Seasonal Influenza Vaccination During Pregnancy and the Risk of Major Congenital Malformations in Live-born Infants: A 2010-2016 Historical Cohort Study.

BACKGROUND: Available evidence indicates that seasonal inactivated influenza vaccination during pregnancy protects both the mother and her newborn and is safe. Nevertheless, ongoing safety assessments are important in sustaining vaccine uptake. Few studies have explored safety in relation to major congenital malformations (MCMs), particularly in the first trimester when most organogenesis occurs. METHODS: Anonymized UK primary care data (the Clinical Practice Research Datalink), including a recently developed Pregnancy Register, were used to identify live-born singletons delivered between 2010 and 2016. Maternal influenza vaccination was determined using primary care records and stratified by trimester. Ascertainment of MCMs from infant primary care records was maximized by linkage to hospitalization data and death certificates. The relationship between vaccination and MCMs recorded in the year after delivery and in early childhood was then assessed using multivariable Cox regression. RESULTS: A total of 78 150 live-birth pregnancies were identified: 6872 (8.8%) were vaccinated in the first trimester, 11 678 (14.9%) in the second, and 12 931 (16.5%) in the third. Overall, 5707 live births resulted in an infant with an MCM recorded in the year after delivery and the adjusted hazard ratio when comparing first-trimester vaccination to no vaccination was 1.06 (99% CI, .94-1.19; P = .2). Results were similar for second- and third-trimester vaccination and for analyses considering MCMs recorded beyond the first birthday. CONCLUSIONS: In this large, population-based historical cohort study there was no evidence to suggest that seasonal influenza vaccine was associated with MCMs when given in the first trimester or subsequently in pregnancy.

The identification and validity of congenital malformation diagnoses in UK electronic health records: A systematic review.

PURPOSE: To describe the methods used to identify and validate congenital malformation diagnoses recorded in UK electronic health records, and the results of validation studies. METHODS: Medline and Embase were searched for publications between 1987 and 2019 that involved identifying congenital malformations from UK electronic health records using diagnostic codes. The methods and code-lists used to identify congenital malformations, and the methods and results of validations, were examined. RESULTS: We retrieved 54 eligible studies; 36 identified congenital malformations from primary care data and 18 from secondary care data alone or in combination with birth and/or death records. Identification in secondary care data relied on codes from the 'Q' chapter for congenital malformations in ICD-10. In contrast, studies using primary care data frequently used additional codes outside of the 'P' chapter for congenital malformation diagnoses in Read, although the exact codes used were not always clear. Eight studies validated diagnoses identified in primary care data. The positive predictive value was highest (80%-100%) for congenital malformations overall, major malformations, and heart defects although the validity of the reference standard used was often uncertain. It was lowest for neural tube defects (71%) and developmental hip dysplasia (56%). CONCLUSIONS: Studies identifying congenital malformations from primary care data provided limited details about the methods used. The few validation studies were limited to diagnoses recorded in primary care. Further assessments of all measures of validity in both data sources and of other malformation subgroups are needed, using robust reference standards and adhering to reporting guidelines.

Allergic disease, corticosteroid use, and risk of Hodgkin lymphoma: A United Kingdom nationwide case-control study.

BACKGROUND: Immunodeficiency syndromes (acquired/congenital/iatrogenic) are known to increase Hodgkin lymphoma (HL) risk, but the effects of allergic immune dysregulation and corticosteroids are poorly understood. OBJECTIVE: We sought to assess the risk of HL associated with allergic disease (asthma, eczema, and allergic rhinitis) and corticosteroid use. METHODS: We conducted a case-control study using the United Kingdom Clinical Practice Research Datalink (CPRD) linked to hospital data. Multivariable logistic regression investigated associations between allergic diseases and HL after adjusting for established risk factors. Potential confounding or effect modification by steroid treatment were examined. RESULTS: One thousand two hundred thirty-six patients with HL were matched to 7416 control subjects. Immunosuppression was associated with 6-fold greater odds of HL (adjusted odds ratio [aOR], 6.18; 95% CI, 3.04-12.57), with minimal change after adjusting for steroids. Any prior allergic disease or eczema alone was associated with 1.4-fold increased odds of HL (aOR, 1.41 [95% CI, 1.24-1.60] and 1.41 [95% CI, 1.20-1.65], respectively). These associations decreased but remained significant after adjustment for steroids (aOR, 1.25 [95% CI, 1.09-1.43] and 1.27 [95% CI, 1.08-1.49], respectively). There was no effect modification by steroid use. Previous steroid treatment was associated with 1.4-fold greater HL odds (aOR, 1.38; 95% CI, 1.20-1.59). CONCLUSIONS: In addition to established risk factors (immunosuppression and infectious mononucleosis), allergic disease and eczema are risk factors for HL. This association is only partially explained by steroids, which are associated with increased HL risk. These findings add to the growing evidence that immune system malfunction after allergic disease or immunosuppression is central to HL development.

Progress toward the development of a microchip electrophoresis separation-based sensor with electrochemical detection for on-line in vivo monitoring of catecholamines.

The development of a separation-based sensor for catecholamines based on microdialysis (MD) coupled to microchip electrophoresis (ME) with electrochemical (EC) detection is described. The device consists of a pyrolyzed photoresist film working electrode and a poly(dimethylsiloxane) microchip with a flow-gated sample injection interface. The chip was partially reversibly sealed to the glass substrate by selectively exposing only the top section of the chip to plasma. This partially reversible chip/electrode integration process not only allows the reuse of the working electrode but also greatly enhanced the reproducibility of electrode alignment with the separation channel. The developed MD-ME-EC system was then tested using l-DOPA, 3-O-MD, HVA, DOPAC, and dopamine standards, which were separated in less than 100 seconds using a background electrolyte consisting of 15 mM sodium phosphate (pH 7.4), 15 mM sodium dodecyl sulfate, and 2.5 mM boric acid. A potential of +1.0 V vs. Ag/AgCl was used for amperometric detection of the analytes. The device was evaluated for on-line monitoring of the conversion of l-DOPA to dopamine in vitro and for monitoring dopamine release in an anesthetized rat in vivo following high K+ stimulation. The system was able to detect stimulated dopamine release in vivo but not endogenous levels of dopamine.

Cellular Mercury Coordination Environment, and Not Cell Surface Ligands, Influence Bacterial Methylmercury Production.

The conversion of inorganic mercury (Hg(II)) to methylmercury (MeHg) is central to the understanding of Hg toxicity in the environment. Hg methylation occurs in the cytosol of certain obligate anaerobic bacteria and archaea possessing the hgcAB gene cluster. However, the processes involved in Hg(II) biouptake and methylation are not well understood. Here, we examined the role of cell surface thiols, cellular ligands with the highest affinity for Hg(II) that are located at the interface between the outer membrane and external medium, on the sorption and methylation of Hg(II) by Geobacter sulfurreducens. The effect of added cysteine (Cys), which is known to greatly enhance Hg(II) biouptake and methylation, was also explored. By quantitatively blocking surface thiols with a thiol binding ligand (qBBr), we show that surface thiols have no significant effect on Hg(II) methylation, regardless of Cys addition. The results also identify a significant amount of cell-associated Hg-S3/S4 species, as studied by high energy-resolution X-ray absorption near edge structure (HR-XANES) spectroscopy, under conditions of high MeHg production (with Cys addition). In contrast, Hg-S2 are the predominant species during low MeHg production. Hg-S3/S4 species may be related to enhanced Hg(II) biouptake or the ability of Hg(II) to become methylated by HgcAB and should be further explored in this context.

Racial discrimination and ethnic racial identity in adolescence as modulators of HPA axis activity.

We review evidence of racial discrimination as a critical and understudied form of adversity that has the potential to impact stress biology, particularly hypothalamic-pituitary-adrenal (HPA) axis activity. We highlight ethnic racial identity (ERI) as a positive regulatory influence on HPA axis activity, as indexed by levels of salivary cortisol. In past research by our group, Black individuals with high adolescent discrimination had low adult cortisol levels (hypocortisolism). Here, we present new analyses showing that ERI, measured prospectively from ages 12 through 32 in 112 Black and white individuals, is related to better-regulated cortisol levels in adulthood, particularly for Black participants. We also describe ongoing research that explores whether the promotion of ERI during adolescence can reduce ethnic-racial disparities in stress biology and in emotional health and academic outcomes.

The validity of dementia diagnoses in routinely collected electronic health records in the United Kingdom: A systematic review.

PURPOSE: The purpose of the study is to assess the validity of codes or algorithms used to identify dementia in UK electronic health record (EHR) primary care and hospitalisation databases. METHODS: Relevant studies were identified by searching the MEDLINE/EMBASE databases from inception to June 2018, hand-searching reference lists, and consulting experts. The search strategy included synonyms for "Dementia", "Europe", and "EHR". Studies were included if they validated dementia diagnoses in UK primary care or hospitalisation databases, irrespective of validation method used. The Quality Assessment for Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess risk of bias. RESULTS: From 1469 unique records, 14 relevant studies were included. Thirteen validated individual diagnoses against a reference standard, reporting high estimates of validity. Most reported only the positive predictive value (PPV), with estimates ranging between 0.09 and 1.0 and 0.62 and 0.85 in primary care and hospitalisation databases, respectively. One study performed a rate comparison, indicating good generalisability of dementia diagnoses in The Health Improvement Network (THIN) database to the UK population. Studies were of low methodological quality. As studies were not comparable, no summary validity estimates were produced. CONCLUSION: While heterogenous across studies, reported validity estimates were generally high. However, the credibility of these estimates is limited by the methodological quality of studies, primarily resulting from insufficient blinding of researchers interpreting the reference test. Inadequate reporting, particularly of the specific codes validated, hindered comparison of estimates across studies. Future validation studies should make use of more robust reference tests, follow established reporting guidelines, and calculate all measures of validity.

Methods to generate and validate a Pregnancy Register in the UK Clinical Practice Research Datalink primary care database.

PURPOSE: Primary care databases are increasingly used for researching pregnancy, eg, the effects of maternal drug exposures. However, ascertaining pregnancies, their timing, and outcomes in these data is challenging. While individual studies have adopted different methods, no systematic approach to characterise all pregnancies in a primary care database has yet been published. Therefore, we developed a new algorithm to establish a Pregnancy Register in the UK Clinical Practice Research Datalink (CPRD) GOLD primary care database. METHODS: We compiled over 4000 read and entity codes to identify pregnancy-related records among women aged 11 to 49 years in CPRD GOLD. Codes were categorised by the stage or outcome of pregnancy to facilitate delineation of pregnancy episodes. We constructed hierarchical rule systems to handle information from multiple sources. We assessed the validity of the Register to identify pregnancy outcomes by comparing our results to linked hospitalisation records and Office for National Statistics population rates. RESULTS: Our algorithm identified 5.8 million pregnancies among 2.4 million women (January 1987-February 2018). We observed close agreement with hospitalisation data regarding completeness of pregnancy outcomes (91% sensitivity for deliveries and 77% for pregnancy losses) and their timing (median 0 days difference, interquartile range 0-2 days). Miscarriage and prematurity rates were consistent with population figures, although termination and, to a lesser extent, live birth rates were underestimated in the Register. CONCLUSIONS: The Pregnancy Register offers huge research potential because of its large size, high completeness, and availability. Further validation work is underway to enhance this data resource and identify optimal approaches for its use.

Sp5 and Sp8 recruit ß-catenin and Tcf1-Lef1 to select enhancers to activate Wnt target gene transcription.

The ancient, highly conserved, Wnt signaling pathway regulates cell fate in all metazoans. We have previously shown that combined null mutations of the specificity protein (Sp) 1/Klf-like zinc-finger transcription factors Sp5 and Sp8 (i.e., Sp5/8) result in an embryonic phenotype identical to that observed when core components of the Wnt/ß-catenin pathway are mutated; however, their role in Wnt signal transduction is unknown. Here, we show in mouse embryos and differentiating embryonic stem cells that Sp5/8 are gene-specific transcriptional coactivators in the Wnt/ß-catenin pathway. Sp5/8 bind directly to GC boxes in Wnt target gene enhancers and to adjacent, or distally positioned, chromatin-bound T-cell factor (Tcf) 1/lymphoid enhancer factor (Lef) 1 to facilitate recruitment of ß-catenin to target gene enhancers. Because Sp5 is itself directly activated by Wnt signals, we propose that Sp5 is a Wnt/ß-catenin pathway-specific transcript on factor that functions in a feed-forward loop to robustly activate select Wnt target genes.

Sequential Information Processing: The "Elevated First Response Effect" Can Contribute to Exaggerated Intra-Individual Variability in Older Adults.

In this study we examined attention-related reaction time (RT) and intra-individual variability (IIV) in younger and older adults using an iPad-based visual search test, in which, for each trial, participants were required to sequentially press a series of on-screen stimuli numbered from 1 to 8. Although overall performance RT was significantly slower, with greater IIV for the older compared to the younger adult group, there was also a disproportionately slowed RT and greater IIV for the first item in the series compared to all other responses within the trial. When the response to the first stimulus was removed from statistical analysis, the significant age-related RT slowing effect remained, but IIV was no longer significantly greater for the older compared to the younger adults. This pattern of results reveals a dichotomy between the preservation of RT and IIV in aging, and one that is strongly related to research methodology. A finding that may account, at least in part, for the outcome heterogeneity in the study of IIV in aging.

The Impact of the National HPV Vaccination Program in England Using the Bivalent HPV Vaccine: Surveillance of Type-Specific HPV in Young Females, 2010-2016.

Background: The national human papillomavirus (HPV) immunization program was introduced in England in September 2008 using the bivalent vaccine. Methods: We collected residual vulva-vaginal swab specimens from 16 to 24-year-old women attending for chlamydia screening between 2010 and 2016 and tested for HPV DNA. We compared changes in type-specific (vaccine and nonvaccine) HPV prevalence over time and association with vaccination coverage. For women with known vaccination status, vaccine effectiveness was estimated. Results: HPV DNA testing was completed for 15459 specimens. Prevalence of HPV16/18 decreased between 2010/2011 and 2016 from 8.2% to 1.6% in 16-18 year olds and from 14.0% to 1.6% in 19-21 year olds. Declines were also seen for HPV31/33/45 (6.5% to 0.6% for 16-18 year olds and 8.6% to 2.6% for 19-21 year olds). Vaccine effectiveness for HPV16/18 was 82.0% (95% confidence interval [CI], 60.6%-91.8%) and for HPV31/33/45 was 48.7% (95% CI, 20.8%-66.8%). Prevalence of HPV16/18 was compared to findings in 2007-2008 (prevaccination) and to predictions from Public Health England's mathematical model. Discussion: Eight years after the introduction of a national HPV vaccination program, substantial declines have occurred in HPV16/18 and HPV31/33/45. The prevalence of other high-risk HPV types has not changed.

Mood Disorders and Risk of Herpes Zoster in 2 Population-Based Case-Control Studies in Denmark and the United Kingdom.

We examined the association between mood disorders and risk of herpes zoster in two case-control studies using data from nationwide Danish registries and practices in the UK Clinical Practice Research Datalink. We included incident zoster cases diagnosed in general practice (using systemic antivirals as a proxy in Denmark) or hospital during 1997-2013 in Denmark (n = 190,671) and during 2000-2013 in the United Kingdom (n = 177,361). We risk-set sampled 4 matched population controls per case. Conditional logistic regression analyses adjusting for zoster risk factors showed that the odds ratios for previous mood disorder among cases versus controls were 1.15 (99% confidence interval (CI): 1.12, 1.19; prevalence 7.1% vs. 6.0%) in Denmark and 1.12 (99% CI: 1.11, 1.14; prevalence 31.6% vs. 29.2%) in the United Kingdom. In Denmark, odds ratios were higher for anxiety (1.23; 99% CI: 1.17, 1.30) and severe stress and adjustment disorder (1.24; 99% CI: 1.18, 1.30) than for depression (1.11; 99% CI: 1.07, 1.14). In the United Kingdom, odds ratios for these conditions were similar: 1.12 (99% CI: 1.10, 1.13), 1.12 (99% CI: 1.10, 1.14), and 1.14 (99% CI: 1.10, 1.19) for depression, anxiety, and severe stress and adjustment disorder, respectively. In conclusion, mood disorders were associated with an increased risk of zoster.

Spectroscopic and Microscopic Evidence of Biomediated HgS Species Formation from Hg(II)-Cysteine Complexes: Implications for Hg(II) Bioavailability.

We investigated the chemistry of Hg(II) during exposure of exponentially growing bacteria ( Escherichia coli, Bacillus subtilis, and Geobacter sulfurreducens) to 50 nM, 500 nM, and 5 µM total Hg(II) with and without added cysteine. With X-ray absorption spectroscopy, we provide direct evidence of the formation of cell-associated HgS for all tested bacteria. The addition of cysteine (100-1000 µM) promotes HgS formation (>70% of total cell-associated Hg(II)) as a result of the biodegradation of added cysteine to sulfide. Cell-associated HgS species are also detected when cysteine is not added as a sulfide source. Two phases of HgS, cinnabar (α-HgS) and metacinnabar (ß-HgS), form depending on the total concentration of Hg(II) and sulfide in the exposure medium. However, α-HgS exclusively forms in assays that contain an excess of cysteine. Scanning transmission electron microscopy images reveal that nanoparticulate HgS(s) is primarily located at the cell surface/extracellular matrix of Gram-negative E. coli and G. sulfurreducens and in the cytoplasm/cell membrane of Gram-positive B. subtilis. Intracellular Hg(II) was detected even when the predominant cell-associated species was HgS. This study shows that HgS species can form from exogenous thiol-containing ligands and endogenous sulfide in Hg(II) biouptake assays under nondissimilatory sulfate reducing conditions, providing new considerations for the interpretation of Hg(II) biouptake results.

Do delays in data availability limit the implementation of near real-time vaccine safety surveillance using the Clinical Practice Research Datalink?

PURPOSE: Near real-time vaccine safety surveillance (NRTVSS) using electronic health records has been used to detect timely vaccine safety signals. Trial implementation of NRTVSS using the Clinical Practice Research Datalink (CPRD) has shown that there is limited power to detect safety signals for rare events. Delays in recording outcomes and receiving data influence the power and timeliness to identify a signal. Our work aimed to compare how different sources of delays influence power and expected time to signal to implement NRTVSS using CPRD. METHODS: We studied seasonal influenza vaccine/Guillain-Barré syndrome and performed power and expected time to signal calculations for the 2013-2014/2014-2015 seasons. We used the Poisson-based maximised sequential probability ratio test, which compares observed-to-expected events. For each study season, we obtained an average Guillain-Barré syndrome/seizures age-sex-adjusted rate from the 5 previous seasons and then used this rate to calculate the expected number of events, assuming a 42-day risk-window. Calculations were performed for detecting rate ratios of 1.5 to 10. We compared power and timeliness considering combinations of the presence/absence of delays in recording outcomes and in receiving data. The R-package Sequential was used. RESULTS: In general, there was ≥80% power to detect increases in risk of ≥4 at the end of the season. Assuming absence of delays slightly improved power (a maximum increase of 4%) but did not noticeably reduce time to detect a signal. CONCLUSION: Removing delays in data availability is insufficient to significantly improve the performance of a NRTVSS system using CPRD. Expansion of CPRD data is required. KEY POINTS The Clinical Practice Research Datalink (CPRD) can be used to implement near real-time vaccine safety surveillance, but there is limited power to detect signals for rare outcomes. Delays in recording outcomes and in receiving data might limit power and timeliness of a system. We assessed the influence of these sources of delays to inform data providers of the steps required to improve a system using CPRD data. Removing delays in recording outcomes and receiving data is unlikely to significantly improve the performance of a system using CPRD data. Expansion of the data available is needed.

Partner Bereavement and Risk of Herpes Zoster: Results from Two Population-Based Case-Control Studies in Denmark and the United Kingdom.

Background: Psychological stress is commonly thought to increase the risk of herpes zoster by causing immunosuppression. However, epidemiological studies on the topic are sparse and inconsistent. We conducted 2 parallel case-control studies of the association between partner bereavement and risk of zoster using electronic healthcare data covering the entire Danish population and general practices in the UK Clinical Practice Research Datalink. Methods: We included patients with a zoster diagnosis from the primary care or hospital-based setting in 1997-2013 in Denmark (n = 190671) and 2000-2013 in the United Kingdom (n = 150207). We matched up to 4 controls to each case patient by age, sex, and general practice (United Kingdom only) using risk-set sampling. The date of diagnosis was the index date for case patients and their controls. We computed adjusted odds ratios with 99% confidence intervals for previous bereavement among case patients versus controls using conditional logistic regression with results from the 2 settings pooled using random-effects meta-analysis. Results: Overall, the adjusted odds ratios for the association between partner bereavement and zoster were 1.05 (99% confidence interval, 1.03-1.07) in Denmark and 1.01 (.98-1.05) in the United Kingdom. The pooled estimates were 0.72, 0.90, 1.10, 1.08, 1.02, 1.04, and 1.03 for bereavement within 0-7, 8-14, 15-30, 31-90, 91-365, 366-1095, and >1095 days before the index date, respectively. Conclusions: We found no consistent evidence of an increased risk of zoster after partner death. Initial fluctuations in estimates may be explained by delayed healthcare contact due to the loss.

Lansoprazole use and tuberculosis incidence in the United Kingdom Clinical Practice Research Datalink: A population based cohort.

BACKGROUND: Recent in vitro and animal studies have found the proton pump inhibitor (PPI) lansoprazole to be highly active against Mycobacterium tuberculosis. Omeprazole and pantoprazole have no activity. There is no evidence that, in clinical practice, lansoprazole can treat or prevent incident tuberculosis (TB) disease. METHODS AND FINDINGS: We studied a cohort of new users of lansoprazole, omeprazole, or pantoprazole from the United Kingdom Clinical Practice Research Datalink to determine whether lansoprazole users have a lower incidence of TB disease than omeprazole or pantoprazole users. Negative control outcomes of myocardial infarction (MI) and herpes zoster were also studied. Multivariable Cox proportional hazards regression was used to adjust for potential confounding by a wide range of factors. We identified 527,364 lansoprazole initiators and 923,500 omeprazole or pantoprazole initiators. Lansoprazole users had a lower rate of TB disease (n = 86; 10.0 cases per 100,000 person years; 95% confidence interval 8.1-12.4) than omeprazole or pantoprazole users (n = 193; 15.3 cases per 100,000 person years; 95% confidence interval 13.3-17.7), with an adjusted hazard ratio (HR) of 0.68 (0.52-0.89). No association was found with MI (adjusted HR 1.04; 95% confidence interval 1.00-1.08) or herpes zoster (adjusted HR 1.03; 95% confidence interval 1.00-1.06). Limitations of this study are that we could not determine whether TB disease was due to reactivation of latent infection or a result of recent transmission, nor could we determine whether lansoprazole would have a beneficial effect if given to people presenting with TB disease. CONCLUSIONS: In this study, use of the commonly prescribed and cheaply available PPI lansoprazole was associated with reduced incidence of TB disease. Given the serious problem of drug resistance and the adverse side effect profiles of many TB drugs, further investigation of lansoprazole as a potential antituberculosis agent is warranted.

Bronchiectasis and the risk of cardiovascular disease: a population-based study.

BACKGROUND: There are limited data on the burden of cardiovascular comorbidities in people with bronchiectasis. Our cross-sectional study estimates the burden of pre-existing diagnoses of coronary heart disease (CHD) and stroke in people with bronchiectasis compared with the general population. The historical cohort study investigates if individuals with bronchiectasis are at increased risk of incident CHD and stroke events. METHODS: We used primary care electronic records from the Clinical Practice Research Datalink. The cross-sectional study used logistic regression to quantify the association between bronchiectasis and recorded diagnoses of CHD or stroke. Cox regression was used to investigate if people with bronchiectasis experienced increased incident CHD and strokes compared with the general population, adjusting for age, sex, smoking habit and other risk factors for cardiovascular disease. RESULTS: Pre-existing diagnoses of CHD (OR 1.33, 95% CI 1.25 to 1.41) and stroke (OR 1.92, 95% CI 1.85 to 2.01) were higher in people with bronchiectasis compared with those without bronchiectasis, after adjusting for age, sex, smoking and risk factors for cardiovascular disease. The rate of first CHD and stroke were also higher in people with bronchiectasis (HR for CHD 1.44 (95% CI 1.27 to 1.63) and HR for stroke 1.71 (95% CI 1.54 to 1.90)). CONCLUSION: The risk of CHD and stroke are higher among people with bronchiectasis compared with the general population. An increased awareness of these cardiovascular comorbidities in this population is needed to provide a more integrated approach to the care of these patients.

A cohort study of low birth weight and health outcomes in the first year of life, Ghana.

OBJECTIVE: To investigate the effect of birth weight on infant mortality, illness and care seeking in rural Ghana. METHODS: Using randomized controlled trial data, we compared infants weighing 2.00-2.49, 1.50-1.99 and < 1.50 kg with non-low-birth-weight infants. We generated adjusted mortality hazard ratios (aHR), adjusted illness rate ratios (aRR) and adjusted odds ratios (aOR) for health-facility admissions and absence of care seeking for four time periods: infancy, the neonatal period, early infancy and late infancy - represented by ages of 0-364, 0-27, 28-182 and 183-364 days, respectively. FINDINGS: Among 22 906 infants, compared with non-low-birth-weight infants: (i) infants weighing 2.00-2.49, 1.50-1.99 and < 1.50 kg were about two (aHR: 2.13; 95% confidence interval, CI: 1.76-2.59), eight (aHR: 8.21; 95% CI: 6.26-10.76) and 25 (aHR: 25.38; 95% CI: 18.36-35.10) times more likely to die in infancy, respectively; (ii) those born weighing < 1.50 kg were about 48 (aHR: 48.45; 95% CI: 32.81-71.55) and eight (aHR: 8.42; 95% CI: 3.09-22.92) times more likely to die in the neonatal period and late infancy, respectively; (iii) those born weighing 1.50-1.99 kg (aRR: 1.57; 95% CI: 1.27-1.95) or < 1.50 kg (aRR: 1.58; 95% CI: 1.13-2.21) had higher neonatal illness rates; and (iv) for those born weighing 1.50-1.99 kg, care was less likely to be sought in the neonatal period (aOR: 3.30; 95% CI: 1.98-5.48) and early infancy (aOR : 1.74; 95% CI: 1.26-2.39). CONCLUSION: For low-birth-weight infants in Ghana, strategies to minimize mortality and improve care seeking are needed.

Cysteine Addition Promotes Sulfide Production and 4-Fold Hg(II)-S Coordination in Actively Metabolizing Escherichia coli.

The bacterial uptake of mercury(II), Hg(II), is believed to be energy-dependent and is enhanced by cysteine in diverse species of bacteria under aerobic and anaerobic conditions. To gain insight into this Hg(II) biouptake pathway, we have employed X-ray absorption spectroscopy (XAS) to investigate the relationship between exogenous cysteine, cellular metabolism, cellular localization, and Hg(II) coordination in aerobically respiring Escherichia coli (E. coli). We show that cells harvested in exponential growth phase consistently display mixtures of 2-fold and 4-fold Hg(II) coordination to sulfur (Hg-S2 and Hg-S4), with added cysteine enhancing Hg-S4 formation. In contrast, cells in stationary growth phase or cells treated with a protonophore causing a decrease in cellular ATP predominantly contain Hg-S2, regardless of cysteine addition. Our XAS results favor metacinnabar (ß-HgS) as the Hg-S4 species, which we show is associated with both the cell envelope and cytoplasm. Additionally, we observe that added cysteine abiotically oxidizes to cystine and exponentially growing E. coli degrade high cysteine concentrations (100-1000 µM) into sulfide. Thermodynamic calculations confirm that cysteine-induced sulfide biosynthesis can promote the formation of dissolved and particulate Hg(II)-sulfide species. This report reveals new complexities arising in Hg(II) bioassays with cysteine and emphasizes the need for considering changes in chemical speciation as well as growth stage.

Assessing recording delays in general practice records to inform near real-time vaccine safety surveillance using the Clinical Practice Research Datalink (CPRD).

PURPOSE: Near real-time vaccine safety surveillance (NRTVSS) is an option for post-licensure vaccine safety assessment. NRTVSS requires timely recording of outcomes in the database used. Our main objective was to examine recording delays in the Clinical Practice Research Datalink (CPRD) for outcomes of interest for vaccine safety to inform the feasibility of NRTVSS using these data. We also evaluated completeness of recording and further assessed reporting delays for hospitalized events in CPRD. METHODS: We selected Guillain-Barré syndrome (GBS), Bell's palsy (BP), optic neuritis (ON) and febrile seizures (FS), from January 2005 to June 2014. We assessed recording delays (e.g. due to feedback from specialist referral) in stand-alone CPRD by comparing the event and system dates and excluding delays >1 year. We used linked CPRD-hospitalization data to further evaluate delays and completeness of recording in CPRD. RESULTS: Among 51 220 patients for the stand-alone CPRD analysis (GBS: n = 830; BP: n = 12 602; ON: n = 1720; and FS: n = 36 236), most had a record entered within 1 month of the event date (GBS: 73.6%; BP: 93.4%; ON: 76.2%; and FS: 85.6%). A total of 13 482 patients, with a first record in hospital, were included for the analysis of linked data (GBS: n = 678; BP: n = 4060; ON: n = 485; and FS: n = 8321). Of these, <50% had a record in CPRD after 1 year (GBS: 41.3%; BP: 22.1%; ON: 22.4%; and FS: 41.8%). CONCLUSION: This work shows that most diagnoses in CPRD for the conditions examined were recorded with delays of ≤30 days, making NRTVSS possible. The pattern of delays was condition-specific and could be used to adjust for delays in the NRTVSS analysis. Despite low sensitivity of recording, implementing NRTVSS in CPRD is worthwhile and could be carried out, at least on a trial basis, for events of interest. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.