Electronic Dose Monitoring Identifies a High-Risk Subpopulation in the Treatment of Drug-resistant Tuberculosis and Human Immunodeficiency Virus.

BACKGROUND: In generalized drug-resistant tuberculosis (DR-TB) human immunodeficiency virus (HIV) epidemics, identifying subpopulations at high risk for treatment failure and loss to care is critically important to improve treatment outcomes and prevent amplification of drug resistance. We hypothesized that an electronic dose-monitoring (EDM) device could empirically identify adherence-challenged patients and that a mixed-methods approach would characterize treatment challenges. METHODS: A prospective study of patients with DR-TB HIV on antiretroviral therapy (ART) initiating bedaquiline-containing regimens in KwaZulu-Natal, South Africa. Separate EDM devices measured adherence for bedaquiline and ART. Patients with low adherence (<85%) to both bedaquiline and ART were identified as high risk for poor outcomes. Baseline survey, study visit notes, and focus group discussions characterized treatment challenges. RESULTS: From December 2016-February 2018, 32 of 198 (16%) enrolled patients with DR-TB HIV were identified as dual-adherence challenged. In a multivariate model including baseline characteristics, only receiving a disability grant was significantly associated with dual nonadherence at 6 months. Mixed-methods identified treatment barriers including alcohol abuse, family conflicts, and mental health issues. Compared with adherent patients, dual-adherence-challenged patients struggled to prioritize treatment and lacked support, and dual-adherence-challenged patients experienced higher rates of detectable HIV viral load and mortality than more adherent patients. CONCLUSIONS: EDM empirically identified a subpopulation of patients with DR-TB HIV with dual-adherence challenges early in treatment. Mixed-methods revealed intense psychosocial, behavioral, and structural barriers to care in this subpopulation. Our data support developing differential, patient-centered, adherence support interventions focused on psychosocial and structural challenges for subpopulations of at-risk DR-TB HIV patients.

Correction: Classes 1 and 2 integrons in faecal Escherichia coli strains isolated from mother-child pairs in Nigeria.

[This corrects the article DOI: 10.1371/journal.pone.0183383.].

Classes 1 and 2 integrons in faecal Escherichia coli strains isolated from mother-child pairs in Nigeria.

BACKGROUND: Antimicrobial resistance among enteric bacteria in Africa is increasingly mediated by integrons on horizontally acquired genetic elements. There have been recent reports of such elements in invasive pathogens across Africa, but very little is known about the faecal reservoir of integron-borne genes. METHODS AND FINDINGS: We screened 1098 faecal Escherichia coli isolates from 134 mother-child pairs for integron cassettes by PCR using primers that anneal to the 5' and 3' conserved ends of the cassette regions and for plasmid replicons. Genetic relatedness of isolates was determined by flagellin and multi-locus sequence typing. Integron cassettes were amplified in 410 (37.5%) isolates and were significantly associated with resistance to trimethoprim and multiple resistance. Ten cassette combinations were found in class 1 and two in class 2 integrons. The most common class 1 cassette configurations were single aadA1 (23.4%), dfrA7 (18.3%) and dfrA5 (14.4%). Class 2 cassette configurations were all either dfrA1-satI-aadA1 (n = 31, 7.6%) or dfrA1-satI (n = 13, 3.2%). A dfr cassette was detected in 294 (31.1%) of trimethoprim resistant strains and an aadA cassette in 242 (23%) of streptomycin resistant strains. Strains bearing integrons carried a wide range of plasmid replicons of which FIB/Y (n = 169; 41.2%) was the most frequently detected. Nine isolates from five different individuals carried the dfrA17-aadA5-bearing ST69 clonal group A (CGA). The same integron cassette combination was identified from multiple distinct isolates within the same host and between four mother-child pairs. CONCLUSIONS: Integrons are important determinants of resistance in faecal E. coli. Plasmids in integron-containing strains may contribute to dispersing resistance genes. There is a need for improved surveillance for resistance and its mechanisms of dissemination and persistence and mobility of resistance genes in the community and clinical settings.

EEG Characteristics in Cooled and Rewarmed Periods in Post-cardiac Arrest Therapeutic Hypothermia Patients.

PURPOSE: Continuous video EEG is a tool to assess brain function in injuries, including cardiac arrest (CA). In post-CA therapeutic hypothermia (TH) studies, some EEG features are linked to poor prognosis, but the evolvement of EEG characteristics during two temperature phases and its significance is unclear. We systematically analyzed EEG characteristics in cooled and rewarmed phases of post-CA therapeutic hypothermia patients and investigated their correlation to patient outcome. METHODS: This is a retrospective study of EEG analyses, from a single academic center, of 20 patients who underwent CA and therapeutic hypothermia. For each patient, three 30-minute EEG segments in cooled and rewarmed phases were analyzed for continuity, frequency, interictal epileptiform discharges, and seizures. Mortality at the time of discharge was used as outcome. RESULTS: Rewarming was associated with the emergence of interictal epileptiform discharges, 2.6 times as likely compared with the cooled period (P = 0.03), and was not affected by systemic factors. Continuity, frequency, and discrete seizures were unaffected by temperature and did not show variance within each temperature phase. There was a trend toward the emergence of interictal epileptiform discharges upon rewarming and mortality, but it was not statistically significant. CONCLUSIONS: Increased interictal epileptiform discharges with rewarming in post-CA therapeutic hypothermia patients may suggest poor prognosis, but a larger scale prospective study is needed.

Invasive Infection and Outcomes in a Humanitarian Surgical Burn Program in Haiti.

BACKGROUND: Compare to high-income settings, survival in burn units in low-income settings is lower with invasive infections one leading cause of death. Médecins Sans Frontières is involved in the treatment of large burns in adults and children in Haiti. METHODS: In 2014, we performed a review of 228 patients admitted consecutively with burn injury during a 6-month period to determine patient outcomes and infectious complications. Microbiology was available through a linkage with a Haitian organization. Regression analysis was performed to determine covariates associated with bloodstream infection and mortality. RESULTS: 102 (45 %) patients were male, the median age was 8 years (IQR, 2-28), and the majority of patients (60 %) were admitted to the unit within 6 h of injury. There were 20 patients (9 %) with culture-proven bacteremia. Among organisms in blood, common isolates were Staphylococcus aureus (42 %), Pseudomonas aeruginosa (23 %), and Acinetobacter baumannii (15 %). Among patients with burns involving <40 % total body area, 4 (2 %) of 192 died and 20 (65 %) of 31 with ≥40 % body surface area involvement died. Factors associated with mortality included involvement of ≥40 % of body surface, depth, and flame as the mechanism. Multidrug-resistant infections were common; 18 % of S. aureus isolates were methicillin resistant, and 83 % of P. aeruginosa isolates were imipenem resistant. CONCLUSIONS: A low mortality rate was observed in a humanitarian burn surgery project in patients with burns involving <40 % of total body surface. Invasive infection was common and alarming rates of antibiotic resistance were observed, including infections not treatable with antibiotics available locally.

Kangaroo mother care: a systematic review of barriers and enablers.

OBJECTIVE: To investigate factors influencing the adoption of kangaroo mother care in different contexts. METHODS: We searched PubMed, Embase, Scopus, Web of Science and the World Health Organization's regional databases, for studies on "kangaroo mother care" or "kangaroo care" or "skin-to-skin care" from 1 January 1960 to 19 August 2015, without language restrictions. We included programmatic reports and hand-searched references of published reviews and articles. Two independent reviewers screened articles and extracted data on carers, health system characteristics and contextual factors. We developed a conceptual model to analyse the integration of kangaroo mother care in health systems. FINDINGS: We screened 2875 studies and included 112 studies that contained qualitative data on implementation. Kangaroo mother care was applied in different ways in different contexts. The studies show that there are several barriers to implementing kangaroo mother care, including the need for time, social support, medical care and family acceptance. Barriers within health systems included organization, financing and service delivery. In the broad context, cultural norms influenced perceptions and the success of adoption. CONCLUSION: Kangaroo mother care is a complex intervention that is behaviour driven and includes multiple elements. Success of implementation requires high user engagement and stakeholder involvement. Future research includes designing and testing models of specific interventions to improve uptake.

Long-Term Distributed Repetitive Transcranial Magnetic Stimulation for Tinnitus: A Feasibility Study.

OBJECTIVES: To assess feasibility and tolerability of long-term distributed therapeutic rTMS for refractory tinnitus, distributed over seven months. MATERIALS AND METHODS: Eight subjects with refractory tinnitus underwent five weekly sessions of 1800 pulses of 1 Hz rTMS targeted toward the temporoparietal junction. Five weeks later (study week 10), subjects meeting predefined responder criteria entered a monthly rTMS treatment phase, for the next five months. Outcome measures were subject satisfaction and compliance, tinnitus severity daily diaries, standardized tinnitus self-rating scales, and adverse events. RESULTS: Subject satisfaction was high, and compliance was virtually 100%. The tinnitus handicap inventory and mini-tinnitus questionnaire scores improved significantly at study week 5 compared with baseline. There were four responders at study week 5; three responders at study week 10; and one responder at study week 30. There were no serious adverse events. CONCLUSIONS: Our study demonstrated that rTMS can be delivered in a distributed schedule that is well-tolerated, feasible and may prove to be clinically beneficial. A long-term distributed rTMS schedule for tinnitus may warrant investigation as an alternative to the short-term aggregated treatment schedules more frequently used previously. For the many varied therapeutic uses of rTMS (established and investigational), treatment schedules are relatively unexplored, and deserve further attention.

Comparison of Clinical Characteristics and Treatment Outcomes of Children Selected for Treatment of Severe Acute Malnutrition Using Mid Upper Arm Circumference and/or Weight-for-Height Z-Score.

OBJECTIVES: Debate for a greater role of mid-upper arm circumference (MUAC) measures in nutritional programming continues, but a shift from therapeutic feeding programs admitting children using MUAC and/or weight-for-height Z (WHZ) to a new model admitting children using MUAC only remains complicated by limited information regarding the clinical profile and response to treatment of children selected by MUAC vs. WHZ. To broaden our understanding of how children identified for therapeutic feeding by MUAC and/or WHZ may differ, we aimed to investigate differences between children identified for therapeutic feeding by MUAC and/or WHZ in terms of demographic, anthropometric, clinical, and laboratory and treatment response characteristics. METHODS: Using secondary data from a randomized trial in rural Niger among children with uncomplicated severe acute malnutrition, we compared children that would be admitted to a therapeutic feeding program that used a single anthropometric criterion of MUAC< 115 mm vs. children that are admitted under current admission criteria (WHZ< -3 and/or MUAC< 115 mm) but would be excluded from a program that used a single MUAC< 115 mm admission criterion. We assessed differences between groups using multivariate regression, employing linear regression for continuous outcomes and log-binomial regression for dichotomous outcomes. RESULTS: We found no difference in terms of clinical and laboratory characteristics and discharge outcomes evaluated between children that would be included in a MUAC< 115 mm therapeutic feeding program vs. children that are currently eligible for therapeutic feeding but would be excluded from a MUAC-only program. CONCLUSIONS: A single anthropometric admission criterion of MUAC < 115 mm did not differentiate well between children in terms of clinical or laboratory measures or program outcomes in this context. If nutritional programming is to use a single MUAC-based criterion for admission to treatment, further research and program experience can help to identify the most appropriate criterion in a broad range of contexts to target children in most urgent need of treatment.

Surgical Care of Pediatric Patients in the Humanitarian Setting: The Médecins Sans Frontières Experience, 2012-2013.

IMPORTANCE: Little is known about the scope of practice and outcomes in pediatric surgery performed by humanitarian organizations in resource-poor settings and conflict zones. This study provides the largest report to date detailing such data for a major nongovernmental organization providing humanitarian surgical relief support in these settings. OBJECTIVE: To characterize pediatric surgical care provision by a major nongovernmental organization in specialized humanitarian settings and conflict zones. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted from August 15, 2014, to March 9, 2015, of 59,928 surgical interventions carried out from January 1, 2012, to December 31, 2013, by the Médecins Sans Frontières Operational Centre Paris (MSF-OCP) program in 20 locations, including South Sudan, Yemen, Syria, Gaza, Pakistan, Nigeria, Central African Republic, Democratic Republic of Congo, and the Philippines. Surgical interventions were primarily for general surgical, traumatic, and obstetric emergencies and were categorized by mechanism, type of intervention, American Society of Anesthesia risk classification, and urgency of intervention. MAIN OUTCOMES AND MEASURES: Operative indications, type of intervention, and operative case mortality. RESULTS: Among all age groups, 59,928 surgical interventions were performed in dedicated trauma, obstetric, and reconstructive centers for 2 years. Nearly one-third of interventions (18,040 [30.1%]) involved preteen patients (aged <13 years) and 4571 (7.6%) involved teenaged patients (aged 13-17 years). The proportion of violence-related injuries in the preteen group was significantly lower than in the teenage group (4.8% vs 17.5%; P < .001). Burns (50.1%), other accidental injuries (16.4%), and infections (23.4%) composed the bulk of indications in the preteen group. Interventions in the teenage group were principally caused by trauma-related injuries (burns, 22.9%; traffic accidents, 10.1%; gunshot wounds, 8.0%). Crude perioperative case mortality rates were 0.07% in the preteen group, 0.15% in the teenage group, and 0.22% in the adult group (>17 years) (P = .001). One-third of the cases (33.4%) were deemed urgent, while most of the remaining cases (57.7%) were deemed semielective (surgical intervention to be performed within 48 hours). CONCLUSIONS AND RELEVANCE: When examining surgical interventions in a population of pediatric patients cared for in the specialized setting of humanitarian aid and conflict zones, burns, other accidental injuries, and infection composed the bulk of indications in the preteen group; interventions in the teenage group were principally caused by trauma-related injuries. Crude perioperative case mortality rates in the preteen group were significantly lower than in the adult group. Further work is needed to examine long-term outcomes of pediatric operations in these settings and to guide context-specific surgical program development.

Regional dissemination of a trimethoprim-resistance gene cassette via a successful transposable element.

BACKGROUND: Antimicrobial resistance is a growing international problem. We observed a 50% increase in the prevalence of trimethoprim resistance among fecal Escherichia coli from healthy Nigerian students between 1998 and 2005, a trend to increase that continued in 2009. METHODS AND FINDINGS: A PCR-based screen revealed that 131 (43.1%) of isolates obtained in Nigeria in 2005 and 2009 carried integron-borne dfrA cassettes. In the case of 67 (51.1%) of these isolates, the cassette was a class 1-integron-borne dfrA7 gene, which has been reported at high prevalence from E. coli isolates from other parts of Africa. Complete sequencing of a 27 Kb dfrA7-bearing plasmid from one isolate located the dfrA7 gene within a Tn21-type transposon. The transposon also contained an IS26-derived bla/sul/str element, encoding resistance to ß-lactams, sulphonamides and streptomycin, and mercury resistance genes. Although the plasmid backbone was only found in 12 (5.8%) of trimethoprim-resistant isolates, dfrA7 and other transposon-borne genes were detected in 14 (16.3%) and 32 (26.3%) of trimethoprim resistant isolates collected in Nigeria in 2005 and 2009, respectively. Additionally, 37 (19.3%) of trimethoprim-resistant E. coli isolates collected between 2006 and 2008 from Ghana were positive for the dfrA7 and a transposon marker, but only 4 (2.1%) harbored the plasmid backbone. CONCLUSIONS: Our data point to transposition as a principal mechanism for disseminating dfrA7 among E. coli from Nigeria and Ghana. On-going intensive use of the affordable broad-spectrum antibacterials is likely to promote selective success of a highly prevalent transposable element in West Africa.

Progression of idiopathic clubfoot correction using the Ponseti method.

The Ponseti technique involves sequential clubfoot correction by abduction, supination, and finally dorsiflexion. Although shown to be effective, correction progression has not been examined. The Dimeglio/Bensahel classification system was used to analyze heel equinus, varus, midfoot rotation, adduction, posterior crease, medial crease, and cavus initially and after each casting. From 2000 to 2008, 123 patients (185 feet) with idiopathic clubfeet, aged below 60 days, without prior treatment were grouped by number of casts required. Successive castings achieved goals of reducing cavus and medial crease first, then gradually correcting midfoot rotation, adduction, and heel varus. Unexpectedly, heel equinus improved simultaneously with midfoot variables, as well as with final casting.

Prdm16 is a physiologic regulator of hematopoietic stem cells.

Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.

Multi-locus sequence typing of enteroaggregative Escherichia coli isolates from Nigerian children uncovers multiple lineages.

BACKGROUND: Enteroaggregative Escherichia coli (EAEC) are defined by their stacked-brick adherence pattern to human epithelial cells. There is no all-encompassing genetic marker for EAEC. The category is commonly implicated in diarrhea but research is hampered by perplexing heterogeneity. METHODOLOGY/PRINCIPAL FINDINGS: To identify key EAEC lineages, we applied multilocus sequence typing to 126 E. coli isolates from a Nigerian case-control study that showed aggregative adherence in the HEp-2 adherence assay, and 24 other EAEC strains from diverse locations. EAEC largely belonged to the A, B1 and D phylogenetic groups and only 7 (4.6%) isolates were in the B2 cluster. As many as 96 sequence types (STs) were identified but 60 (40%) of the EAEC strains belong to or are double locus variants of STs 10, 31, and 394. The remainder did not belong to predominant complexes. The most common ST complex, with predicted ancestor ST10, included 32 (21.3%) of the isolates. Significant age-related distribution suggests that weaned children in Nigeria are at risk for diarrhea from of ST10-complex EAEC. Phylogenetic group D EAEC strains, predominantly from ST31- and ST394 complexes, represented 38 (25.3%) of all isolates, include genome-sequenced strain 042, and possessed conserved chromosomal loci. CONCLUSIONS/SIGNIFICANCE: We have developed a molecular phylogenetic framework, which demonstrates that although grouped by a shared phenotype, the category of 'EAEC' encompasses multiple pathogenic lineages. Principal among isolates from Nigeria were ST10-complex EAEC that were associated with diarrhea in children over one year and ECOR D strains that share horizontally acquired loci.

Clubfoot classification: correlation with Ponseti cast treatment.

BACKGROUND: Many different clubfoot classification systems have been proposed, but no single one is universally accepted. Two frequently cited systems, developed by Dimeglio/Bensahel and Catterall/Pirani, are often used for evaluation purposes in the treatment of idiopathic clubfoot. Our hypothesis was that the initial scores would be positively correlated with the number of casts required for clubfoot correction, indicating to us that the more severe score would require more casts, and therefore truly show the accuracy and usefulness of the scoring system. METHODS: From May 2000 to April 2008, 123 patients (185 feet) with idiopathic clubfeet were treated. All patients were below 60 days of age (mean 15.3 d, range: 2 to 57 d) at the time of their initial evaluation, and had not received prior clubfoot treatment. All cast placements were under the supervision of the same pediatric orthopedic surgeon. Initial correction was achieved in all patients. RESULTS: The mean number of casts required for correction was 5.1 (range: 2 to 8). On the basis of number of casts required, no significant differences were found in final total scores (Dimeglio/Bensahel P=0.14 and Catterall/Pirani P=0.44), indicating a similar level of correction for all feet. The Dimeglio/Bensahel and Catterall/Pirani classification systems were both similarly, poorly correlated with the number of casts needed [Spearman rank correlation coefficients (rs)=0.34 vs. 0.33]. The 2 components with the highest correlations were equinus (rs=0.39) and forefoot adduction (rs=0.35) for the Dimeglio/Bensahel system and coverage of the lateral head of the talus (rs=0.40) and rigid equinus (rs=0.39) for the Catterall/Pirani system. CONCLUSIONS: When using the initial scores, both the Dimeglio/Bensahel and Catterall/Pirani classification systems had a low correlation with the number of Ponseti casts required. Analysis of the individual components revealed variability in the coefficients, with some having low-to-moderate correlation and others having none. There was no difference between the Dimeglio/Bensahel and Catterall/Pirani classification systems when measuring their correlation with the number of Ponseti casts required for clubfoot correction. An improved classification system is needed to predict the length of treatment and, ultimately, the risk of recurrence. LEVEL OF EVIDENCE: Prognostic Level IV.