Autoantibodies inhibit Plasmodium falciparum growth and are associated with protection from clinical malaria.

Many infections, including malaria, are associated with an increase in autoantibodies (AAbs). Prior studies have reported an association between genetic markers of susceptibility to autoimmune disease and resistance to malaria, but the underlying mechanisms are unclear. Here, we performed a longitudinal study of children and adults (n = 602) in Mali and found that high levels of plasma AAbs before the malaria season independently predicted a reduced risk of clinical malaria in children during the ensuing malaria season. Baseline AAb seroprevalence increased with age and asymptomatic Plasmodium falciparum infection. We found that AAbs purified from the plasma of protected individuals inhibit the growth of blood-stage parasites and bind P. falciparum proteins that mediate parasite invasion. Protected individuals had higher plasma immunoglobulin G (IgG) reactivity against 33 of the 123 antigens assessed in an autoantigen microarray. This study provides evidence in support of the hypothesis that a propensity toward autoimmunity offers a survival advantage against malaria.

SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.

OBJECTIVE: Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities. METHODS: Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. RESULTS: The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability. INTERPRETATION: Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024.

Contrasting the Reinforcing Effects of the Novel Dopamine Transport Inhibitors JJC8-088 and JJC8-091 in Monkeys: Potential Translation to Medication Assisted Treatment.

Despite considerable efforts, there remains no FDA-approved medications for cocaine use disorder (CUD). One strategy to mitigate cocaine craving and relapse is to elevate dopamine (DA). The DA transport inhibitor and releaser d-amphetamine has been shown to decrease cocaine self-administration (SA), although it has abuse liability. Recently, several modafinil analogues reduced cocaine SA in rats and monkeys, including JJC8-088, characterized as "cocaine like" in rats, and JJC8-091, characterized as "atypical" and not SA by rats. The present studies evaluated the reinforcing effects of both compounds in monkeys under several conditions. For Experiment 1, four male cocaine-experienced rhesus monkeys self-administered cocaine (0.001-0.3 mg/kg/injection), JJC8-088 (0.001-0.3 mg/kg/injection), and JJC8-091 (0.1-3.0 mg/kg/injection) under a progressive-ratio (PR) schedule of reinforcement. Both JJC compounds functioned as reinforcers with equal reinforcing strength to cocaine. Although JJC8-091 was less potent than cocaine, JJC8-088 and cocaine had similar potencies. For Experiment 2, one male and two females drug-naïve cynomolgus monkeys responded on a fixed-ratio schedule of food reinforcement. JJC8-091 was self-administered at rates higher than saline in all three monkeys. In Experiment 3, monkeys from Experiment 2 responded under a concurrent drug vs. food choice paradigm and given access to cocaine or JJC8-091 under these conditions. At doses equal to or one-half log-units higher than doses used in Experiment 2, cocaine, but not JJC8-091, was chosen over food. Together, these results demonstrate that while JJC8-091 may be reinforcing under some conditions, its reinforcing strength, in the presence of an alternative reinforcer, is substantially less than cocaine. Significance Statement JJC8-088 and JJC8-091 have shown efficacy is reducing cocaine self-administration in rats and in nonhuman primates. This study found that both compounds maintained self-administration in monkeys responding under several conditions. However, when given access to an alternative reinforcer during the self-administration session, JJC8-091 was not reinforcing, suggesting that JJC8-091 may be a viable candidate for CUD since, in the human population, alternatives to drug use are often available.

Predictors of birth weight in pregnant women with malaria: a prospective cohort facility-based study in Webuye-Kenya.

In sub-Saharan Africa, malaria, which remains a major public health burden, has a prevalence of 9 to 28% and malaria in pregnancy is associated with severe adverse outcomes for the mother and her baby. Here, we sought to determine the predictors of birth weight in a cohort of 140 women with malaria in pregnancy, who were recruited at the Webuye County hospital in Western Kenya. All study participants underwent malaria diagnosis through microscopic examination of blood smear samples and were grouped into the malaria-positive and malaria-negative groups. Both groups were followed up beginning at the first antenatal visit (March 2022) until delivery (December 2022) and various data, including demographic, parity, gravidity, socioeconomic, maternal and fetal outcomes were collected. Data analyses were done using SPSS version 27. Chi-square and Fisher's Exact tests were used for bivariate and relative risk analyses at a p-value of ≤0.05 (95%) confidence level. Most of the participants were aged 18-25 years, were primigravidas and married, had secondary school-level education, earned 20-30 thousand Kenya shillings, resided in rural areas, and were in the second trimester. There were 6 (4.6%) cases of low birth weight, 3 (4.5%) in the malaria-negative group and 3 (4.7%) in the malaria-positive group. During pregnancy, 41 (31.5%) were anaemic, 5 (3.8%) were HIV-positive, 5 (3.8%) had preeclampsia, and 2 (1.5%) had gestational diabetes. Our analyses show that confounding factors like anaemia, HIV, pre-eclampsia and gestational diabetes did not influence birthweight (p ≥ 0.923). The malaria-positive and malaria-negative groups did not differ significantly with regard to the low birth weight (relative risk: 0.999, 95% confidence interval: 0.926-1.077). Marital status, gestational age, and area of residence were associated with malaria p ≤ 0.001, ≤ 0.001 and 0.028 respectively. In both groups, 124 of the 140 deliveries had normal birth weights and of these 63 (95.4%, n = 70) were in the malaria-negative group, whereas 61 (95.3%, n = 70) belonged to the malaria-positive group.

Genomic surveillance of SARS-COV-2 reveals diverse circulating variant lineages in Nairobi and Kiambu Counties, Kenya.

Genomic surveillance and identification of COVID-19 outbreaks are important in understanding the genetic diversity, phylogeny, and lineages of SARS-CoV-2. Genomic surveillance provides insights into circulating infections, and the robustness and design of vaccines and other infection control approaches. We sequenced 57 SARS-CoV-2 isolates from a Kenyan clinical population, of which 55 passed quality checks using the Ultrafast Sample placement on the Existing tRee (UShER) workflow. Phylo-genome-temporal analyses across two regions in Kenya (Nairobi and Kiambu County) revealed that B.1.1.7 (Alpha; n = 32, 56.1%) and B.1 (n = 9, 15.8%) were the predominant lineages, exhibiting low Ct values (5-31) suggesting high infectivity, and variant mutations across the two regions. Lineages B.1.617.2, B.1.1, A.23.1, A.2.5.1, B.1.596, A, and B.1.405 were also detected across sampling sites within target populations. The lineages and genetic isolates were traced back to China (A), Costa Rica (A.2.5.1), Europe (B.1, B.1.1, A.23.1), the USA (B.1.405, B.1.596), South Africa (B.1.617.2), and the United Kingdom (B.1.1.7), indicating multiple introduction events. This study represents one of the genomic SARS-CoV-2 epidemiology studies in the Nairobi metropolitan area, and describes the importance of continued surveillance for pandemic control.

Learning curve for active robotic total knee arthroplasty.

PURPOSE: Total Knee Arthroplasty (TKA) procedures incorporate technology in an attempt to improve outcomes. The Active Robot (ARo) performs a TKA with automated resections of the tibia and femur in efforts to optimize bone cuts. Evaluating the Learning Curve (LC) is essential with a novel tool. The purpose of this study was to assess the associated LC of ARo for TKA. METHODS: A multi-center prospective FDA cohort study was conducted from 2017 to 2018 including 115 patients that underwent ARo. Surgical time of the ARo was defined as Operative time (OT), segmented as surgeon-dependent time (patient preparation and registration) and surgeon-independent time (autonomous bone resection by the ARo). An average LC for all surgeons was computed. Complication rates and patient-reported outcome (PRO) scores were recorded and examined to evaluate for any LC trends in these patient related factors. RESULTS: The OT for the cases 10-12 were significantly quicker than the OT time of cases 1-3 (p < 0.028), at 36.5 ± 7.4 down from 49.1 ± 17 min. CUSUM and confidence interval analysis of the surgeon-dependent time showed different LCs for each surgeon, ranging from 12 to 19 cases. There was no difference in device related complications or PRO scores over the study timeframe. CONCLUSION: Active Robotic total knee arthroplasty is associated with a short learning curve of 10-20 cases. The learning curve was associated with the surgical time dedicated to the robotic specific portion of the case. There was no learning curve-associated device-related complications, three-dimensional component position, or patient-reported outcome scores. LEVEL OF EVIDENCE: Level II.

An increase in CD62Ldim neutrophils precedes the development of pulmonary embolisms in COVID-19 patients.

OBJECTIVES: A high incidence of pulmonary embolism (PE) is reported in patients with critical coronavirus disease 2019 (COVID-19). Neutrophils may contribute to this through a process referred to as immunothrombosis. The aim of this study was to investigate the occurrence of neutrophil subpopulations in blood preceding the development of COVID-19 associated PE. METHODS: We studied COVID-19 patients admitted to the ICU of our tertiary hospital between 19-03-2020 and 17-05-2020. Point-of-care fully automated flow cytometry was performed prior to ICU admission, measuring the neutrophil activation/maturation markers CD10, CD11b, CD16 and CD62L. Neutrophil receptor expression was compared between patients who did or did not develop PE (as diagnosed on CT angiography) during or after their ICU stay. RESULTS: Among 25 eligible ICU patients, 22 subjects were included for analysis, of whom nine developed PE. The median (IQR) time between neutrophil phenotyping and PE occurrence was 9 (7-12) days. A significant increase in the immune-suppressive neutrophil phenotype CD16bright /CD62Ldim was observed on the day of ICU admission (P = 0.014) in patients developing PE compared to patients who did not. CONCLUSION: The increase in this neutrophil phenotype indicates that the increased number of CD16bright /CD62Ldim neutrophils might be used as prognostic marker to predict those patients that will develop PE in critical COVID-19 patients.

Fostering cardiovascular health at work - case study from Senegal.

BACKGROUND: Of the 15 million annual premature deaths from non-communicable diseases (NCDs), 85% occur in low- and middle-income countries (LMICs). Affecting individuals in the prime of their lives, NCDs impose severe economic damage to economies and businesses, owing to the high mortality and morbidity within the workforce. The Novartis Foundation urban health initiative, Better Hearts Better Cities, was designed to improve cardiovascular health in Dakar, Senegal through a combination of interventions including a workplace health program. In this study, we describe the labor policy environment in Senegal and the outcomes of a Novartis Foundation-supported multisector workplace health coalition bringing together volunteering private companies. METHODS: A mixed method design was applied between April 2018 and February 2020 to evaluate the workplace health program as a case study. Qualitative methods included a desk review of documents relevant to the Senegalese employment context and work environment and in-depth interviews with eight key informants including human resource representatives and physicians working in the participating companies. Quantitative methods involved an analysis of workplace health program indicators, including data on diagnosis, treatment and control of hypertension in employees, provided by the coalition companies, and a cost estimate of NCD-related ill-health as compared to the investment needed for hypertension screening and awareness raising events. RESULTS: Senegal has a legal and regulatory system that ensures employee protection, supports social security benefits, and promotes health and hygiene in companies. The Dakar Workplace Health Coalition comprised 18 companies, with a range of staff between 300 and 4'220, covering 36'268 employees in total. Interviews suggested that the main enablers for workplace program success were strong leadership support within the company and a central coordination mechanism for the program. The main barrier to monitor progress and outcomes was the reluctance of companies to share data. Four companies provided aggregated anonymized cohort data, documenting a total of 21'392 hypertension screenings and an increasing trend in blood pressure control (from 34% in Q4 2018 to 39% in Q2 2019) in employees who received antihypertensive treatment. CONCLUSION: Evidence on workplace health and wellness programs in Africa is scarce. This study highlights how private sector companies can play a significant role in improving cardiovascular population health in LMICs.

Active robotic technologies for total knee arthroplasty.

INTRODUCTION: When active robotic technologies for Total Knee Arthroplasty (TKA) were introduced over 20 years ago, broad usage of robotic technology was not felt to be needed as early data suggested no clear improvement in clinical outcomes compared to conventional techniques of implantation. Only recently has there been renewed enthusiasm for use of robotic technologies for implantation. MATERIALS AND METHODS: Active robotic technology specifically refers to the use of a robot for planning and executing the surgical procedure-with surgeon guidance and control. The physical work of bone preparation is performed by a milling tool, following a cut path defined by a CT-based preoperative plan. This manuscript describes the IDE experience of the only active robotic system (ARoS) available in the US, which took place from February 2017 through December 2018. RESULTS: 115 patients were enrolled in an IDE study to evaluate the safety and efficacy of an ARoS for TKA. No previously described safety issues for TKA occurred. Three-dimensional accuracy of component placement used the preoperative CT plan compared to the 3-months postoperative CT scan to demonstrate accuracy of all autonomous resections to within 1.5 mm and/or 1.5 degrees. Surgical planning and execution to restore alignment along kinematic principles were used in 40 procedures and to achieve mechanical alignment in 75 procedures. CONCLUSIONS: This FDA study of an active robotic approach for TKA represented the first multicenter trial and first US experience with this technology. Results demonstrated an excellent safety profile and high degree of accuracy. Advantages of this approach relate to standardization of the technique, multiple device options in the implant library, an excellent safety and accuracy profile, and consistency of results. Active robotics for TKA represents a viable and safe technique for primary TKA.

Clinical outcome results of total ankle replacement and ankle arthrodesis: a pilot randomised controlled trial.

BACKGROUND: Ankle arthrodesis (AA) and replacement (TAA) are widely accepted options in managing end-stage ankle arthritis (ESAA). We hypothesize that clinical outcomes would be similar for both interventions. METHODS: We conducted a multicenter randomized controlled trial that collected data on patient demographics, complication rates, Ankle Osteoarthritis Scale (AOS) and Short Form-36 (SF-36) scores. We evaluated pre and postoperative scores within and between cohorts. RESULTS: The thirty-nine ankles enrolled had a mean follow-up of 5.1 ± 2.8 years. Total AOS scores improved significantly in both groups; 59.4 ± 15.9 to 38 ± 20 (p-value = 0.002) for TAA and 64.6 ± 19.7 to 31.8 ± 16.5 (p-value < 0.001) for AA at last follow-up. Complication rate was higher in the AA cohort with four major complications (20%). CONCLUSION: We observed a statistically significant benefit with TAA and AA. As a pilot trial, this study is meant to inform on design and feasibility of future RCTs. LEVEL OF EVIDENCE: II.

Nurses' experience with palliative sedation procedures in line with the 2005 Swiss guidelines: an exploratory study.

Many international studies have shown that the process of palliative sedation in an end-of-life context can be an adverse, even emotionally distressing experience for nurses. However, to the best of our knowledge, the experience of nurses working in palliative care in Switzerland has never been explored. The purpose of our study was, therefore, to understand and describe nurses' experience with the process of palliative sedation in line with the Swiss guidelines developed in 2005. We opted for an exploratory qualitative monocentric study using comprehensive individual interviews to achieve this objective. A total of 10 nurses were approached, and nine agreed to take part. After the interviews were transcribed, eight were ultimately included in the analysis. This analysis shows that nurses' attitudes toward the process of palliative sedation tended to be hesitant, resistant, or confident and that this was linked to the length of time they had worked in palliative care. These findings suggest that the 2005 Swiss guidelines do not protect nurses against the uncertainty related to process of palliative sedation. A national comprehensive multicentric study therefore needs to be developed to consolidate these results.

Succinate is an inflammatory signal that induces IL-1ß through HIF-1α.

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1ß but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1ß as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1ß production during inflammation.

Symbiotic performance of grain and wild herbaceous legumes in the Okavango Delta and Tswapong region of Botswana.

The low inherent soil fertility, especially nitrogen (N) constrains arable agriculture in Botswana. Nitrogen is usually added to soil through inorganic fertilizer application. In this study, biological nitrogen fixation by legumes is explored as an alternative source of N. The objectives of this study were to measure levels of N2 fixation by grain legumes such as cowpea, Bambara groundnut and groundnut in farmers' fields as well as to estimated N2 fixation by indigenous herbaceous legumes growing in the Okavango Delta. Four flowering plants per species were sampled from the panhandle part of the Okavango Delta and Tswapong area. Nitrogen fixation was measured using the 15N stable isotope natural abundance technique. The δ15N values of indigenous herbaceous legumes indicated that they fixed N2 (-1.88 to +1.35 ‰) with the lowest value measured in Chamaecrista absus growing in Ngarange (Okavango Delta). The δ15N values of grain legumes growing on farmers' fields ranging from -1.2 ‰ to +3.3 ‰ indicated that they were fixing N2. For grain legumes growing at most farms, %Ndfa were above 50% indicating that they largely depended on symbiotic fixation for their N nutrition. With optimal planting density, Bambara groundnuts on farmers' fields could potentially fix over 90 kg N/ha in some parts of Tswapong area and about 60 kg N/ha in areas around the Okavango Delta. Results from this study have shown that herbaceous indigenous legumes and cultivated legumes play an important role in the cycling of N in the soil. It has also been shown that biological N2 on farmer's field could potentially supply the much needed N for the legumes and the subsequent cereal crops if plant densities are optimized with the potential to increase food security and mitigate climate change.

Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans.

Ciliopathies are characterized by a pattern of multisystem involvement that is consistent with the developmental role of the primary cilium. Within this biological module, mutations in genes that encode components of the cilium and its anchoring structure, the basal body, are the major contributors to both disease causality and modification. However, despite rapid advances in this field, the majority of the genes that drive ciliopathies and the mechanisms that govern the pronounced phenotypic variability of this group of disorders remain poorly understood. Here, we show that mutations in CSPP1, which encodes a core centrosomal protein, are disease causing on the basis of the independent identification of two homozygous truncating mutations in three consanguineous families (one Arab and two Hutterite) affected by variable ciliopathy phenotypes ranging from Joubert syndrome to the more severe Meckel-Gruber syndrome with perinatal lethality and occipital encephalocele. Consistent with the recently described role of CSPP1 in ciliogenesis, we show that mutant fibroblasts from one affected individual have severely impaired ciliogenesis with concomitant defects in sonic hedgehog (SHH) signaling. Our results expand the list of centrosomal proteins implicated in human ciliopathies.

The differential impact of natural killer (NK) cell education via KIR2DL3 and KIR3DL1 on CCL4 secretion in the context of in-vitro HIV infection.

Carriage of certain inhibitory natural killer (NK) cell receptor (iNKR)/HLA ligand pairs is associated with protection from infection and slow time to AIDS implicating NK cells in HIV control. NK cells acquire functional potential through education, which requires the engagement of iNKRs by their human leucocyte antigen (HLA) ligands. HIV infection down-regulates cell surface HLA-A/B, but not HLA-C/E. We investigated how NK cell populations expressing combinations of the iNKRs NKG2A, KIR2DL3 (2DL3) and KIR3DL1 (3DL1) responded to autologous HIV infected CD4 (iCD4) cells. Purified NK cells from HIV-uninfected individuals were stimulated with autologous HIV iCD4 or uninfected CD4 T cells. Using flow cytometry we gated on each of the 8 NKG2A+/- 2DL3+/- 3DL1+/- populations and analysed all possible combinations of interferon (IFN)-γ, CCL4 and CD107a functional subsets responding to iCD4 cells. Infected CD4 cells induced differential frequencies of NKG2A+/- 2DL3+/- 3DL1+/- populations with total IFN-γ+ , CCL4+ and CD107a+ functional profiles. 2DL3+ NKG2A+ NK cells had a higher frequency of responses to iCD4 than other populations studied. A higher frequency of 2DL3+ NK cells responded to iCD4 from individuals that were not HLA-C1 homozygotes. These results show that 2DL3+ NK cells are mediators of HIV-specific responses. Furthermore, responses of NK cell populations to iCD4 are influenced not only by NK cell education through specific KIR/HLA pairs, but also by differential HIV-mediated changes in HLA expression.

Neuroimaging Findings and Repeat Neuroimaging Value in Pediatric Chronic Ataxia.

BACKGROUND: Chronic ataxia, greater than two months in duration, is encountered relatively commonly in clinical pediatric neurology practise and presents with diagnostic challenges. It is caused by multiple and diverse disorders. Our aims were to describe the neuroimaging features and the value of repeat neuroimaging in pediatric chronic ataxia to ascertain their contribution to the diagnosis and management. MATERIALS AND METHODS: A retrospective charts and neuroimaging reports review was undertaken in 177 children with chronic ataxia. Neuroimaging in 130 of 177 patients was also reviewed. RESULTS: Nineteen patients had head computed tomography only, 103 brain magnetic resonance imaging only, and 55 had both. Abnormalities in the cerebellum or other brain regions were associated with ataxia. Neuroimaging was helpful in 73 patients with 30 disorders: It was diagnostic in 9 disorders, narrowed down the diagnostic possibilities in 14 disorders, and revealed important but non-diagnostic abnormalities, e.g. cerebellar atrophy in 7 disorders. Having a normal magnetic resonance imaging scan was mostly seen in genetic diseases or in the early course of ataxia telangiectasia. Repeat neuroimaging, performed in 108 patients, was generally helpful in monitoring disease evolution and in making a diagnosis. Neuroimaging was not directly helpful in 36 patients with 10 disorders or by definition the 55 patients with unknown disease etiology. CONCLUSIONS: Normal or abnormal neuroimaging findings and repeat neuroimaging are very valuable in the diagnosis and management of disorders associated with pediatric chronic ataxia.

Factors associated with postnatal care utilisation in Rwanda: A secondary analysis of 2010 Demographic and Health Survey data.

BACKGROUND: Postnatal care (PNC) in the first seven days is important for preventing morbidity and mortality in mothers and new-borns. Sub-Saharan African countries, which account for 62 % of maternal deaths globally, have made major efforts to increase PNC utilisation, but utilisation rates remains low even in countries like Rwanda where PNC services are universally available for free. This study identifies key socio-economic and demographic factors associated with PNC utilisation in Rwanda to inform improved PNC policies and programs. METHODS: This is a secondary analysis of the 2010 Demographic and Health Survey, a national multi-stage, cross-sectional survey. In bivariate analysis, we used chi-square tests to identify demographic and socio-economic factors associated with PNC utilisation at α = 0.1. Pearson's R statistic (r > 0.5) was used to identify collinear covariates, and to choose which covariate was more strongly associated with PNC utilisation. Manual backward stepwise logistic regression was performed on the remaining covariates to identify key factors associated with PNC utilisation at α = 0.05. All analyses were performed in Stata 13 adjusting for sampling weights, clustering, and stratification. RESULTS: Of the 2,748 women with a live birth in the last two years who answered question about PNC utilisation, 353 (12.8 %) returned for PNC services within seven days after birth. Three factors were positively associated with PNC use: delivering at a health facility (OR: 2.97; 95 % CI: 2.28-3.87), being married but not involved with one's own health care decision-making (OR: 1.69; 95 % CI: 1.17, 2.44) compared to being married and involved; and being in the second (OR: 1.46; 95 % CI: 1.01-2.09) or richest wealth quintile (OR: 2.04; 95 % CI: 1.27-3.29) compared to the poorest. Mother's older age at delivery was negatively associated with PNC use (20-29 - OR: 0.51, 95 % CI: 0.29-0.87; 30-39 - OR: 0.47, 95 % CI: 0.27-0.83; 40-49 - OR: 0.32, 95 % CI: 0.16-0.64). CONCLUSIONS: Low PNC utilisation in Rwanda appears to be a universal problem though older age and poverty are further barriers to PNC utilisation. A recent change in the provision of BCG vaccination to new-borns might promote widespread PNC utilisation. We further recommend targeted campaigns to older mothers and poorest mothers, focusing on perceptions of health system quality, cultural beliefs, and pregnancy risks.

Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome.

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.

Phenotypical and functional profiles of natural killer cells exhibiting matrix metalloproteinase-mediated CD16 cleavage after anti-HIV antibody-dependent activation.

Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been linked to protection from HIV infection and slower progression towards AIDS. However, antibody-dependent activation of NK cells results in phenotypical alterations similar to those observed on NK cells from individuals with progressive HIV infection. Activation of NK cells induces matrix metalloproteinase (MMP)-mediated cleavage of cell surface CD16. In the present study we assessed the phenotype and functional profile of NK cells exhibiting post-activation MMP-mediated CD16 cleavage. We found that NK cells achieving the highest levels of activation during stimulation exhibit the most profound decreases in CD16 expression. Further, we observed that educated KIR3DL1(+) NK cells from human leucocyte antigen (HLA)-Bw4-carrying donors exhibit larger decreases in CD16 expression post-activation than the KIR3DL1(-) NK cell subset containing cells educated via other inhibitory receptor/ligand combinations and non-educated NK cells. Lastly, we assessed the ex-vivo expression of CD16 on educated KIR3DL1(+) NK cells and the KIR3DL1(-) NK cell subset from HLA-Bw4-carrying HIV-uninfected and HIV-infected donors. Suggestive of in-vivo activation of KIR3DL1(+) NK cells during HIV infection, CD16 expression was higher on KIR3DL1(+) than KIR3DL1(-) NK cells in uninfected donors but similar on both subsets in HIV-infected donors. These results are discussed in the context of how they may assist with understanding HIV disease progression and the design of immunotherapies that utilize antibody-dependent NK cell responses.

Severe adverse effects of bromocriptine in lactation inhibition: a pharmacovigilance survey.

OBJECTIVE: To assess the nature and conditions of the occurrence of adverse drug reactions (ADRs) of bromocriptine, which is used to inhibit lactation. DESIGN: Observational study. SETTING: Cases from the French pharmacovigilance database and the marketing authorisation holders. SAMPLE: Serious ADRs reported between 1994 and 2010 in association with bromocriptine used for lactation inhibition in France. METHODS: Each case was checked to confirm the bromocriptine indication, the seriousness of the ADR, the modalities of bromocriptine use, and to identify possible associated predisposing factors. MAIN OUTCOME MEASURES: Number and description of serious ADRs, with a particular focus on misuse and associated predisposing factors. RESULTS: Among 105 serious ADRs, including two fatal cases, the most frequent were cardiovascular (70.5%), neurological (14.3%), and psychiatric (8.6%) disorders. Cardiovascular disorders primarily consisted of ischaemic manifestations (n = 47): acute ischaemic stroke (n = 18, one death), myocardial infarction (n = 11, one death), and reversible postpartum cerebral angiopathy (n = 10). Misuse was identified in 52 cases (70.3%) of cardiovascular disorders, and mostly consisted of bromocriptine continuation despite the occurrence of first symptoms suggesting an ADR or the absence of a progressive titration of bromocriptine. About half of these women had cardiovascular predisposing factors, mainly tobacco smoking, overweight or obesity, or a history of hypertension or pre-eclampsia. CONCLUSIONS: This survey, together with published data, provides further evidence that serious ADRs still occur after bromocriptine use in lactation inhibition, and that most of these ADRs could have been avoided. The use of bromocriptine should therefore be limited to cases where no other options are available to inhibit lactation.