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Objective: To determine pregnancy outcome in women with atrial switch repair for transposition of the great arteries (TGA) and to compare follow up with a control group of childless women with the same repair.Design: Retrospective cohort study.Setting: Tertiary care medical centre.Population: About 21 patients compared with 15 controls.Methods: Review of records from joint cardiac-obstetric clinic 1993-2013.Main Outcome Measures: Occurrence of cardiovascular events: maternal death, heart failure, arrhythmia, thromboembolic events, worsening systemic ventricular function, worsening tricuspid valve regurgitation and newly detected baffle problems.Results: There were 34 pregnancies in 21 women. Mean follow up was 100 months. No deaths or recurrence occurred. Events (few arrhythmias, thromboembolic events and baffle issues) were common in both groups: 13 (62%) patients and eight (53%) controls (P = 0.736). Worsening of ventricular function was similar in both groups: six (29%) patients and four (27%) controls (P = 0.899). Worsening tricuspid regurgitation was more common in patients [11 (52%)] than controls (0)] (P < 0.001). Labour was induced in 76% cases: 32% for cardiac deterioration, 37% to control timing of delivery, and 26% for intrauterine growth restriction. Delivery was vaginal in 84% cases. Median gestational age was 37 (30-40) weeks, median birthweight 2525 g (1460-3530). In all, 38% babies were premature and 38% were small-for-gestational-age.Conclusions: Cardiac events after atrial repair for TGA are equally common in pregnant women and non-pregnant controls, although worsening tricuspid regurgitation occurs more frequently in pregnancy. Induction of labour is to be expected but vaginal delivery is achievable in most cases. Infants are likely to be premature and small-for-gestational-age.Tweetable Abstract: Pregnancy in atrial repair for TGA: cardiac events similar to controls, prematurity and small babies likely. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Basude S, Hein C, Curtis S, Clark A, Trinder J. Low-molecular-weight heparin or warfarin for anticoagulation in pregnant women with mechanical heart valves: what are the risks? A retrospective observational study. BJOG 2012;119:1008-1013. The management of anticoagulation in pregnant women with mechanical heart valves is complex. The maternal and fetal outcomes of 32 pregnancies in 15 women on three different anticoagulation regimens were compared. Anticoagulation with low-molecular-weight heparin ( n = 4), warfarin ( n = 22) and combination therapy ( n = 6) resulted in adverse maternal events in four (100%), three (50%) and three (14%) women, and resulted in fetal losses in one (25%), 17(77%) and three (50%) pregnancies, respectively. Whereas the rate of fetal loss in the warfarin group was high, all women in the LMWH and half of those in the combination group had serious adverse maternal events, including valve thrombosis, maternal death and postpartum haemorrhage. [ABSTRACT FROM AUTHOR]

Adenoviruses (Ads) have demonstrated significant success as replication-deficient (RD) viral vectored vaccines, as well as broad potential across gene therapy and cancer therapy. Ad vectors transduce human cells via direct interactions between the viral fiber knob and cell surface receptors, with secondary cellular integrin interactions. Ad receptor usage is diverse across the extensive phylogeny. Commonly studied human Ad serotype 5 (Ad5), and chimpanzee Ad-derived vector "ChAdOx1" in licensed ChAdOx1 nCoV-19 vaccine, both form primary interactions with the coxsackie and adenovirus receptor (CAR), which is expressed on human epithelial cells and erythrocytes. CAR usage is suboptimal for targeted gene delivery to cells with low/negative CAR expression, including human dendritic cells (DCs) and vascular smooth muscle cells (VSMCs). We evaluated the performance of an RD Ad5 vector pseudotyped with the fiber knob of human Ad serotype 49, termed Ad5/49K vector. Ad5/49K demonstrated superior transduction of murine and human DCs over Ad5, which translated into significantly increased T cell immunogenicity when evaluated in a mouse cancer vaccine model using 5T4 tumor-associated antigen. Additionally, Ad5/49K exhibited enhanced transduction of primary human VSMCs. These data highlight the potential of Ad5/49K vector for both vascular gene therapy applications and as a potent vaccine vector., Competing Interests: A.L.P. is founder and CSO of Trocept Therapeutics (part of Accession Therapeutics Ltd.), who are developing unrelated viral platforms for oncolytic virotherapy applications., (© 2024 The Author(s).)

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5' untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN., (© 2024. The Author(s).)

Background: After a 40% reduction in maternal mortality ratio (MMR) during 2001-2010 in Bangladesh, the MMR level stagnated between 2010 and 2016 despite a steady increase in maternal health services use and improvements in overall socioeconomic status. We revisited the factors that contributed to MMR decline during 2001-2010 and examined the changes in these factors between 2010 and 2016 to explain the MMR stagnation in Bangladesh., Methods: We used data from the 2001, 2010, and 2016 Bangladesh Maternal Mortality Surveys, which sampled 566 115 households in total, to estimate the changes in the risk of dying of maternal causes associated with a pregnancy or birth between 2001-2010 and 2010-2016. We carried out Poisson regression analyses with random effects at the sub-district level to explore the relationship between the change in risk of maternal death from 2001 to 2016 and a range of demographic, socioeconomic, and health care factors., Results: Between 2001 and 2016, the proportion of high-risk pregnancies decreased, except for teenage pregnancies. Meanwhile, there were notable improvements in socioeconomic status, access to health services, and the utilisation of maternal health services. A comparison of factors affecting the risk of maternal death between 2001-2010 and 2010-2016 indicated that first pregnancies continued to offer significant protection against maternal deaths. However, subsequent pregnancies among girls under 20 years became a significant risk factor during 2010-2016, increasing the risk of maternal deaths by nearly 3-fold. Among the key maternal health services, only skilled birth attendants (SBA) were identified as a key contributor to MMR reduction during 2001-2010. However, SBA is no longer significantly associated with reducing mortality risk during 2010-2016., Conclusions: Despite continued improvements in the overall socioeconomic status and access to maternal health services in Bangladesh, the stagnation of MMR decline between 2010 and 2016 is associated with multiple teenage pregnancies and the lack of capacity in health facilities to provide quality delivery services, as SBA has been primarily driven by facility delivery. The findings provide a strong rationale for targeting at-risk mothers and strengthening reproductive health services, including family planning, to further reduce maternal mortality in Bangladesh., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Pregnancy is a dynamic process associated with profound hormonally mediated haemodynamic changes which result in structural and functional adaptations in the cardiovascular system. An understanding of the myocardial adaptations is important for echocardiographers and clinicians undertaking or interpreting echocardiograms on pregnant and post-partum women. This guideline, on behalf of the British Society of Echocardiography and United Kingdom Maternal Cardiology Society, reviews the expected echocardiographic findings in normal pregnancy and in different cardiac disease states, as well as echocardiographic signs of decompensation. It aims to lay out a structure for echocardiographic scanning and surveillance during and after pregnancy as well as suggesting practical advice on scanning pregnant women., (© 2023. The Author(s).)

Aortic dissection is one of the most common causes of death in pregnancy. Most cases are caused by hereditary thoracic aortopathy (HTA), and women are often unaware they are at risk. Awareness, early recognition and involvement of senior clinicians from the expert cardio-obstetric team are essential to facilitate early diagnosis and carefully planned and coordinated antenatal and postnatal care. Frequent imaging antenatally and good blood pressure control are key. Delivery needs particular attention with optimal pain control and techniques to minimise maternal effort. Dissection is most common post partum and a period of close surveillance with meticulous blood pressure control after delivery is crucial, as well as follow-up of the baby in paediatric services. All women with a family history of aortic dissection or sudden death should be investigated. Women with known HTA should be offered specialist individualised pre-pregnancy counselling, including advice about genetics and inheritance, before starting a family. Future research is directed towards more individualised risk assessment, pre-pregnancy advice and pharmacological options to reduce dissection risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Obstetric fistula, which develops after a prolonged or obstructed labour, is preventable and treatable. However, many women are still afflicted with the condition and remain untreated in low-income and middle-income countries. Concerns have also been raised that an increasing trend of caesarean sections is increasing the risk and share of iatrogenic obstetric fistula in these countries. The true prevalence of this condition is not known, which makes it difficult for health planners and policy makers to develop appropriate national health strategies to address the problem. The estimation of obstetric fistula with surveys is difficult because self-reporting of incontinence symptoms is subject to misclassification bias. In this study, we aimed to estimate the prevalence and burden of obstetric fistula in Bangladesh., Methods: For a valid estimation addressing misclassification bias, we implemented the study in two steps. First, we did the Maternal Morbidity Validation Study (MMVS) among a population of 65 740 women in Sylhet, Bangladesh, to assess the sensitivity, specificity, positive predictive values (PPVs), and negative predictive values of the survey questions. This was done through confirmation of the diagnosis with clinical examinations of suspected cases by female physicians; a sample of women who screened positive for pelvic organ prolapse and other urinary incontinence symptoms were also examined and used as controls for clinical diagnosis confirmation. Second, we used the estimated diagnostic test values, after correcting for verification bias, to adjust the reported prevalence in the nationally representative Bangladesh Maternal Mortality and Health Care Survey 2016 for the unbiased estimation of obstetric fistula prevalence in Bangladesh., Findings: The MMVS, done from Aug 3 to Dec 9, 2016, identified 67 potential cases of obstetric fistula; of them, 57 (85%) women completed the clinical examination, and 19 were confirmed as obstetric fistula cases. The adjusted sensitivity of the self-reports of obstetric fistula was 100% (95% uncertainty interval [UI] 99·8-100) and the observed specificity was 99·9% (95% UI 99·9-100) among women aged 15-49 years. However, the PPV was low, at 31·6% (95% UI 19·2-46·2), suggesting that almost two thirds of the self-reported cases were not true obstetric fistula cases. We estimated an adjusted obstetric fistula prevalence rate of 38 (90% UI 25-58) per 100 000 women aged 15-49 years in Bangladesh. Nationally, we estimated about 13 376 (90% UI 8686-20 112) women of reproductive age living with obstetric fistula. Additionally, we estimated 4081 (1773-8790) women aged 50-64 years to be living with obstetric fistula in Bangladesh; overall, we estimated that there are 17 457 (10 459-28 902) women aged 15-64 years in Bangladesh with obstetric fistula., Interpretation: The burden of obstetric fistula is still high in Bangladesh. Prevention and provision of surgical treatment to so many women will need coordinated efforts, planning, allocation of resources, and training of surgeons., Funding: US Agency for International Development, Government of Bangladesh, and UKAid., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Ventriculo-arterial (VA) coupling in bicuspid aortic valve (BAV) patients can be affected by the global aortopathy characterizing BAV disease and the presence of concomitant congenital lesions such as aortic coarctation (COA). This study aimed to isolate the COA variable and use cardiovascular magnetic resonance (CMR) imaging to perform wave intensity analysis non-invasively to shed light on VA coupling changes in BAV. The primary hypothesis was that BAV patients with COA exhibit unfavorable VA coupling, and the secondary hypothesis was that BAV patients with COA exhibit increased wave speed as a marker of reduced aortic distensibility despite successful surgical correction., Methods: Patients were retrospectively identified from a CMR database and divided into two groups: isolated BAV and BAV associated with repaired COA. Aortic and ventricular dimensions, global longitudinal strain (GLS), and ascending aortic flow data and area were collected and used to derive wave intensity from CMR data. The main variables for the analysis included all wave magnitudes (forward compression/expansion waves, FCW and FEW, respectively, and reflected backward compression wave, BCW) and wave speed., Results: In the comparison of patients with isolated BAV and those with BAV associated with repaired COA ( n = 25 in each group), no differences were observed in left ventricular ejection fraction, GLS, or ventricular volumes, whilst significant increases in FCW and FEW magnitude were noted in the BAV and repaired COA group. The FCW inversely correlated with age and aortic size. Whilst the BCW was not significantly different compared with that in patients with/without COA, its magnitude tends to increase with a lower COA index. Patients with repaired COA exhibited higher wave speed velocity. Aortic wave speed (inversely related to distensibility) was not significantly different between the two groups., Conclusion: In the absence of a significant restenosis, VA coupling in patients with BAV and COA is not negatively affected compared to patients with isolated BAV. A reduction in the magnitude of the early systolic FCW was observed in patients who were older and with larger aortic diameters., Competing Interests: CB-D is the CEO (part-time) of the Society for Cardiovascular Magnetic Resonance, and she received speaker's fees from Circle Cardiovascular Imaging and Siemens. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Milano, Neumann, Sophocleous, Pontecorboli, Curtis, Bedair, Caputo, Luciani, Bucciarelli-Ducci and Biglino.)

Objective: Bangladesh achieved the fourth Millennium Development Goal well ahead of schedule, with a significant reduction in under-5 mortality between 1990 and 2015. However, the reduction in neonatal mortality has been stagnant in recent years. The purpose of this study is to explore the association between place of delivery and newborn care with early neonatal mortality (ENNM), which represents more than 80% of total neonatal mortality in Bangladesh., Methods: In this study, 2014 Bangladesh Demographic and Health Survey data were used to assess early neonatal survival in children born in the three years preceding the survey. The roles of place of the delivery and newborn care in ENNM were examined using multivariable logistic regression models adjusted for clustering and relevant socio-economic, pregnancy, and newborn characteristics., Results: Between 2012 and 2014, there were 4,624 deliveries in 17,863 sampled households, 39% of which were delivered at health facilities. The estimated early neonatal mortality rate during this period was 15 deaths per 1,000 live births. We found that newborns who had received at least 3 components of essential newborn care (ENC) were 56% less likely to die during the first seven days of their lives compared to their counterparts who received 0-2 components of ENC (aOR: 0.44; 95% CI: 0.24-0.81). In addition, newborns who had received any postnatal care (PNC) were 68% less likely to die in the early neonatal period than those who had not received any PNC (aOR: 0.32; 95% CI: 0.16-0.64). Facility delivery was not significantly associated with the risk of early newborn death in any of the models., Conclusion: Our study findings highlight the importance of newborn and postnatal care in preventing early neonatal deaths. Further, findings suggest that increasing the proportion of women who give birth in a healthcare facility is not sufficient to reduce ENNM by itself; to realize the theoretical potential of facility delivery to avert neonatal deaths, we must also ensure quality of care during delivery, guarantee all components of ENC, and provide high-quality early PNC. Therefore, sustained efforts to expand access to high-quality ENC and PNC are needed in health facilities, particularly in facilities serving low-income populations., Competing Interests: The authors have declared that no competing interests exist.

The reproductive calendar is a data collection tool that collects month-by-month retrospective histories of contraceptive use. This survey instrument is implemented in large-scale demographic surveys, but its reliability is not well-understood. Our analysis helps to address this research gap, using longitudinal panel data with overlapping calendars from urban Kenya. Our findings indicate calendar data collected in 2014 underestimated 2012 reports of current use by 5 percentage points. And while the overall percentage of women reporting at least one episode of contraceptive use was similar across the two calendars (67 percent vs. 70 percent), there was notable disagreement in contraceptive behavior when comparing the histories of individual women; less than 20 percent of women with any contraceptive use reported the exact same pattern of use in both calendars. Low calendar reliability was especially apparent for younger women and those with complicated contraceptive histories. Individual-level discordance resulted in a small difference in 12-month discontinuation rates for the period of calendar overlap; when surveyed in 2014, women reported a 12-month discontinuation rate of 39 percent, compared to a rate of 34 percent reported in 2012. When using retrospective calendar data, attention must be paid to the potential for individual reporting errors., (© 2021 The Population Council, Inc.)

Objectives: The coexistence of two complex physiologies such as Fontan and pregnancy is still not fully understood. We aim to add a unique and essential knowledge to help our colleagues in the management of Fontan patients that undergo pregnancy as well as the fetus and the placenta perfusion., Methods and Results: We analyse the coexistence of Fontan and pregnancy physiology on a complex case of a woman with hypoplastic left heart syndrome palliated with a univentricular repair who became pregnant, delivered very prematurely and had atypical placental findings., Conclusion: Histopathological analysis of the placenta could help us to refine the understanding of Fontan physiology adaptation during pregnancy, predict women and fetal outcomes as well as to plan a better pre-pregnancy status. However, further evidence is needed in order to reach a more solid and unified conclusion., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Women's concerns about contraceptive-induced menstrual changes can lead to method discontinuation and nonuse, contributing to unmet need for contraception. Research on women's perceptions of amenorrhea related to longer acting methods and in low-income countries is limited., Methods: Data were from nationally representative household surveys and focus group discussions with women of reproductive age conducted in Burkina Faso and Uganda in 2016-2017. Bivariate cross-tabulations and multivariate logistic regression analyses were used to examine sociodemographic and reproductive characteristics associated with women's attitudes about contraceptive-induced amenorrhea (n=2,673 for Burkina Faso and 2,281 for Uganda); menstrual health determinants were also examined for Burkina Faso. Qualitative data from focus group discussions were analyzed to understand reasons behind women's attitudes and how they influence contraceptive decision making., Results: Sixty-five percent of women in Burkina Faso and 40% in Uganda reported they would choose a method that caused amenorrhea during use. In Burkina Faso, the predicted probability of accepting amenorrhea was higher for women aged 15-19 (compared with older women), living in rural areas, married and cohabiting (compared with never married), currently using a contraceptive method (compared with never users) and from Mossi households (compared with Gourmantché); menstrual health practices were not associated with amenorrhea acceptability. In Uganda, the least wealthy women had the highest predicted probability of accepting amenorrhea (51%). Qualitative analysis revealed a variety of reasons for women's attitudes about amenorrhea and differences by country, but the relationship between these attitudes and contraceptive decision making was similar across countries., Conclusions: Addressing misconceptions about contraception and menstruation may result in more informed method decision making.

The assay in serum of non-caeruloplasmin copper, as exchangeable copper after complexation with EDTA (ExCu) and total copper has been evaluated and compared in patients with varying c-reactive protein(CRP). Measurement of ExCu and total copper, range 0.2-47.2 µmol/L, was developed using ICP-MS. The chelating agents EDTA and TEPA were compared over 0.0-10 g/L after incubation with serum for 60 mins followed by ultrafiltration with Amicon 10 kDa filter. The assay for ExCu was optimised with EDTA 3 g/L (8.1 mmol/L) maintained at pH 7.0-8.0 before ultrafiltration. TEPA was not as selective in chelation of copper. Patients n  = 82 were studied in relation to changes in inflammatory marker CRP and a group of patients n  = 37 with normal CRP. The ExCu assay gave excellent recoveries (94-102 % but poor recovery for free uncomplexed copper), good repeatability, limit of quantitation 0.19 µmol/l with a provisional reference range 0.48 to 1.63 µmol/L ( n  = 37 patients). The range for relative exchangeable copper (exchangeable copper divided by total serum copper) was 2.49 to 9.96 %. ExCu was elevated in conditions with increased CRP greater than 100 mg/L suggesting an effect of inflammation on the free copper fraction. A reliable and reproducible assay for ExCu and total copper has been developed. The upregulated inflammatory state increases the ExCu suggesting excess free copper.

Oncolytic virotherapies (OV) based on human adenoviral (HAdV) vectors hold significant promise for the treatment of advanced ovarian cancers where local, intraperitoneal delivery to tumour metastases is feasible, bypassing many complexities associated with intravascular delivery. The efficacy of HAdV-C5-based OV is hampered by a lack of tumour selectivity, where the primary receptor, hCAR, is commonly downregulated during malignant transformation. Conversely, folate receptor alpha (FRα) is highly expressed on ovarian cancer cells, providing a compelling target for tumour selective delivery of virotherapies. Here, we identify high-affinity FRα-binding oligopeptides for genetic incorporation into HAdV-C5 vectors. Biopanning identified a 12-mer linear peptide, DWSSWVYRDPQT, and two 7-mer cysteine-constrained peptides, CIGNSNTLC and CTVRTSAEC that bound FRα in the context of the phage particle. Synthesised lead peptide, CTVRTSAEC, bound specifically to FRα and could be competitively inhibited with folic acid. To assess the capacity of the elucidated FRα-binding oligopeptides to target OV to FRα, we genetically incorporated the peptides into the HAdV-C5 fiber-knob HI loop including in vectors genetically ablated for hCAR interactions. Unfortunately, the recombinant vectors failed to efficiently target transduction via FRα due to defective intracellular trafficking following entry via FRα, indicating that whilst the peptides identified may have potential for applications for targeted drug delivery, they require additional refinement for targeted virotherapy applications.

T cell recognition of peptides presented by human leukocyte antigens (HLAs) is mediated by the highly variable T cell receptor (TCR). Despite this built-in TCR variability, individuals can mount immune responses against viral epitopes by using identical or highly related TCRs expressed on CD8 + T cells. Characterization of these TCRs has extended our understanding of the molecular mechanisms that govern the recognition of peptide-HLA. However, few examples exist for CD4 + T cells. Here, we investigate CD4 + T cell responses to the internal proteins of the influenza A virus that correlate with protective immunity. We identify five internal epitopes that are commonly recognized by CD4 + T cells in five HLA-DR1 + subjects and show conservation across viral strains and zoonotic reservoirs. TCR repertoire analysis demonstrates several shared gene usage biases underpinned by complementary biochemical features evident in a structural comparison. These epitopes are attractive targets for vaccination and other T cell therapies., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Broadly expressed, highly differentiated tumor-associated antigens (TAA) can elicit antitumor immunity. However, vaccines targeting TAAs have demonstrated disappointing clinical results, reflecting poor antigen selection and/or immunosuppressive mechanisms., Experimental Design: Here, a panel of widely expressed, novel colorectal TAAs were identified by performing RNA sequencing of highly purified colorectal tumor cells in comparison with patient-matched colonic epithelial cells; tumor cell purification was essential to reveal these genes. Candidate TAA protein expression was confirmed by IHC, and preexisting T-cell immunogenicity toward these antigens tested., Results: The most promising candidate for further development is DNAJB7 [DnaJ heat shock protein family (Hsp40) member B7], identified here as a novel cancer-testis antigen. It is expressed in many tumors and is strongly immunogenic in patients with cancers originating from a variety of sites. DNAJB7-specific T cells were capable of killing colorectal tumor lines in vitro , and the IFNγ + response was markedly magnified by control of immunosuppression with cyclophosphamide in patients with cancer., Conclusions: This study highlights how prior methods that sequence whole tumor fractions (i.e., inclusive of alive/dead stromal cells) for antigen identification may have limitations. Through tumor cell purification and sequencing, novel candidate TAAs have been identified for future immunotherapeutic targeting., (©2020 American Association for Cancer Research.)

Informal fees are payments made by patients to their health care provider that are over and above the official cost of services. Payments may be motivated by a combination of factors such as low supervision, weak sanctions, and inadequate provider salaries. The practice of soliciting informal fees from patients may result in restricted access to medical care and reduced care-seeking behavior among vulnerable populations. The objective of this study is to examine nuanced health care provider perspectives on informal fee payments solicited from reproductive health patients in Kenya. We conducted in-depth semistructured interviews in 2015-2016 among a sample of 20 public and private-sector Kenyan health care workers. Interviews were coded and analyzed using an iterative thematic approach. More than half of participants reported that solicitation of informal fees is common practice in health care facilities. Providers reported low public-sector wages were a primary driver of informal fee solicitation coupled with collusion among senior staff. Additionally, patients may be unaware that they are being asked to pay more than the official cost of services. Strategies for reducing this behavior include more adequate and timely remuneration within the public sector, educating patient populations of free or low-cost services, and evidence-based methods to increase provider motivation., (© 2020 The Population Council, Inc.)

Background: It has been estimated that 20-30% of repaired aortic coarctation (CoA) patients develop hypertension, with significant cardiovascular morbidity and mortality. Vertebral artery hypoplasia (VAH) with an incomplete posterior circle of Willis (ipCoW; VAH + ipCoW) is associated with increased cerebrovascular resistance before the onset of increased sympathetic nerve activity in borderline hypertensive humans, suggesting brainstem hypoperfusion may evoke hypertension to maintain cerebral blood flow: the "selfish brain" hypothesis. We now assess the "selfish brain" in hypertension post-CoA repair., Methods: Time-of-flight cardiovascular magnetic resonance angiography from 127 repaired CoA patients (34 ± 14 years, 61% male, systolic blood pressure (SBP) 138 ± 19 mmHg, diastolic blood pressure (DBP) 76 ± 11 mmHg) was compared with 33 normotensive controls (42 ± 14 years, 48% male, SBP 124 ± 10 mmHg, DBP 76 ± 8 mmHg). VAH was defined as < 2 mm and ipCoW as hypoplasia of one or both posterior communicating arteries., Results: VAH + ipCoW was more prevalent in repaired CoA than controls (odds ratio: 5.8 [1.6-20.8], p = 0.007), after controlling for age, sex and body mass index (BMI). VAH + ipCoW was an independent predictor of hypertension (odds ratio: 2.5 [1.2-5.2], p = 0.017), after controlling for age, gender and BMI. Repaired CoA subjects with VAH + ipCoW were more likely to have difficult to treat hypertension (odds ratio: 3.3 [1.01-10.7], p = 0.049). Neither age at time of CoA repair nor any specific repair type were significant predictors of VAH + ipCoW in univariate regression analysis., Conclusions: VAH + ipCoW predicts arterial hypertension and difficult to treat hypertension in repaired CoA. It is unrelated to age at time of repair or repair type. CoA appears to be a marker of wider congenital cerebrovascular problems. Understanding the "selfish brain" in post-CoA repair may help guide management., Journal Subject Codes: High Blood Pressure; Hypertension; Magnetic Resonance Imaging (MRI); Cardiovascular Surgery; Cerebrovascular Malformations.

Objectives: Information to guide counselling and management for pregnancy in women with Marfan syndrome (MFS) is limited. We therefore conducted a UK multicentre study., Methods: Retrospective observational study of women with MFS delivering between January 1998 and March 2018 in 12 UK centres reporting data on maternal and neonatal outcomes., Results: In total, there were 258 pregnancies in 151 women with MFS (19 women had prior aortic root replacements), including 226 pregnancies ≥24 weeks (two sets of twins), 20 miscarriages and 12 pregnancy terminations. Excluding miscarriages and terminations, there were 221 live births in 139 women. Only 50% of women received preconception counselling. There were no deaths, but five women experienced aortic dissection (1.9%; one type A and four type B-one had a type B dissection at 12 weeks and subsequent termination of pregnancy). Five women required cardiac surgery postpartum. No predictors for aortic dissection could be identified. The babies of the 131 (65.8%) women taking beta-blockers were on average 316 g lighter (p<0.001). Caesarean section rates were high (50%), particularly in women with dilated aortic roots. In 55 women, echocardiographic aortic imaging was available prepregnancy and postpregnancy; there was a small but significant average increase in AoR size of 0.84 mm (Median follow-up 2.3 months) CONCLUSION: There were no maternal deaths, and the aortic dissection rate was 1.9% (mainly type B). There with no identifiable factors associated with aortic dissection in our cohort. Preconception counselling rates were low and need improvement. Aortic size measurements increased marginally following pregnancy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Healthcare worker absenteeism is common in resource limited settings and contributes to poor quality of care in maternal and child health service delivery. There is a dearth of qualitative information on the scope, contributing factors, and impact of absenteeism in Kenyan healthcare facilities., Methods: In-depth semi-structured interviews were conducted between July 2015 and June 2016 with 20 healthcare providers in public and private healthcare facilities in Central and Western Kenya. Interviews were audio-recorded, transcribed, coded, and analyzed using an iterative thematic approach., Results: Half of providers reported that absenteeism occurs in both private and public health facilities. Absenteeism was most commonly characterized by providers arriving late or leaving early during scheduled work hours. The practice was attributed to institutional issues including: infrequent supervision, lack of professional consequences, limited accountability, and low wages. In some cases, healthcare workers were frequently absent because they held multiple positions at different health facilities. Provider absences result in increased patient wait times and may deter patients from seeking healthcare in the future., Conclusion: There is a significant need for policies and programs to reduce provider absenteeism in Kenya. Intervention approaches must be cognizant of the contributors to absenteeism which occur at the institutional level.

Objectives: We have assessed the effect of elevated concentrations of hydroxyphenylpyruvic acid (HPPA), hydroxyphenyllactic acid (HPLA) and tyrosine, on a range of chemistry tests in serum and urine to explore the potential for chemical interference on routine laboratory analyses in patients with alkaptonuria (AKU) treated with nitisinone and similarly implications for patients with hereditary tyrosinemia type 1 (HT-1)., Materials and Methods: HPPA, HPLA and tyrosine were added separately to pooled serum from subjects without AKU in a range of assays with Roche Modular chemistries. Effects on urine were assessed by changes in urine strip chemistries after mixing a positive control urine with various amounts of the test compounds and reading on a Siemens urine strip meter., Results: No significant effect (p > 0.1) was observed up to 225 μmol/L of HPPA and HPLA, and up to 5000 μmol/L tyrosine, on any of the serum-based assays including those with peroxidase-coupled reaction systems of enzymatic creatinine, urate, total cholesterol, HDL cholesterol and triglyceride. Both the monohydroxy HPPA, and the dihydroxy homogentisic acid (HGA), at increased urine concentrations typical of nitisinone-treated AKU and non-treated AKU respectively, did however show marked negative interference in strip assays for glucose and leucocytes; i.e. those with peroxide-linked endpoints. The effect of increased HPLA was less marked., Conclusions: In patients with AKU or on nitisinone treatment and HT-1 patients on nitisinone, urine strip chemistry testing should be used sparingly, if at all, to avoid false negative reporting. It is recommended that urine assays should be organised with a suitable specialist laboratory., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: In 2006, the Government of India launched the accredited social health activist (ASHA) program, with the goal to connect marginalized communities to the health care system. We assessed the effect of the ASHA program on the utilization of maternity services., Methods: We used data from Indian Human Development Surveys done in 2004-2005 and in 2011-2012 to assess demographic and socioeconomic factors associated with the receipt of ASHA services, and used difference-in-difference analysis with cluster-level fixed effects to assess the effect of the program on the utilization of at least one antenatal care (ANC) visit, four or more ANC visits, skilled birth attendance (SBA), and giving birth at a health facility., Results: Substantial variations in the receipt of ASHA services were reported with 66% of women in northeastern states, 30% in high-focus states, and 16% of women in other states. In areas where active ASHA activity was reported, the poorest women, and women belonging to scheduled castes and other backward castes, had the highest odds of receiving ASHA services. Exposure to ASHA services was associated with a 17% (95% CI 11.8-22.1) increase in ANC-1, 5% increase in four or more ANC visits (95% CI - 1.6-11.1), 26% increase in SBA (95% CI 20-31.1), and 28% increase (95% CI 22.4-32.8) in facility births., Conclusions: Our results suggest that the ASHA program is successfully connecting marginalized communities to maternity health services. Given the potential of the ASHA in impacting service utilization, we emphasize the need to strengthen strategies to recruit, train, incentivize, and retain ASHAs.

The Fontan operation is a palliative surgical procedure for patients whose hearts cannot support a biventricular circulation. The haemodynamic changes that occur in pregnancy are particularly challenging for Fontan patients and the outcomes are variable. We present a case where fetal outcome was particularly poor despite a lack of high risk features pre-pregnancy.

Background: Evidence suggests that gender equality positively influences family planning. However, the evidence from urban Africa is sparse. This study aimed to examine the association between changes in gender norms and modern contraceptive use over time among women in urban Nigeria., Methods: Data were collected in 2010/2011 from 16,118 women aged 15-49 living in six cities in Nigeria (Abuja, Benin, Ibadan, Ilorin, Kaduna, and Zaria) and again in 2014 from 10,672 of the same women (34% attrition rate). The analytical sample included 9933 women living in 480 neighborhoods. A four-category outcome variable measured their change in modern contraceptive use within the study period. The exposure variables measured the changes in the level of gender-equitable attitudes towards: a) wife beating; b) household decision-making; c) couples' family planning decisions; and d) family planning self-efficacy. Multilevel multinomial logistic regression models estimated the associations between the exposure variables at the individual and neighborhood levels and modern contraceptive use controlling for the women's age, education, marital status, religion, parity, household wealth, and city of residence., Results: The proportion of women who reported current use of modern contraceptive methods increased from 21 to 32% during the four-year study period. At both surveys, 58% of the women did not report using modern contraceptives while 11% reported using modern contraceptives; 21% did not use in 2010/2011 but started using by 2014 while 10% used in 2010/2011 but discontinued use by 2014. A positive change in the gender-equitable attitudes towards household decision-making, couples' family planning decisions, and family planning self-efficacy at the individual and neighborhood levels were associated with increased relative probability of modern contraceptive use (adoption and continued use) and decreased relative probability of modern contraceptive discontinuation by 2014. No such associations were found between the individual and neighborhood attitudes towards wife beating and modern contraceptive use. Accounting for the individual and neighborhood gender-equitable attitudes and controlling for the women's demographic characteristics accounted for 55-61% of the variation between neighborhoods in the change in modern contraceptive use during the study period., Conclusion: Interventions that promote gender equality have the potential to increase modern contraceptive use in Nigerian cities.

Ukraine is among the top 20 highest drug-resistant tuberculosis burden countries in the world. Driving the high drug-resistant tuberculosis rates is an unchecked treatment default rate. This evaluation measures the effect of social support provided to tuberculosis patients at risk of defaulting on treatment during outpatient treatment. Five tuberculosis patient cohorts, served in three oblasts from 2011 and 2012, were constructed from medical records to compare risk factors for default, receipt of social services, and treatment outcome. Regression analyses were used to identify risk factors predictive of treatment default and to estimate the impact of the social support program on treatment default, controlling for risk, disease status, and demographics. In 2012, tuberculosis patients receiving social support in Ukraine reduced their probability of defaulting on continuation treatment by 10 percentage points compared to high-risk patients who did not receive social support in 2012 or 2011. Treatment success rates for the high-risk patients receiving social support were comparable to the low-risk cohorts and significantly improved over the high-risk comparison cohorts. Further research is recommended to quantify the costs and benefits for scaling-up social support services, evaluate social support program fidelity, identify which populations respond best to select services, and what barriers might still exist to achieve better adherence. With that information, tailoring programs to most effectively reach and serve clients in a patient-centered approach may reap substantial rewards for Ukraine., Competing Interests: The authors have read the journal's policy and have the following conflicts: Stephanie Mullen is employed by John Snow Inc. This affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Abortion clinics provide an ideal setting for women to receive contraceptive care because the women served may not have other contacts with the health system and are at risk for unintended pregnancies. The objective of this study was to understand practices, preferences, and barriers to use of contraception for women obtaining abortions at clinics in North Carolina., Methods: We conducted a cross-sectional survey of abortion clients and facilities at 10 abortion clinics in North Carolina. We collected data on contraceptive availability at each clinic. We collected individual responses on women's experiences obtaining contraception before the current pregnancy and their intentions for future use of contraception., Results: From October 2015 to February 2016, 376 client surveys were completed at 9 clinics, and 10 clinic surveys were completed. Almost one-third of women (29%) reported that they had wanted to use contraception in the last year but were unable. Approximately three-fourths of respondents (76%) stated that they intend to use contraception after this pregnancy. Approximately one-fifth of women stated that would like to use long-acting reversible contraception (LARC) after this abortion. Only the clinics that accepted insurance for abortion and other services provided LARC at the time of the abortion (40%)., Conclusions: This study provides a unique, statewide view into the contraceptive barriers for women seeking abortion in North Carolina. Addressing the relatively high demand for LARC after abortion could help significantly reduce unintended pregnancy and recourse to abortion in North Carolina.

Ovarian cancer is often termed a silent killer due to the late onset of symptoms. Whilst patients initially respond to chemotherapy, they rapidly develop chemo-resistance. Oncolytic adenoviruses (OAds) are promising anti-cancer agents engineered to "hijack" the unique molecular machinery of cancer cells enabling tumour-selective viral replication. This allows spread to adjacent cells and amplification of oncolysis within the tumour. OAds represent an excellent opportunity for ovarian cancer therapy via intra-peritoneal delivery, however the efficacy of OAds thus far is limited. Here, we evaluate chromatin (histone) modification in chemo-resistant cells and its relationship to Ad efficacy (wild-type or oncolytic Ad). In contrast to cisplatin-sensitive A2780 cells that show an efficient reduction of cell viability by Ad in the presence of cisplatin, cisplatin-resistant A2780/cp70 cells show diminishing Ad-mediated reduction of cell viability with escalating doses of cisplatin. Histone deacetylase (HDAC)-2 and to a lesser extent HDAC1 were up-regulated in cisplatin-resistant but not cisplatin-sensitive cells. Cisplatin-resistant cells treated with a pan-HDAC inhibitor trichostatin A (TsA) significantly enhanced Ad-mediated reduction of cell viability in the presence of cisplatin. Cells treated with TsA alone did not reduce cell viability suggesting these findings are Ad-dependent. Thus, we identify HDAC inhibition as a potential means to sensitise cisplatin-resistant ovarian cancer cells to virotherapies, an observation that may offer improved outcomes for patients with late stage, chemotherapy-resistant ovarian cancer., Competing Interests: CONFLICTS OF INTEREST None of the authors declare conflicts of interest.

Background: The population of women of childbearing age palliated with a Fontan repair is increasing. The aim of this study was to describe the progress of pregnancy and its outcome in a cohort of patients with a Fontan circulation in the UK., Methods: A retrospective study of women with a Fontan circulation delivering between January 2005 and November 2016 in 10 specialist adult congenital heart disease centres in the UK., Results: 50 women had 124 pregnancies, resulting in 68 (54.8%) miscarriages, 2 terminations of pregnancy, 1 intrauterine death (at 30 weeks), 53 (42.7%) live births and 4 neonatal deaths. Cardiac complications in pregnancies with a live birth included heart failure (n=7, 13.5%), arrhythmia (n=6, 11.3%) and pulmonary embolism (n=1, 1.9%). Very low baseline maternal oxygen saturations at first obstetric review were associated with miscarriage. All eight women with saturations of less than 85% miscarried, compared with 60 of 116 (51.7%) who had baseline saturations of ≥85% (p=0.008). Obstetric and neonatal complications were common: preterm delivery (n=39, 72.2%), small for gestational age (<10th percentile, n=30, 55.6%; <5th centile, n=19, 35.2%) and postpartum haemorrhage (n=23, 42.6%). There were no maternal deaths in the study period., Conclusion: Women with a Fontan circulation have a high rate of miscarriage and, even if pregnancy progresses to a viable gestational age, a high rate of obstetric and neonatal complications., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Cardiac disease remains a major cause of morbidity and mortality in pregnant and post-partum women, although progress has been made, with specialist joint obstetric-cardiology clinics providing an integrated, safe and personalised service to these women. As a result, fewer non-specialist cardiologists are managing women in pregnancy with cardiovascular disease. The aim of this review is to provide a brief overview of current knowledge and practice in the field, with an emphasis on the major physiological changes which occur during pregnancy, focussing on progress through the trimesters, clinical assessment in pregnancy, management of delivery (concentrating on managed vaginal delivery), drug treatment, key conditions and risk assessment. The latter factor is particularly important in terms of being able to identify high-risk women earlier and to counsel them appropriately. Pregnant women with cardiovascular conditions can, with appropriate knowledge and counselling, be managed safely in specialist multidisciplinary services, but there is a need for cardiologists to understand the key changes and risks involved in pregnancy, delivery and the post-partum period.

Bangladesh has made significant social, economic, and health progress in recent decades, yet many reproductive health indicators remain weak. Access to television (TV) is increasing rapidly and provides a potential mechanism for influencing health behavior. We present a conceptual framework for the influence of different types of TV exposure on individual's aspirations and health behavior through the mechanisms of observational learning and ideational change. We analyze data from two large national surveys conducted in 2010 and 2011 to examine the association between women's TV watching and five reproductive health behaviors controlling for the effects of observed confounders. We find that TV watchers are significantly more likely to desire fewer children, are more likely to use contraceptives, and are less likely to have a birth in the two years before the survey. They are more likely to seek at least four antenatal care visits and to utilize a skilled birth attendant. Consequently, continued increase in the reach of TV and associated growth in TV viewing is potentially an important driver of health behaviors in the country.

Background: Bangladesh has achieved a low total fertility rate of 2.3. Two-thirds of currently married women of reproductive age (CMWRA) want to limit fertility, and many women achieve their desired fertility before age 30. The incidence of unintended pregnancy and pregnancy termination is high, however. Long-acting reversible contraceptives (LARCs), consisting of the intrauterine device and implant, and permanent methods (PM), including female sterilization and vasectomy, offer several advantages in this situation, but only 8% of CMWRA or 13% of method users use these methods., Program: The Mayer Hashi (MH) program (2009-2013) aimed to improve access to and the quality of LARC/PM services in 21 of the 64 districts in Bangladesh. It was grounded in the SEED (supply-enabling environment-demand) Programming Model. Supply improvements addressed provider knowledge and skills, system strengthening, and logistics. Creating an enabling environment involved holding workshops with local and community leaders, including religious leaders, to encourage them to help promote demand for LARCs and PMs and overcome cultural barriers. Demand promotion encompassed training of providers in counseling, distribution of behavior change communication materials in the community and in facilities, and community mobilization., Methods: We selected 6 MH program districts and 3 nonprogram districts to evaluate the program. We used a before-after and intervention-comparison design to measure the changes in key contraceptive behavior outcomes, and we used a difference-in-differences (DID) specification with comparison to the nonprogram districts to capture the impact of the program. In addition to the outcome evaluation, we considered intermediate indicators that measured the processes through which the interventions were expected to affect the use of LARCs and PMs., Results: The use of LARCs/PMs among CMWRA increased between 2010 and 2013 in both program (from 5.3% to 7.5%) and nonprogram (from 5.0% to 8.9%) districts, but the rate of change was higher in the nonprogram districts. Client-provider interaction and exposure to LARCs/PMs were lower in the program than nonprogram districts, and the MH program districts had higher vacancies of key providers than the nonprogram areas, both indications of a more difficult health system environment., Conclusion: The weaknesses in the health system in the MH districts apparently undermined the effectiveness of the program. More attention to system weaknesses, such as additional supportive supervision for providers, might have improved the outcome., (© Rahman et al.)

Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer., Competing Interests: The authors declare no conflict of interest.

Objective: To determine pregnancy outcome in women with atrial switch repair for transposition of the great arteries (TGA) and to compare follow up with a control group of childless women with the same repair., Design: Retrospective cohort study., Setting: Tertiary care medical centre., Population: About 21 patients compared with 15 controls., Methods: Review of records from joint cardiac-obstetric clinic 1993-2013., Main Outcome Measures: Occurrence of cardiovascular events: maternal death, heart failure, arrhythmia, thromboembolic events, worsening systemic ventricular function, worsening tricuspid valve regurgitation and newly detected baffle problems., Results: There were 34 pregnancies in 21 women. Mean follow up was 100 months. No deaths or recurrence occurred. Events (few arrhythmias, thromboembolic events and baffle issues) were common in both groups: 13 (62%) patients and eight (53%) controls (P = 0.736). Worsening of ventricular function was similar in both groups: six (29%) patients and four (27%) controls (P = 0.899). Worsening tricuspid regurgitation was more common in patients [11 (52%)] than controls (0)] (P < 0.001). Labour was induced in 76% cases: 32% for cardiac deterioration, 37% to control timing of delivery, and 26% for intrauterine growth restriction. Delivery was vaginal in 84% cases. Median gestational age was 37 (30-40) weeks, median birthweight 2525 g (1460-3530). In all, 38% babies were premature and 38% were small-for-gestational-age., Conclusions: Cardiac events after atrial repair for TGA are equally common in pregnant women and non-pregnant controls, although worsening tricuspid regurgitation occurs more frequently in pregnancy. Induction of labour is to be expected but vaginal delivery is achievable in most cases. Infants are likely to be premature and small-for-gestational-age., Tweetable Abstract: Pregnancy in atrial repair for TGA: cardiac events similar to controls, prematurity and small babies likely., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Background: Performance-based financing (PBF) strategies are promoted as a supply-side, results-based financing mechanism to improve primary health care. This study estimated the effects of Rwanda's PBF program on less-incentivized child health services and examined the differential program impact by household poverty., Methods: Districts were allocated to intervention and comparison for PBF implementation in Rwanda. Using Demographic Health Survey data from 2005 to 2007-08, a community-level panel dataset of 5781 children less than 5 years of age from intervention and comparison districts was created. The impacts of PBF on reported childhood illness, facility care-seeking, and treatment received were estimated using a difference-in-differences model with community fixed effects. An interaction term between poverty and the program was estimated to identify the differential effect of PBF among children from poorer families., Results: There was no measurable difference in estimated probability of reporting illness with diarrhea, fever or acute respiratory infections between the intervention and comparison groups. Seeking care at a facility for these illnesses increased over time, however no differential effect by PBF was seen. The estimated effect of PBF on receipt of treatment for poor children is 45 percentage points higher (p = 0.047) compared to the non-poor children seeking care for diarrhea or fever., Conclusions: PBF, a supply-side incentive program, improved the quality of treatment received by poor children conditional on patients seeking care, but it did not impact the propensity to seek care. These findings provide additional evidence that PBF incentivizes the critical role staff play in assuring quality services, but does little to influence consumer demand for these services. Efforts to improve child health need to address both supply and demand, with additional attention to barriers due to poverty if equity in service use is a concern.

Background: Accurate measurement of maternal mortality is needed to develop a greater understanding of the scale of the problem, to increase effectiveness of program planning and targeting, and to track progress. In the absence of good quality vital statistics, interim methods are used to measure maternal mortality. The purpose of this study is to document experience with three community-based interim methods that measure maternal mortality using verbal autopsy., Methods: This study uses a post-census mortality survey, a sample vital registration with verbal autopsy, and a large-scale household survey to summarize the measures of maternal mortality obtained from these three platforms, compares and contrasts the different methodologies employed, and evaluates strengths and weaknesses of each approach. Included is also a discussion of issues related to death identification and classification, estimating maternal mortality ratios and rates, sample sizes and periodicity of estimates, data quality, and cost., Results: The sample sizes vary considerably between the three data sources and the number of maternal deaths identified through each platform was small. The proportion of deaths to women of reproductive age that are maternal deaths ranged from 8.8% to 17.3%. The maternal mortality rate was estimable using two of the platforms while obtaining an estimate of the maternal mortality ratio was only possible using one of the platforms. The percentage of maternal deaths due to direct obstetric causes ranged from 45.2% to 80.4%., Conclusions: This study documents experiences applying standard verbal autopsy methods to estimate maternal mortality and confirms that verbal autopsy is a feasible method for collecting maternal mortality data. None of these interim methods are likely to be suitable for detecting short term changes in mortality due to prohibitive sample size requirements, and thus, comprehensive and continuous civil registration systems to provide high quality vital statistics are essential in the long-term.

Context: Family planning is highly beneficial to women's overall health, particularly in developing countries. Yet, in much of Sub-Saharan Africa, contraceptive prevalence remains low and unmet need for family planning remains high. It is hypothesized that the poor quality of family planning service provision in many low-income settings is a barrier to contraceptive use, but this hypothesis has not been rigorously tested., Methods: Survey data from 3,990 women were used to investigate whether family planning service quality was associated with current modern contraceptive use in five cities in Kenya in 2010. In addition, audits of selected facilities and service provider interviews were conducted in 260 facilities, and exit interviews were conducted with family planning clients at 126 high-volume clinics. Individual- and facility-level data were linked according to the source of the woman's current method or other health service. Binomial regression was used to estimate adjusted prevalence ratios, and robust standard errors were used to account for clustering of observations within facilities., Results: Sixty-five percent of women reported currently using a modern contraceptive method. Provider's solicitation of clients' method preferences, assistance with method selection, provision of information on side effects and good treatment of clients were positively associated with current modern contraceptive use (prevalence ratios, 1.1 each); associations were often stronger among younger and less educated women., Conclusion: Efforts to assist with method selection and to improve the content of contraceptive counseling and treatment of clients by providers have the potential to increase contraceptive use in urban Kenya.

In the field of international family planning, quality of care as a reproductive right is widely endorsed, yet we lack validated data-collection instruments that can accurately assess quality in terms of its public health importance. This study, conducted within 19 public and private facilities in Kisumu, Kenya, used the simulated client method to test the validity of three standard data-collection instruments used in large-scale facility surveys: provider interviews, client interviews, and observation of client-provider interactions. Results found low specificity and low positive predictive values in each of the three instruments for a number of quality indicators, suggesting that the quality of care provided may be overestimated by traditional methods of measurement. Revised approaches to measuring family planning service quality may be needed to ensure accurate assessment of programs and to better inform quality-improvement interventions., (© 2014 The Population Council, Inc.)

Bones' strength is achieved and maintained through adaptation to load bearing. The role of the protein kinase PKCα in this process has not been previously reported. However, we observed a phenotype in the long bones of Prkca(-/-) female but not male mice, in which bone tissue progressively invades the medullary cavity in the mid-diaphysis. This bone deposition progresses with age and is prevented by disuse but unaffected by ovariectomy. Castration of male Prkca(-/-) but not WT mice results in the formation of small amounts of intramedullary bone. Osteoblast differentiation markers and Wnt target gene expression were up-regulated in osteoblast-like cells derived from cortical bone of female Prkca(-/-) mice compared with WT. Additionally, although osteoblastic cells derived from WT proliferate following exposure to estradiol or mechanical strain, those from Prkca(-/-) mice do not. Female Prkca(-/-) mice develop splenomegaly and reduced marrow GBA1 expression reminiscent of Gaucher disease, in which PKC involvement has been suggested previously. From these data, we infer that in female mice, PKCα normally serves to prevent endosteal bone formation stimulated by load bearing. This phenotype appears to be suppressed by testicular hormones in male Prkca(-/-) mice. Within osteoblastic cells, PKCα enhances proliferation and suppresses differentiation, and this regulation involves the Wnt pathway. These findings implicate PKCα as a target gene for therapeutic approaches in low bone mass conditions., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Reasons for Performing the Study: To explore whether genetic susceptibility is a potential risk factor for superficial digital flexor (SDF) tendinopathy in Thoroughbred (TB) racehorses., Objectives: To identify informative single nucleotide polymorphisms (SNPs) that capture genetic diversity across a range of candidate genes and to investigate, in a case-control study, their association with SDF tendinopathy in UK National Hunt TB racehorses in training., Study Design: Case-control candidate gene association study., Methods: This study used in silico gene assembly and DNA sequencing to screen candidate genes for SNPs. Seven candidate genes were selected using a hypothesis-driven approach: tenascin-C (TNC), collagen, type 1, α 1 (COL1A1), collagen, type 5, α 1 (COL5A1), matrix metalloproteinase type 3 (MMP3), matrix metalloproteinase type 13 (MMP13), fibromodulin (FMOD) and cartilage oligomeric matrix protein (COMP). The SNPs were validated in DNA isolated from 48 TB racehorses and used to genotype 270 racehorses with SDF tendinopathy and 270 yard-matched controls. Genotyping of cases and controls was performed using SNaPshot™., Results: Racehorses heterozygous for the TNC BIEC2-696469 polymorphism were less likely to have SDF tendinopathy than racehorses homozygous for the wild-type allele (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.36-0.85, P = 0.01). This finding remained significant after adjustment for age and racing background (OR 0.57, 95% CI 0.36-0.92, P = 0.03). Racehorses homozygous for the novel COL5A1 COL5A1&#95;01 variant allele were nearly 3 times more likely to have SDF tendinopathy than those homozygous for the wild-type allele (OR 2.82, 95% CI 1.25-6.35, P = 0.01); this association remained significant after adjustment for age and racing background (OR 2.77, 95% CI 1.18-6.53, P = 0.03)., Conclusions: Results suggest that sequence variants in TNC and COL5A1 genes are associated with SDF tendinopathy in TB racehorses. In future genetic markers may be used to identify horses at risk of SDF tendinopathy., (© 2013 EVJ Ltd.)

Objectives: We have assessed the effect of elevated concentrations of homogentisic acid (HGA) as in alkaptonuria (AKU), on a range of routine chemistry tests in serum and urine., Design and Methods: HGA was added to pooled serum and a range of assays was analysed with Roche Modular chemistries. Effects on urine were assessed by diluting normal urine with urine from a patient with AKU, adding HGA to urine and after lowering output of urinary HGA with nitisinone treatment., Results: Serum enzymatic creatinine showed 30% negative interference with 100μmol/L HGA and >50% at 400μmol/L. Serum urate 100 to 480μmol/L was reduced up to 20% at 100 and to 50% with 400μmol/L HGA. Serum cholesterol between 3 and 11mmol/L was reduced by 0.5mmol/L with 400μmol/L HGA. Urine enzymatic creatinine and urate with >2mmol/L HGA showed concentration dependent negative interference up to 80%. A positive interference in urine total protein by benzethonium turbidometric assay was observed, with 10mmol/L HGA equivalent to 1g/L protein. Jaffe creatinine, Na, K, Cl, Mg, Ca, phosphate, ALT, GGT, ALP activities and urea in serum and or urine were not affected by increases in HGA., Conclusions: To avoid interferences by HGA in alkaptonuria concentration of HGA should be established before samples are assayed with peroxidase assays and benzethonium urine protein., (Copyright © 2013 The Canadian Society of Clinical Chemists. All rights reserved.)

Objectives: To compare the maternal, fetal and cardiac outcomes in women who have undergone aortic valve replacement., Method: Retrospective observational study of all women with aortic valve replacement, who underwent a pregnancy (1998-2012). Maternal-, fetal- and valve-related cardiac outcomes were assessed., Results: Thirty-two pregnancies in 16 women with aortic valve replacement (nine bioprosthetic, six Ross and 17 mechanical) were evaluated. There were no adverse maternal events in the bioprosthetic and Ross groups but three in the mechanical group. Fetal loss rate was highest in the mechanical valve pregnancies (53%). One woman in the bioprosthetic group needed valve re-operation, and one woman in the mechanical valve group died. There was no difference in the change of Vmax over the follow-up between the valves (p = 0.25)., Conclusions: There was no difference in deterioration between aortic valve replacements during and after pregnancy. The highest risk of maternal and fetal complications occurred in the mechanical valve group.

This longitudinal study investigated the extent to which substance abuse (SA) clinician turnover is associated with SA-specific knowledge loss due to change in professions (professional turnover) versus SA-specific knowledge transfer due to movement from one SA clinical setting to another (treatment program turnover). For this study, clinicians had to have voluntarily left their current treatment program. Eligible clinicians completed a quantitative survey while employed and a qualitative post-employment exit interview 1 year later. Compared to those that exited the SA profession (n = 99), clinicians who changed treatment programs (n = 120) had greater SA-specific formal knowledge and were more likely to be personally in recovery. No differences were found between the two groups in terms of SA-specific practical knowledge.

Maternal health services continue to favour the wealthiest in lower and middle income countries. Debate about the potential of performance-based financing (PBF) to address these disparities continues. As PBF is adopted by countries, it is critical to understand the equity effects for maternal services. The aim of this study is to examine the effects of PBF on equity in maternal health service use when no specific provisions target the poorest in the population. In Rwanda, PBF was designed to increase health service use, which was universally low. Paired districts were randomly assigned to intervention and control for PBF implementation. Using Rwanda's Demographic Health Survey data from 2005 (pre-intervention) and 2007-8 (post-intervention), a cluster-level panel dataset of 7899 women 15-49 years of age from intervention (4477) and control districts (3422) was created. The impact of PBF on reported use of facility deliveries, antenatal care (ANC) and modern contraceptive use was estimated using a difference-in-differences model with community fixed effects. Interaction terms between wealth quintiles and PBF were estimated to identify the differential effect of PBF among poorer women. The probability of a facility delivery increased by 10 percentage points in the intervention when compared with the control districts (P = 0.014), while no significant effects were noted for ANC visits or modern contraceptive use. Service use increased for intervention and control populations and across all wealth quintiles from 2005 to 2007, with no evidence that PBF was a pro-poor or a pro-rich strategy. Insurance remained a positive predictor of service use. This research suggests that if service use is uniformly low then a PBF programme that incentivizes select services, such as facility deliveries, may improve service use overall. However, if the equity gap is extreme, then a PBF programme without equity targets will do little to alleviate disparities.

Background: The relationship between health services and population outcomes is an important area of public health research that requires bringing together data on outcomes and the relevant service environment. Linking independent, existing datasets geographically is potentially an efficient approach; however, it raises a number of methodological issues which have not been extensively explored. This sensitivity analysis explores the potential misclassification error introduced when a sample rather than a census of health facilities is used and when household survey clusters are geographically displaced for confidentiality., Methods: Using the 2007 Rwanda Service Provision Assessment (RSPA) of all public health facilities and the 2007-2008 Rwanda Interim Demographic and Health Survey (RIDHS), five health facility samples and five household cluster displacements were created to simulate typical SPA samples and household cluster datasets. Facility datasets were matched with cluster datasets to create 36 paired datasets. Four geographic techniques were employed to link clusters with facilities in each paired dataset. The links between clusters and facilities were operationalized by creating health service variables from the RSPA and attaching them to linked RIDHS clusters. Comparisons between the original facility census and undisplaced clusters dataset with the multiple samples and displaced clusters datasets enabled measurement of error due to sampling and displacement., Results: Facility sampling produced larger misclassification errors than cluster displacement, underestimating access to services. Distance to the nearest facility was misclassified for over 50% of the clusters when directly linked, while linking to all facilities within an administrative boundary produced the lowest misclassification error. Measuring relative service environment produced equally poor results with over half of the clusters assigned to the incorrect quintile when linked with a sample of facilities and more than one-third misclassified due to displacement., Conclusions: At low levels of geographic disaggregation, linking independent facility samples and household clusters is not recommended. Linking facility census data with population data at the cluster level is possible, but misclassification errors associated with geographic displacement of clusters will bias estimates of relationships between service environment and health outcomes. The potential need to link facility and population-based data requires consideration when designing a facility survey.