) during pregnancy. We conducted a descriptive observational postlicensure safety surveillance study in Kaiser Permanente Southern California and Northern California to assess congenital anomaly and miscarriage among pregnancies exposed to 4vHPV. Using electronic medical records, we identified women who received a dose of 4vHPV between August 2006 and March 2008 within 30 days preconception or any time during a possible pregnancy. A broad algorithm was developed using diagnostic and procedure codes and laboratory tests to identify pregnancy, congenital anomalies, and miscarriages. Medical records of all potential congenital anomaly cases and a random sample of 100 potential miscarriage cases were reviewed to confirm pregnancy exposure and diagnosis. Results were reviewed by an independent Safety Review Committee (SRC). Among the population of 189,629 females who received at least one dose of 4vHPV during the study period, 2,678 females were identified as possibly having a 4vHPV-exposed pregnancy. Among 170 potential congenital anomalies identified, 44 (26%) were found to be both 4vHPV-exposed and confirmed congenital anomaly cases. Among the 633 potential miscarriages identified, the records of a random sample of 100 cases were reviewed, and 9 cases (9%) were confirmed as 4vHPV-exposed miscarriages. The SRC noted no safety signal for congenital anomaly or miscarriage associated with 4vHPV exposure during pregnancy. The rate of major congenital anomaly (3.6%) was in the range of background estimates from the literature. There was no apparent pattern of timing of 4vHPV exposure among 4vHPV-exposed miscarriages.

Introduction An increased risk of diagnosed chorioamnionitis in women vaccinated with Tdap during pregnancy was previously detected at two Vaccine Safety Datalink (VSD) sites. The clinical significance of this finding related to infant outcomes remains uncertain. Methods Retrospective cohort study of singleton live births born to women who were continuously insured from 6 months prior to their last menstrual period through 6 weeks postpartum, with ≥1 outpatient visit during pregnancy from January 1, 2010 to November 15, 2013 at seven integrated United States health care systems part of the VSD. We re-evaluated the association between maternal Tdap and chorioamnionitis and evaluated whether specific infant morbidities differ among infants born to mothers who did and did not receive Tdap during pregnancy. We focused on 2 Tdap exposure windows: the recommended 27–36 weeks gestation or anytime during pregnancy. We identified inpatient diagnostic codes for transient tachypnea of the newborn (TTN), neonatal sepsis, neonatal pneumonia, respiratory distress syndrome (RDS), and newborn convulsions associated with an infant's first hospitalization. A generalized linear model with Poisson distribution and log-link was used to estimate propensity score adjusted rate ratios (ARR) with 95% confidence intervals (CI). Results The analyses included 197,564 pregnancies. Chorioamnionitis was recorded in 6.4% of women who received Tdap vaccination any time during pregnancy and 5.2% of women who did not (ARR [95% CI]: 1.23 [1.17, 1.28]). Compared with unvaccinated women, there were no significant increased risks (ARR [95% CI]) for TTN (1.04 [0.98, 1.11]), neonatal sepsis (1.06 [0.91, 1.23]), neonatal pneumonia (0.94 [0.72, 1.22]), RDS (0.91 [0.66, 1.26]), or newborn convulsions (1.16 [0.87, 1.53]) in infants born to Tdap-vaccinated women. Conclusions and Relevance Despite an observed association between maternal Tdap vaccination and maternal chorioamnionitis, we did not find increased risk for clinically significant infant outcomes associated with maternal chorioamnionitis.

Objective.To identify modifiable patient and provider factors associated with allopurinol adherence and the achievement of a serum urate acid (SUA) goal in gout.Methods.We identified a retrospective cohort of patients with gout, newly treated with allopurinol. All patient data came from administrative datasets at a large integrated health delivery system. Patients were ≥ 18 years old at time of initial allopurinol dispensing, and had 12 months or more of membership and drug eligibility prior to the index date. Allopurinol adherence was defined as a proportion of days covered ≥ 0.80, evaluated during the first 12 months of observation after the initial dispensing. Multivariable logistic regression was used to examine factors associated with allopurinol nonadherence and attaining an SUA concentration < 6.0 mg/dl.Results.We identified 13,341 patients with gout with incident allopurinol use (mean age 60 yrs, 78% men). Of these, 9581 patients (72%) had SUA measured both at baseline and during followup. Only 3078 patients (32%) attained an SUA target of < 6.0 mg/dl during followup. Potentially modifiable factors associated with treatment adherence and obtaining the SUA goal in the multivariable analysis included concomitant diuretic use, prescriber specialty, and allopurinol dosing practices. Adherent patients were 2.5-fold more likely than nonadherent patients to achieve an SUA < 6.0 mg/dl during observation.Conclusion.Among patients with gout initiating allopurinol in our study, 68% did not reach the SUA goal and 57% of patients were nonadherent. Modifiable factors, including allopurinol dose escalation, treatment adherence, rheumatology referral, and concomitant medication use, could be important factors to consider in efforts aimed at optimizing gout treatment outcomes.

Objective In response to widespread pertussis outbreaks and infant deaths, in 2010, the California Department of Health (CDPH) and in 2011 the Advisory Committee on Immunization Practices (ACIP) advised that the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine be administered during pregnancy. The goals of this study were to describe Tdap coverage among pregnant women following these recommendations. Methods In this observational cohort study, we utilized electronic medical record and claims data from seven Vaccine Safety Datalink sites to identify pregnancies and Tdap administrations. All Tdap doses were classified as pre-pregnancy, during pregnancy or post-pregnancy/postpartum. For pregnancies ending in a live birth, we evaluated factors associated with Tdap vaccination. Results Among 289,141 live births at the California VSD sites, receipt of Tdap during pregnancy increased substantially in the years 2010, 2011, and 2012, when coverage was 15.9, 30.0 and 19.5%, respectively. Among 82,398 women with live births at the Oregon, Washington, Colorado, Wisconsin and Minnesota VSD sites, receipt of Tdap during pregnancy first increased in 2012, at 16.0%. Women receiving early prenatal care and other vaccine(s) during pregnancy had higher Tdap coverage. Conclusion We observed substantial increases in Tdap coverage during pregnancy following CDPH and ACIP recommendations.

The Facial Action Coding System (Ekman & Friesen) has shown promise as a behavioral measure of emotional experience. The current study examined the degree of (de)synchrony between self-reported and facial expressions of fear, disgust, and sadness in response to a traumatic event–relevant film among individuals who had experienced a traumatic motor vehicle accident. Given high rates of comorbidity between posttraumatic stress symptoms (PTSS) and depressive symptoms, the potential impacts of both PTSS and depressive symptoms on emotional responding were examined. Results demonstrated synchrony between self-reported and facial expressions of disgust and sadness; however, no association between measures of fear was observed. Furthermore, depressive symptoms were associated with greater fear responding and PTSS were associated only with self-reported fear. Together, results support the importance of examining discrete negative emotions, rather than broad valence categories, when examining fear-based responding in traumatic event–exposed populations. Additional research examining the psychometric properties of the Facial Action Coding System as a measure of discrete emotional experiences among traumatic event–exposed individuals is needed to advance multimodal assessment approaches that yield incremental information for understanding emotional responding in this population.

Introduction: In July 2013, during annual independence celebrations in Kiribati, staff at Tungaru Central Hospital on South Tarawa reported an increase in children presenting with severe diarrhoea. This report describes the outbreak investigation, findings and response. Method: After notification of the outbreak, all health facilities on South Tarawa began reporting cases of acute diarrhoea and/or vomiting through the early warning syndromic surveillance system on a daily basis. Community awareness was raised and the public was encouraged to present to a health facility if ill with acute gastroenteritis. Specimens were collected and sent for laboratory testing. Results: Between 10 and 24 July 2013, 1118 cases of gastroenteritis were reported; 103 were hospitalized and six died. The median age of cases was one year (range: 0–68 years); 93.4% were aged less than five years. Rotavirus was identified in 81% of specimens tested. The outbreak response included enhanced surveillance, community education, clinical training and changes to in-hospital patient management for infection control. Discussion: This outbreak was the largest diarrhoea outbreak in Kiribati in five years. Factors that may have contributed to the magnitude and severity of the outbreak included high household density, inadequate sanitation infrastructure and a mass gathering – all increasing the chance of transmission – as well as limited clinical response capacity. The current outbreak highlights the importance of clinical management to minimize severe dehydration and death. Rotavirus vaccination should be considered as an adjunct to other comprehensive enteric disease control measures as recommended by the World Health Organization.

To examine the psychometric properties and validity of the 8-item Osteoporosis-Specific Morisky Medication Adherence Scale (OS-MMAS-8) in postmenopausal women prescribed bisphosphonates (BPs) for at least 15 months. A random sample of women aged ≥55 years with osteoporosis prescribed daily or weekly BPs was identified. Pharmacy fill data were extracted to calculate the medication possession ratio (MPR). Eligible women were stratified by low (

Primary nonadherence to a medication occurs when a drug is prescribed but the patient fails to pick the prescription up from the pharmacy. Managed care organizations that provide integrated care using electronic medical records (EMR) are an ideal setting to study primary nonadherence. To identify patient and provider characteristics that are significantly associated with primary nonadherence to statin medications compared with a population of patients who picked up their first statin order. This was a retrospective cohort study of patients with a new statin prescription. Patients with a new order for a statin prescription between December 1, 2009, and February 28, 2010, were eligible. A statin order was considered new if the patient had no statin prescriptions in the previous 12 months. Study participants were 24 years and older with 12 months of continuous membership prior to the statin order. Patients were defined as primary nonadherent if they did not pick up their new prescription within 90 days. Descriptive and multivariate (conditional logistic regression) analyses of patients who did and did not pick up their new statin prescriptions were performed using demographic and socioeconomic information, health care utilization, health conditions, medical benefits, and prescriber characteristics. A total of 19,826 patients with a new statin order that met all of the inclusion and exclusion criteria was identified. Of these, 3,049 patients (15.4%) did not pick up their statin prescriptions within 90 days of the order date. Primary nonadherent patients tended to be younger (55 vs. 57 years, P less than 0.001) and healthier, with fewer comorbid conditions (Charlson Comorbidity Index ≥ 1, 42.2% vs. 52.3%, P less than 0.001), lower rates of hospitalizations (7.2% vs. 12.0%, P less than 0.001), fewer concurrent prescriptions (3 vs. 4, P less than 0.001) and fewer clinic (4 vs. 5, P less than 0.001) and emergency department visits (18.2% vs. 24.6%, P less than 0.001) in the prior year than adherent patients. Although the multivariate model agreed well with the observed data, the characteristics included had a poor ability to predict primary nonadherence (c-statistic = 0.603). Primary nonadherence has been recognized as a significant problem for many years, and electronic health records are allowing researchers to investigate the extent of the problem. In this study, almost 1 in 6 patients (15.4%) failed to pick up their new statin order within 90 days. However, clinical and demographic information available in electronic health care data may not be useful in predicting primary nonadherence. New methods and interventions need to be developed to improve primary adherence.

Background The need for research on the safety of vaccination during pregnancy is widely recognized. Large, population-based data systems like the Vaccine Safety Datalink (VSD) may be useful for this research, but identifying pregnancies using electronic medical record (EMR) and claims data can be challenging. Methods We modified an existing data processing algorithm to identify pregnancies within seven of the ten VSD sites. We validated the algorithm by calculating the agreement in pregnancy outcome type, end date, and gestational age between the algorithm and manual medical record review. At each participating site, we randomly sampled 15 episodes within four outcome type strata (live births, spontaneous abortions, elective abortions, and other pregnancy outcomes) for a total of 60 episodes per site. We also developed and validated methods to link mothers to their infants in the electronic data. Results We identified 595,929 pregnancy episodes ending in 2002 through 2006 among women 12 through 55 years of age. Of these pregnancies, 75% ended in live births, 12% in spontaneous abortions, and 9% in elective abortions. We were able to confirm a pregnancy within 28 days of the algorithm-estimated pregnancy start date for 99% of live births, 93% of spontaneous abortions, 92% of elective abortions, and 90% of other outcomes sampled. The agreement between the algorithm-identified and the abstractor-identified outcome date ranged from 70% (elective abortion) to 96% (live birth) depending on outcome type. When gestational age was available in the EMR, agreement ranged from 82% (other) to 98% (live birth) depending on outcome type. We confirmed 100% of the 350 sampled mother–infant linkages with manual medical record review. Conclusions The VSD algorithm accurately identifies pregnancy episodes and mother–infant pairs across participating sites. Additional manual record review may be needed to improve the precision of the pregnancy date estimates depending on specific study needs. These algorithms will allow us to conduct large, population-based studies of the safety of vaccination during pregnancy.

This study aims to estimate the prevalence of and temporal trends in prenatal antipsychotic medication use within a cohort of pregnant women in the U.S. We identified live born deliveries to women aged 15–45 years in 2001–2007 from 11 U.S. health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program. We ascertained prenatal exposure to antipsychotics from health plan pharmacy dispensing files, gestational age from linked infant birth certificate files, and ICD-9-CM diagnosis codes from health plan claims files. We calculated the prevalence of prenatal use of atypical and typical antipsychotics according to year of delivery, trimester of pregnancy, and mental health diagnosis. Among 585,615 qualifying deliveries, 4,223 (0.72 %) were to women who received an atypical antipsychotic and 548 (0.09 %) were to women receiving a typical antipsychotic any time from 60 days before pregnancy through delivery. There was a 2.5-fold increase in atypical antipsychotic use during the study period, from 0.33 % (95 % confidence interval: 0.29 %, 0.37 %) in 2001 to 0.82 % (0.76 %, 0.88 %) in 2007, while the use of typical antipsychotics remained stable. Depression was the most common mental health diagnosis among deliveries to women with atypical antipsychotic use (63 %), followed by bipolar disorder (43 %) and schizophrenia (13 %). The number and proportion of pregnancies exposed to atypical antipsychotics has increased dramatically in recent years. Studies are needed to examine the comparative safety and effectiveness of these medications relative to other therapeutic options in pregnancy.

Background Combined hormonal contraceptives (CHCs) place women at increased risk of venous thromboembolic events (VTEs) and arterial thrombotic events (ATEs), including acute myocardial infarction and ischemic stroke. There is concern that three recent CHC preparations [drospirenone-containing pills (DRSPs), the norelgestromin-containing transdermal patch (NGMN) and the etonogestrel vaginal ring (ETON)] may place women at even higher risk of thrombosis than other older low-dose CHCs with a known safety profile. Study Design All VTEs and all hospitalized ATEs were identified in women, ages 10–55 years, from two integrated health care programs and two state Medicaid programs during the time period covering their new use of DRSP, NGMN, ETON or one of four low-dose estrogen comparator CHCs. The relative risk of thrombotic and thromboembolic outcomes associated with the newer CHCs in relation to the comparators was assessed with Cox proportional hazards regression models adjusting for age, site and year of entry into the study. Results The hazards ratio for DRSP in relation to low-dose estrogen comparators among new users was 1.77 (95% confidence interval 1.33–2.35) for VTE and 2.01 (1.06–3.81) for ATE. The increased risk of DRSP was limited to the 10–34-year age group for VTE and the 35–55-year group for ATE. Use of the NGMN patch and ETON vaginal ring was not associated with increased risk of either thromboembolic or thrombotic outcomes. Conclusions In new users, DRSP was associated with higher risk of thrombotic events (VTE and ATE) relative to low-dose estrogen comparator CHCs, while the use of the NGMN patch and ETON vaginal ring was not.

To describe the prevalence, trends, and patterns in use of antidiabetic medications to treat hyperglycemia and insulin resistance before and during pregnancy in a large U.S. cohort of insured pregnant women.Pregnancies resulting in live births were identified (N=437,950) from 2001 to 2007 among 372,543 females 12-50 years of age at delivery from 10 health maintenance organizations participating in the Medication Exposure in Pregnancy Risk Evaluation Program. Information for these descriptive analyses, including all antidiabetic medications dispensed during this period, was extracted from electronic health records and newborn birth certificates.A little more than 1% (1.21%) of deliveries were to women dispensed antidiabetic medication in the 120 days before pregnancy. Use of antidiabetic medications before pregnancy increased from 0.66% of deliveries in 2001 to 1.66% of deliveries in 2007 (P.001) because of an increase in metformin use. Most women using metformin before pregnancy had a diagnosis code for polycystic ovaries or female infertility (67.2%), whereas only 13.6% had a diagnosis code for diabetes. The use of antidiabetic medications during the second or third trimester of pregnancy increased from 2.8% of deliveries in 2001 to 3.6% in 2007 (P.001). Approximately two thirds (68%) of women using metformin before pregnancy did not use any antidiabetic medications during pregnancy.Antidiabetic medication use before and during pregnancy increased from 2001 to 2007, possibly because of increasing prevalence of gestational diabetes mellitus, type 1 and type 2 diabetes, and other conditions associated with insulin resistance.III.

Background and purpose To determine maximum tolerated dose (MTD) and toxicities of sorafenib combined with stereotactic radiotherapy (SBRT) or whole liver radiotherapy (WLRT) in patients with liver metastases. Material and methods Eligible patients had unresectable liver metastases. Sorafenib dose was escalated in 2 strata: I – SBRT: effective liver volume irradiated ( V eff ) V eff >80% (21.6Gy in 6 fractions). Four weeks of sorafenib, with radiotherapy during weeks 2–3, was delivered at 3 escalating dose levels (200–400mg twice daily). Dose limiting toxicity was defined as any grade 3+ liver toxicity, or grade 4+ treatment-related toxicity. Results Thirty-three patients were treated: 18 in stratum I (median dose 42Gy), 15 in stratum II. The MTD was not reached. Grade 3+ toxicity was seen in 33% of patients, at a median of 10days. Two deaths from non-classic liver toxicity occurred post WLRT in stratum II. The median overall survival was 22.3 and 5.7months for strata I and II respectively. Conclusions Sorafenib and 21.6Gy in 6 fraction WLRT resulted in unacceptably high rates of liver toxicity. Although sorafenib combined with SBRT was tolerable, the observed efficacy does not merit further clinical evaluation.

OBJECTIVE To determine effects of oral administration of metronidazole or doxycycline on olfactory function in explosives detection (ED) dogs. ANIMALS 18 ED dogs. PROCEDURES Metronidazole was administered (25 mg/kg, PO, q 12 h for 10 days); the day prior to drug administration was designated day 0. Odor detection threshold was measured with a standard scent wheel and 3 explosives (ammonium nitrate, trinitrotoluene, and smokeless powder; weight, 1 to 500 mg) on days 0, 5, and 10. Lowest repeatable weight detected was recorded as the detection threshold. There was a 10-day washout period, and doxycycline was administered (5 mg/kg, PO, q 12 h for 10 days) and the testing protocol repeated. Degradation changes in the detection threshold for dogs were assessed. RESULTS Metronidazole administration resulted in degradation of the detection threshold for 2 of 3 explosives (ammonium nitrate and trinitrotoluene). Nine of 18 dogs had a degradation of performance in response to 1 or more explosives (5 dogs had degradation on day 5 or 10 and 4 dogs had degradation on both days 5 and 10). There was no significant degradation during doxycycline administration. CONCLUSIONS AND CLINICAL RELEVANCE Degradation in the ability to detect odors of explosives during metronidazole administration at 25 mg/kg, PO, every 12 hours, indicated a potential risk for use of this drug in ED dogs. Additional studies will be needed to determine whether lower doses would have the same effect. Doxycycline administered at the tested dose appeared to be safe for use in ED dogs.

Objective.To examine the associations between lowering low-density lipoprotein cholesterol (LDL-C) and cardiovascular (CV) outcomes among patients with rheumatoid arthritis (RA) and patients without it.Methods.Adult patients with RA and 2 age- and sex-matched control cohorts [RA plus general controls (RA/GN), RA plus osteoarthritis (OA) controls (RA/OA)] were identified between January 1, 2007, and December 31, 2011. Patients with a diagnosis of hyperlipidemia who initiated statin therapy without prior CV events were included. Multivariable Cox proportional hazard analyses were used.Results.The study identified 1522 patients with RA with 6511 general controls (RA/GN cohort); and 1746 patients with RA with 2554 OA controls (RA/OA cohort). During followup, mean (SD) LDL-C (mg/dl) was 96.8 (32.7) for RA, 100.1 (35.1) for general controls, and 99.1 (34.3) for OA. The relationship between lowering LDL-C and CV outcomes was similar for both RA and non-RA controls (p for interaction = 0.852 in RA/GN cohort, and p = 0.610 in RA/OA cohort). After adjusting for baseline CV risk factors, lowering LDL-C was associated with a 29%–50% lower risk of CV events (HR [95% CI] = 0.71 [0.57–0.89] in RA/GN, 0.50 [0.43–0.58] in RA/OA). Subgroup analyses showed that lowering LDL-C was associated with a similar degree of reduction of CV events in RA and non-RA controls (HR of 0.67–0.68 for RA, 0.72 for general controls, 0.76 for OA controls).Conclusion.Lowering LDL-C levels was associated with reduced CV events. The relationship between lowering LDL-C and CV outcomes in RA was similar to the relationship found in matched general and OA controls.

Tamoxifen (TAM) has been prescribed for decades and aromatase inhibitors (AIs) have been used since the early 2000s in preventing subsequent breast cancer. However, outside of clinical trials, the effectiveness of AIs is not established. We examined the long-term risk of subsequent breast cancer among survivors treated with TAM and AIs in a large health plan. The study included 22,850 survivors, diagnosed with initial breast cancer (stages 0-IV) from 1996 to 2006, and followed 13 years maximum. We compared the risk of subsequent breast cancer in those who used TAM and/or AIs versus nonusers (the reference group). Hazard ratios (HR) adjusted for patient, tumor, treatment, and health-care characteristics were estimated using Cox models with time-dependent drug use status. Women who used TAM/AIs had a large reduction in risk of subsequent breast cancer compared with nonusers. While confidence intervals (CI) for all hormone treatment groups overlapped, women with high adherence (medication possession ratio ≥80%) who used AIs exclusively and had positive ER or PR receptor status had the greatest risk reduction (HR = 0.34, 95% CI: 0.28-0.41), followed by those who switched from TAM to AIs (HR = 0.39, 95% CI: 0.30-0.49), and those who used TAM exclusively (HR = 0.42, 95% CI: 0.36-0.47). Women with high adherence had the greatest risk reduction in subsequent breast cancer, but the results were not substantially different from women who took the drugs less regularly. Compared with nonusers, the reduction in subsequent breast cancer risk ranged from 58% to 66% across the hormone treatment groups and degree of adherence.