Dental Caries Severity and Nutritional Status of Nigerian Preschool Children.

INTRODUCTION: Malnutrition in children is one of the most prevalent global health challenges, and malnourished children have a higher risk of death from childhood diseases. Early childhood caries (ECC) is the most common chronic disease of childhood. Complications from ECC such as pain, loss of tooth/teeth, and infection can undermine a child's nutrition and growth. AIM: This study aims to evaluate the severity of decay, missing, and filled tooth (dmft) by nutritional status using the z scores of the anthropometric measurements: height for age (HFA), weight for age (WFA), weight for height (WFH), and body mass index for age (BMIA) among children with ECC in Nigeria. STUDY DESIGN: This is a cross-sectional study conducted in 5 local government areas (LGAs) in Lagos State, Nigeria. A multistage sampling technique was used. RESULTS: A total of 273 cases of ECC were included in the analyses (mean age 4.19 ± 0.96 y). Overall, the mean dmft was 3.04 ± 2.28, and most (96%) were accounted for by untreated decay. The distribution of dmft within the different z score categories of BMIA (<-3 = severely wasted, -2 to -3 = wasted, -2 to +2 = normal, +2 to +3 = overweight and >+3 = obese) showed the highest dmft scores among the combined severely wasted and wasted groups, lowest among children with normal z scores, and intermediate in the overweight and obese groups. There was a significant negative correlation between BMIA z score, WFH z score, and dmft (r = -0.181, P < 0.05 and r = -0.143, P < 0.05, respectively). However, the correlations between HFA z score, WFA z score, and dmft were positive but not significant (r = 0.048, P = 0.44 and r = 0.022, P = 0.77, respectively). CONCLUSION: Our study showed an increased severity of dental caries among severely wasted or wasted children with ECC compared to those of normal or overweight. KNOWLEDGE TRANSFER STATEMENT: The results from this study will raise awareness among clinicians and policy makers on the need for a primary prevention program for early childhood caries in countries with high burden of malnutrition and limited resources. Also, it will help draw the attention of clinicians to the caries status of malnourished children that can be managed to improve the nutritional outcomes.

Genome-wide Gene-by-Sex Interaction Studies Identify Novel Nonsyndromic Orofacial Clefts Risk Locus.

Risk loci identified through genome-wide association studies have explained about 25% of the phenotypic variations in nonsyndromic orofacial clefts (nsOFCs) on the liability scale. Despite the notable sex differences in the incidences of the different cleft types, investigation of loci for sex-specific effects has been understudied. To explore the sex-specific effects in genetic etiology of nsOFCs, we conducted a genome-wide gene × sex (GxSex) interaction study in a sub-Saharan African orofacial cleft cohort. The sample included 1,019 nonsyndromic orofacial cleft cases (814 cleft lip with or without cleft palate and 205 cleft palate only) and 2,159 controls recruited from 3 sites (Ethiopia, Ghana, and Nigeria). An additive logistic model was used to examine the joint effects of the genotype and GxSex interaction. Furthermore, we examined loci with suggestive significance (P < 1E-5) in the additive model for the effect of the GxSex interaction only. We identified a novel risk locus on chromosome 8p22 with genome-wide significant joint and GxSex interaction effects (rs2720555, p2df = 1.16E-08, pGxSex = 1.49E-09, odds ratio [OR] = 0.44, 95% CI = 0.34 to 0.57). For males, the risk of cleft lip with or without cleft palate at this locus decreases with additional copies of the minor allele (p < 0.0001, OR = 0.60, 95% CI = 0.48 to 0.74), but the effect is reversed for females (p = 0.0004, OR = 1.36, 95% CI = 1.15 to 1.60). We replicated the female-specific effect of this locus in an independent cohort (p = 0.037, OR = 1.30, 95% CI = 1.02 to 1.65), but no significant effect was found for the males (p = 0.29, OR = 0.86, 95% CI = 0.65 to 1.14). This locus is in topologically associating domain with craniofacially expressed and enriched genes during embryonic development. Rare coding mutations of some of these genes were identified in nsOFC cohorts through whole exome sequencing analysis. Our study is additional proof that genome-wide GxSex interaction analysis provides an opportunity for novel findings of loci and genes that contribute to the risk of nsOFCs.

Recovery of menses after functional hypothalamic amenorrhoea: if, when and why.

BACKGROUND: Prolonged amenorrhoea occurs as a consequence of functional hypothalamic amenorrhoea (FHA) which is most often induced by weight loss, vigorous exercise or emotional stress. Unfortunately, removal of these triggers does not always result in the return of menses. The prevalence and conditions underlying the timing of return of menses vary strongly and some women report amenorrhoea several years after having achieved and maintained normal weight and/or energy balance. A better understanding of these factors would also allow improved counselling in the context of infertility. Although BMI, percentage body fat and hormonal parameters are known to be involved in the initiation of the menstrual cycle, their role in the physiology of return of menses is currently poorly understood. We summarise here the current knowledge on the epidemiology and physiology of return of menses. OBJECTIVE AND RATIONALE: The aim of this review was to provide an overview of (i) factors determining the recovery of menses and its timing, (ii) how such factors may exert their physiological effects and (iii) whether there are useful therapeutic options to induce recovery. SEARCH METHODS: We searched articles published in English, French or German language containing keywords related to return of menses after FHA published in PubMed between 1966 and February 2020. Manuscripts reporting data on either the epidemiology or the physiology of recovery of menses were included and bibliographies were reviewed for further relevant literature. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria served to assess quality of observational studies. OUTCOMES: Few studies investigate return of menses and most of them have serious qualitative and methodological limitations. These include (i) the lack of precise definitions for FHA or resumption of menses, (ii) the use of short observation periods with unsatisfactory descriptions and (iii) the inclusion of poorly characterised small study groups. The comparison of studies is further hampered by very inhomogeneous study designs. Consequently, the exact prevalence of resumption of menses after FHA is unknown. Also, the timepoint of return of menses varies strongly and reliable prediction models are lacking. While weight, body fat and energy availability are associated with the return of menses, psychological factors also have a strong impact on the menstrual cycle and on behaviour known to increase the risk of FHA. Drug therapies with metreleptin or naltrexone might represent further opportunities to increase the chances of return of menses, but these require further evaluation. WIDER IMPLICATIONS: Although knowledge on the physiology of return of menses is presently rudimentary, the available data indicate the importance of BMI/weight (gain), energy balance and mental health. The physiological processes and genetics underlying the impact of these factors on the return of menses require further research. Larger prospective studies are necessary to identify clinical parameters for accurate prediction of return of menses as well as reliable therapeutic options.

The effects of diet and sex in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, suggesting there are multiple contributing factors that influence the disease risk, onset, and progression. Diet and sex are two factors that have been reported to alter ALS risk, onset and progression in humans and in animal models, providing potential modifiers of disease. Several epidemiological studies have identified diets that positively affect ALS patients, including various high-calorie fat or sugar-based diets, while animal models have been developed to test how these diets are working on a molecular level. These diets may offset the metabolic alterations that occur in ALS, such as hypermetabolism, lowered body mass index(BMI), and hyperlipidemia. Sex-dependent differences have also come forth from large-scale epidemiological studies as well as mouse-model studies. In addition, sex hormones have been shown to affect disease risk or progression. Herein, studies on the effects of diet and sex on ALS risk, onset, and progression will be reviewed. Understanding these diet- and sex-dependent outcomes may lead to optimized patient-specific therapies for ALS.

Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis.

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 µg/ml; the mean NTZ maximum concentration (Cmax) in plasma was 10.2 µg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.).

Diagnostic yield of active case finding for tuberculosis at human immunodeficiency virus testing in Haiti.

SETTING: The Groupe Haïtien d'étude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) Centres, Port-au-Prince, Haiti, facilitate "test and treat" strategies by screening all patients for tuberculosis (TB) at human immunodeficiency virus (HIV) testing.OBJECTIVE: 1) To determine the proportion of patients with chronic cough at HIV testing diagnosed with TB, stratified by HIV test results; and 2) to evaluate the additional diagnostic yield of Xpert® MTB/RIF vs. sputum microscopy.DESIGN: We conducted a retrospective cohort analysis including all adults tested for HIV at GHESKIO from August 2014 to July 2015.RESULTS: Of 29 233 adult patients tested for HIV, 2953 (10%) were diagnosed as HIV-positive. Chronic cough lasting ≥2 weeks was reported by 1116 (38%) HIV-positive patients; 984 (88%) were tested and 265 (27%) were diagnosed with TB. Chronic cough was reported by 5985 (23%) HIV-negative patients; 5654 (94%) were tested and 1179 (21%) were diagnosed with TB. Of all bacteriologically confirmed cases, 27% were smear-negative and Xpert-positive. Among all TB patients, 81% were HIV-negative.CONCLUSIONS: Screening for TB at HIV testing was high-yield, among both HIV-infected and HIV-negative individuals. Testing for both diseases should be conducted among patients who present with chronic cough at HIV testing.

Four-year review of admissions to a South African regional hospital general surgery department.

BACKGROUND: There are limited published data describing surgical admissions at a regional hospital level in the South African (SA) context. OBJECTIVES: To retrospectively review data from an electronic discharge summary  database at a regional SA hospital from 2012 to 2016 to describe the burden of surgical disease by analysing characteristics of the patients admitted. METHODS: All discharge summary records for the 4-year period were reviewed after extraction from a database created for the surgery department. Admissions were classified into 5 types: (i) elective surgery or investigations (ESI); (ii) trauma; (iii) burns; (iv) non-traumatic surgical emergencies (NTSE); and (v) unplanned readmission within 30 days. Other variables reviewed were demographic data, the International Statistical Classification of Diseases and Related Health Problems - Version 10 (ICD-10) diagnosis; area of origin; and outcome (death, tertiary referral, discharge). Data were subgrouped into 12-month periods to facilitate trend analysis. RESULTS: Discharge summaries (N=9 805) over the 4-year study period were assessed and 9 799 were included in the analysis. All data were entered by the attending medical personnel. A total of 5 647 male patients (57.6%) and 4 152 female patients (42.4%) were admitted, with a mean age of 43.3 years (95% confidence interval (CI) 43.0 - 43.8) and a mean length of stay of 4.9 days (95% CI 4.7 - 5.1). Male patients comprised a larger proportion of trauma (83.7%) and burn (63.9%) admissions. The mean length of stay ranged from 3.5 days for elective patients to 9.1 days for burn patients. The most common diagnoses for emergency admissions were appendicitis, peripheral vascular disease and peptic ulcer disease. Common diagnoses for elective admissions were gallstone disease, inguinal hernia, anal fistulas/fissures, and ventral and incisional hernia. The most common cancer diagnoses were of the colorectum, oesophagus, breast and stomach. The overall mortality rate was 2.2%, and highest by subtype was burn patients (6.3%). Trend analysis showed a statistically significant increase in admission for NTSE (p=0.019), trauma (p<0.001) and 30-day readmission rates (p<0.001), with a decrease in admissions for ESI (p=0.001) over the 4 years. CONCLUSIONS: A precise understanding of the burden of disease profile is essential for national, provincial and district budgeting and resource allocation. Ongoing surveillance such as that performed in the study provides this critical information.

Outcomes across the tuberculosis care continuum among adolescents in Haiti.

Setting: GHESKIO (Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes) clinic, Port-au-Prince, Haiti. Objective: To evaluate tuberculosis (TB) care continuum outcomes among adolescents. Design: Among a retrospective cohort of 10-24 year olds diagnosed with active TB, we report completion of the following steps of the TB care continuum stratified by human immunodeficiency virus (HIV) status: diagnosis of microbiologically confirmed TB, initiation of anti-tuberculosis treatment, retention in care at 2 months on anti-tuberculosis treatment, and TB treatment success. Factors associated with attrition at each step were identified using multivariable regression. Results: A total of 1005 adolescents were diagnosed with active TB; 74 (7%) were HIV-positive at the time of TB diagnosis. HIV-positive patients had poorer outcomes than non-HIV-infected patients: 73% vs. 85% initiated anti-tuberculosis treatment (P < 0.01), 46% vs. 74% were retained in care at 2 months (P < 0.01), and 41% vs. 68% achieved TB treatment success (P < 0.01). Among those who initiated treatment, same-day initiation resulted in less treatment failure. Attrition before treatment initiation was associated with female sex and HIV coinfection. Attrition after treatment initiation was associated with age ⩾16 years and HIV coinfection. Conclusion: Outcomes across the TB care continuum are suboptimal among adolescents, with only two thirds of patients achieving treatment success. Interventions tailored to adolescents are needed to improve retention in care, particularly for those who are co-infected with HIV.

Contexte : Centre de santé, Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, Port-au-Prince, Haïti.Objectif : Evaluer les résultats tout au long de la prise en charge de la tuberculose (TB) parmi les adolescents.Schéma : Parmi une cohorte rétrospective d'adolescents âgés de 10­24 ans ayant eu un diagnostic de TB active, nous rapportons le déroulement des étapes suivantes des soins de la TB stratifiés par statut virus de l'immunodéficience humaine (VIH) : diagnostic de TB confirmée par microbiologie ; mise en route du traitement de la TB ; rétention en soins à 2 mois sous traitement de TB ; et succès du traitement de TB. Les facteurs associés à l'attrition à chaque étape ont été identifiés grâce à une régression logistique multivariée.Résultats: Des 1005 adolescents qui ont eu un diagnostic de TB active, 74 (7%) ont été positifs au VIH au moment du diagnostic de TB. Les patients VIH positifs ont eu des résultats plus médiocres comparés aux patients non infectés par le VIH : 73% contre 85% ont mis en route le traitement de TB (P < 0,01), 46% contre 74% sont restés sous traitement à 2 mois (P < 0,01) et 41% contre 68% ont achevé le traitement avec succès (P < 0,01). Parmi ceux qui ont mis en route le traitement, une prise dès le premier jour a abouti à moins d'échec du traitement. L'attrition avant le début du traitement a été associée au sexe féminin et à la coinfection à VIH. L'attrition après mise en route du traitement a été associée à un âge ⩾16 ans et à la coinfection à VIH.Conclusion : Les résultats au niveau de la continuité des soins de TB sont sousoptimaux parmi les adolescents, dont seulement deux tiers achèvent le traitement avec succès. Des interventions adaptées aux adolescents sont requises pour améliorer la rétention en soins, particulièrement pour ceux qui sont coinfectés par le VIH.

Marco de Referencia: El centro du Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes de Port-au-Prince, en Haití.Objetivo: Evaluar los resultados del proceso asistencial continuo de la tuberculosis (TB) en los adolescentes.Método: En una cohorte retrospectiva de jóvenes de 10­24 años de edad con diagnóstico de TB activa, se comunican los resultados logrados en las siguientes etapas del proceso asistencial continuo de la TB, estratificados según la situación frente al virus de la inmunodeficiencia humana (VIH): diagnóstico de TB confirmada microbiológicamente; inicio del tratamiento antituberculoso; retención en la atención a los 2 meses del tratamiento; y el éxito del tratamiento antituberculoso. Se determinaron los factores asociados con el abandono en cada etapa mediante un modelo de regresión multivariante.Resultados: Se diagnosticó TB activa en 1005 adolescentes; 74 de ellos (7%) eran positivos frente al VIH en el momento del diagnóstico de TB. Los pacientes positivos frente al VIH presentaron desenlaces más desfavorables que los pacientes sin infección por el VIH (73% contra 85% inició el tratamiento antituberculoso, P < 0,01; 46% contra 74% continuaba en la atención a los 2 meses, P < 0,01; y 41% contra 68% alcanzó un tratamiento antituberculoso exitoso, P < 0,01). Los jóvenes que iniciaron tratamiento el mismo día de la consulta presentaron menos fracasos terapéuticos. El abandono antes de iniciar el tratamiento se asoció con el sexo femenino y la coinfección por el VIH. El abandono después de haber iniciado el tratamiento se asoció con la edad ⩾16 años y la coinfección por el VIH.Conclusión: Los resultados a lo largo de la continuidad asistencial de la TB son deficientes en los adolescentes, pues solo dos tercios de ellos alcanzan el éxito terapéutico. Se precisan intervenciones adaptadas a los adolescentes que mejoren la retención en los servicios de atención, sobre todo en los pacientes coinfectados por el VIH.

Blood transcriptomic markers of Mycobacterium tuberculosis load in sputum.

BACKGROUND: Peripheral blood transcriptome signatures that distinguish active pulmonary tuberculosis (TB) from control groups have been reported, but correlations of these signatures with sputum mycobacterial load are incompletely defined. METHODS: We assessed the performance of published TB transcriptomic signatures in Haiti, and identified transcriptomic biomarkers of TB bacterial load in sputum as measured by Xpert® MTB/RIF molecular testing. People in Port au Prince, Haiti, with untreated pulmonary TB (n = 51) formed the study cohort: 19 people with low and 32 with high sputum Mycobacterium tuberculosis load. Peripheral whole blood transcriptomes were generated using RNA sequencing. RESULTS: Twenty of the differentially expressed transcripts in TB vs. no TB were differentially expressed in people with low vs. high sputum mycobacterial loads. The difference between low and high bacterial load groups was independent of radiographic severity. In a published data set of transcriptomic response to anti-tuberculosis treatment, this 20-gene subset was more treatment-responsive at 6 months than the full active TB signature. CONCLUSION: We identified genes whose transcript levels in the blood distinguish active TB with high vs. low M. tuberculosis loads in the sputum. These transcripts may reveal mechanisms of mycobacterial control of M. tuberculosis during active infection, as well as identifying potential biomarkers for bacterial response to anti-tuberculosis treatment.

Trends in proportion of older HIV-infected people in care in Latin America and the Caribbean: a growing challenge.

We aimed to quantify the proportion of people receiving care for HIV-infection that are 50 years or older (older HIV patients) in Latin America and the Caribbean between 2000 and 2015 and to estimate the contribution to the growth of this population of people enrolled before (<50yo) and after 50 years old (yo) (⩾50yo). We used a series of repeated, cross-sectional measurements over time in the Caribbean, Central and South American network (CCASAnet) cohort. We estimated the percentage of patients retained in care each year that were older HIV patients. For every calendar year, we divided patients into two groups: those who enrolled before age 50 and after age 50. We used logistic regression models to estimate the change in the proportion of older HIV patients between 2000 and 2015. The percentage of CCASAnet HIV patients over 50 years had a threefold increase (8% to 24%) between 2000 and 2015. Most of the growth of this population can be explained by the increasing proportion of people that enrolled before 50 years and aged in care. These changes will impact needs of care for people living with HIV, due to multiple comorbidities and high risk of disability associated with aging.

Diagnostic yield of active case finding for tuberculosis and HIV at the household level in slums in Haiti.

SETTING: Haiti has the highest burden of tuberculosis (TB) in the Americas, with an estimated prevalence of 254 per 100 000 population. The Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, GHESKIO) conducted active case finding (ACF) for TB at the household level in nine slums in Port-au-Prince. OBJECTIVE: We report on the prevalence of undiagnosed TB detected through GHESKIO's ACF campaign. DESIGN: From 1 August 2014 to 31 July 2015, we conducted a retrospective cohort analysis using GHESKIO's ACF campaign data. All individuals who reported chronic cough (cough 2 weeks) were tested for TB at GHESKIO, and those aged 10 years were included in the analyses. RESULTS: Of 104 097 individuals screened in the community, 5598 (5%) reported chronic cough and satisfied the study inclusion criteria. A total of 1110 (20%) were diagnosed with active TB disease (prevalence of 1066/100 000). Of the 5472 (98%) patients tested for human immunodeficiency virus (HIV), 528 (10%) were HIV-positive; 143 (3%) patients were diagnosed with both diseases. CONCLUSION: Household-level screening for cough with TB and HIV testing for symptomatic patients was a high-yield strategy, leading to the detection of a prevalence of undiagnosed disease exceeding national estimates by more than four-fold for TB, and by five-fold for HIV.

Impact of Early Consumption of High-Fat Diet on the Mesolimbic Dopaminergic System.

Increasing evidence suggest that consumption of high-fat diet (HFD) can impact the maturation of brain circuits, such as during adolescence, which could account for behavioral alterations associated with obesity. In the present study, we used behavioral sensitization to amphetamine to investigate the effect of periadolescent HFD exposure (pHFD) in rats on the functionality of the dopamine (DA) system, a central actor in food reward processing. pHFD does not affect responding to an acute injection, however, a single exposure to amphetamine is sufficient to induce locomotor sensitization in pHFD rats. This is paralleled by rapid neurobiological adaptations within the DA system. In pHFD-exposed animals, a single amphetamine exposure induces an increase in bursting activity of DA cells in the ventral tegmental area (VTA) as well as higher DA release and greater expression of (tyrosine hydroxylase, TH) in the nucleus accumbens (NAc). Post-synaptically, pHFD animals display an increase in NAc D2 receptors and c-Fos expression after amphetamine injection. These findings highlight the vulnerability of DA system to the consumption of HFD during adolescence that may support deficits in reward-related processes observed in obesity.

Developing an Electronic Medical Record for Interlinked Care Services in Haiti.

A large clinical care and research organization in Haiti required an electronic medical record system (EMR) to serve the needs of its 30 interlinked clinical programs. After assessing available open source software, the local team designed and implemented a modular proprietary EMR that is improving data quality and patient care. Despite the many benefits of existing open source medical record systems, clinical centers with complex workflow patterns--even those in resource-limited settings--should consider developing sustainable, local systems that fit their care model.

CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5-year data from CIPRA HT-001.

SETTING: Port-au-Prince, Haiti. OBJECTIVE: To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals. DESIGN: Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was <200 cells/mm(3). The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up. RESULTS: A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm(3), 95% confidence interval [CI] 477-515 vs. 373 cells/mm(3), 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis. CONCLUSION: Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm(3) can result in long-term immune dysfunction and persistent increased risk for TB.

[Psychological trauma as risk for delayed psychiatric disorders: epigenetic mechanisms]. / Psychotrauma als Risiko für spätere psychische Störungen : Epigenetische Mechanismen.

BACKGROUND: Psychological trauma is considered to be a risk factor for the development of a number of psychiatric disorders. Although 40-90% of the population is exposed to a traumatic event in their lifetime, only a small fraction of individuals will develop a disorder. In recent years, numerous studies described epigenetic changes, such as DNA methylation, histone modifications and non-coding RNA as potential biological mechanisms by which the environment can have long-term effects on an organism. METHODS AND RESULTS: This article reviews the accumulating evidence for the involvement of epigenetic factors in the development of psychiatric disorders associated with psychological trauma. Clinically the review focuses on posttraumatic stress disorder (PTSD) for which trauma is a diagnostic criterion. In this context, we specifically focus on studies that show trauma and disease-associated epigenetic changes in humans and animal models. Both tissue-specific as well as cross-tissue effects have been described and underline the global consequences of psychological trauma on the whole organism. In addition, possible epigenetic mechanisms are presented which could be responsible for the long-lasting effects of gene-environment interactions in psychiatric disorders. Finally, the review addresses how a better understanding of these epigenetic mechanisms could suggest avenues for possible future pharmacological and psychotherapeutic treatment approaches.

Stepwise implementation of a new diagnostic algorithm for multidrug-resistant tuberculosis in Haiti.

SETTING: The uptake of tests endorsed by the World Health Organization to detect and appropriately confirm multidrug-resistant tuberculosis (MDR-TB) in low-income countries remains insufficient. OBJECTIVE: To validate the implementation of line-probe assays (LPA) and liquid culture to develop an algorithm to detect MDR-TB in the challenging setting of Haiti. METHODS: Through an EXPAND-TB (Expanding Access to New Diagnostics for TB) partnership, proficiency testing and validation of 221 acid-fast bacilli positive specimens were performed. Sensitivity, cost and processing time were analysed. RESULTS: Using liquid vs. solid culture shortened the turnaround time from 54 to 19 days, with a sensitivity of 100% vs. 98.6% and a total cost reduction of 13%. LPA detected all TB and MDR-TB cases at a lower cost than culture, in a mean time of 7.5 days. CONCLUSION: The combined use of molecular and liquid culture techniques accelerates the accurate diagnosis of TB and susceptibility testing against first-line drugs in a significantly shorter time, and is less expensive. The implementation of this new algorithm could significantly and accurately improve the screening and treatment follow-up of patients affected with TB and MDR-TB.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Outcomes of HIV-infected patients treated for recurrent tuberculosis with the standard retreatment regimen.

SETTING: The Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (the GHESKIO AIDS and TB Center) in Port-au-Prince, Haiti. OBJECTIVE: To measure the effectiveness of the standard TB retreatment regimen (2HRZES/1HRZE/5HRE) in human immunodeficiency virus (HIV) infected adults. DESIGN: Cohort study. RESULTS: Of 1318 HIV-infected patients with access to antiretroviral therapy following World Health Organization guidelines, 56 were diagnosed with recurrent pulmonary TB and retreated with the standard retreatment regimen: 10 patients (18%) died during retreatment, 3 (5%) defaulted, and 2 (4%) failed treatment. Forty-one patients (73%) achieved retreatment 'success' (cure, treatment completed). Of these, 8 (20%) died during follow-up, 5 (12%) were lost, and 5 (12%) had a second recurrence of TB. Only 26 (46%) of the 56 patients remained alive, in care, and TB-free after a median of 36 months of follow-up. CONCLUSION: HIV-infected patients treated for recurrent TB with the standard retreatment regimen have high mortality and poor long-term outcomes.

PP051. Prediction of preeclampsia with the sFlt-1/PLGF ratio: impact of the slope of repeated measurements.

INTRODUCTION: Patients with preeclampsia (PE) exhibit different serum concentrations of sFlt-1 and PlGF. The sFlt-1/PlGF ratio can be used as an aid in the diagnosis of preeclampsia. OBJECTIVES: The objective of this study was to explore the use of the sFlt-1/PlGF ratio as an aid in the prediction of preeclampsia in women with a high risk of the condition. METHODS: 150 patients with high risk of preeclampsia were included in this prospective study. Groups were compared according to the outcome of pregnancy: healthy pregnant women (controls, n=114), pregnancies complicated by intrauterine growth restriction without PE (IUGR, n=14), early PE<34 weeks of gestation (early PE, n=6) and late PE⩾34 weeks of gestation (late PE, n=16). Measurements of sFlt-1 and PlGF were performed on the automated Elecsys system. Statistical comparison of the sFlt-1/PlGF ratio in different outcome groups and multilevel analysis for logistic data using the random slope model was performed. RESULTS: We found significant differences in the sFlt-1/PlGF ratio between the outcome groups in weeks 24-36 of gestation (p=0,05). A significant difference in the sFlt-1/PlGF ratio between controls, IUGR and PE (early and late PE) could be measured up to six weeks before diagnosis (PE) or birth (IUGR, controls) (p=0,05). The random slope model showed significant different slopes (p=0,05) for individual outcome groups (controls 0,657; IUGR 1,786; early PE 1,951; late PE 0,881). CONCLUSION: The sFlt-1/PlGF ratio is able to identify pathologic pregnancy outcomes in gestational weeks 24-36. Prediction is feasible up to six weeks before clinical diagnosis (PE) or 6 weeks before birth (IUGR, controls). Repeated measurements are necessary beginning in 24 weeks of gestation with a maximum distance of six weeks. The slope between two measurements of the sFlt-1/PlGF ratio is predictive of further pregnancy outcome and the risk of developing preeclampsia.