Adverse effects of bedaquiline in patients with extensively drug-resistant tuberculosis.

BACKGROUND: The World Health Organisation (WHO) guidelines recommend that, because of the resistance patterns of extensively drug-resistant (XDR) tuberculosis (TB) and its unique mechanism of action, bedaquiline be included in the regimen. Although the results of clinical trials have shown bedaquiline to be beneficial, it also carries the risk of adverse effects, some potentially life-threatening. The aim of the study was to determine the incidence of adverse effects caused by bedaquiline in patients diagnosed with XDR-TB. The subsequent management of these adverse effects was also analysed. METHODS: The medical records of patients aged 18 years or older living with XDR-TB who were prescribed bedaquiline in combination with a background regimen at a public-sector drug-resistant TB hospital in the Eastern Cape were reviewed. RESULTS: Thirty records were reviewed in September 2016. Female patients constituted 66.67% (n = 20) of the sample. Nearly half (46.67%; n = 14) of the patients were living with human immunodeficiency virus, and six (42.86%) of them were female. Adverse effects were recorded for 26 patients (86.67%) including corrected QT prolongation (40%; n = 12), skin rash (33.33%; n = 10) and hyperlactataemia (33.33%; n = 10) as the most common. There were no treatment discontinuations or deaths. The management of adverse effects varied from omitting doses of bedaquiline to pharmacological intervention. CONCLUSION: All patients completed bedaquiline treatment, indicating that the adverse effects did not require discontinuation of the drug. However, when pharmacological intervention is required for the management of adverse effects, care should be taken to ensure that there is minimal interaction with other TB drugs and a low risk of further adverse effects.

Should Charity Air Medical Organizations Require Commercial Certification of Their Pilots?

OBJECTIVE: Fixed wing medical transportation crashes operating under 14 CFR Part 91 show higher fatal outcomes than nonmedical Part 91 flights. Advanced certification may translate into increased safety, yet we know of no charity air medical transportation requiring such certification. Herein, in a retrospective study, we determined whether commercial certification is associated with a reduced fatality rate compared with the less stringent private pilot certificate and accident causes. METHODS: The National Transportation Safety Board accident database was queried for fatal accidents in single-engine aircraft occurring between 2002 and 2012. Poisson and proportion tests were used in statistical analyses. RESULTS: For the period spanning 2002-2012, commercial pilots showed a lower fatality rate. Under visual meteorologic conditions, aerodynamic stall was a frequent cause for fatal accidents affecting both airman cohorts equally. For operations in instrument meteorologic conditions, fatal accidents were most commonly attributed to instrument approach deficiency and spatial disorientation. At night, failure to maintain obstacle/terrain clearance was the most prevalent cause of fatal crashes. CONCLUSION: Our data suggest that charity air medical transportation organizations should encourage their pilots to acquire commercial certification. Furthermore, our study indicates areas in which general aviation training/currency should be directed to reduce fatal accidents.

Microscopic saw mark analysis: an empirical approach.

Microscopic saw mark analysis is a well published and generally accepted qualitative analytical method. However, little research has focused on identifying and mitigating potential sources of error associated with the method. The presented study proposes the use of classification trees and random forest classifiers as an optimal, statistically sound approach to mitigate the potential for error of variability and outcome error in microscopic saw mark analysis. The statistical model was applied to 58 experimental saw marks created with four types of saws. The saw marks were made in fresh human femurs obtained through anatomical gift and were analyzed using a Keyence digital microscope. The statistical approach weighed the variables based on discriminatory value and produced decision trees with an associated outcome error rate of 8.62-17.82%.

Acute effects of rearfoot manipulation on dynamic standing balance in healthy individuals.

Dynamic standing balance is essential to perform functional activities and is included in the treatment of many lower extremity injuries. Physiotherapists utilize many methods to restore standing balance including stability exercises, functional retraining, and manual therapy. The purpose of this study was to investigate the effects of a rearfoot distraction manipulation on dynamic standing balance. Twenty healthy participants (age: 24.4 ± 2.8 years; height: 162.9 ± 37.7 cm; mass: 68.0 ± 4.8 kg; right leg dominant = 20) completed this study. Following familiarization, dynamic standing balance was assessed during: (1) an experimental condition immediately following a rearfoot distraction manipulation, and (2) a control condition. Dominant leg balance was quantified using the Y-balance test which measures lower extremity reach distances. Reach distances were normalized to leg length and measured in the anterior, posteromedial and posterolateral directions. Overall balance was calculated through the summing of all normalized directions. Paired t-tests and Wilcoxon rank tests were used to compare balance scores for parametric and non-parametric data as appropriate. Significance was set at 0.05 a priori. Effect size (ES) was calculated to determine the clinical impact of the manipulation. Increased reach distances (indicating improved balance) were noted following manipulation for overall balance (p = 0.03, ES = 0.26) and in the posteromedial direction (p = 0.01, ES = 0.42). Reach distances did not differ for the anterior (p = 0.11, ES = 0.16) or posterolateral (p = 0.11, ES = 0.25) components. Dynamic standing balance improved after a rearfoot distraction manipulation in healthy participants. It is hypothesized that manual therapy applied to the foot and ankle may be beneficial to augment other therapeutic modalities when working with patients to improve dynamic standing balance.

Validation of tool mark analysis of cut costal cartilage.

This study was designed to establish the potential error rate associated with the generally accepted method of tool mark analysis of cut marks in costal cartilage. Three knives with different blade types were used to make experimental cut marks in costal cartilage of pigs. Each cut surface was cast, and each cast was examined by three analysts working independently. The presence of striations, regularity of striations, and presence of a primary and secondary striation pattern were recorded for each cast. The distance between each striation was measured. The results showed that striations were not consistently impressed on the cut surface by the blade's cutting edge. Also, blade type classification by the presence or absence of striations led to a 65% misclassification rate. Use of the classification tree and cross-validation methods and inclusion of the mean interstriation distance decreased the error rate to c. 50%.

Measurement of ion beam profiles in a superconducting linac with a laser wire.

A laser wire ion beam profile monitor system has been developed at the Spallation Neutron Source accelerator complex. The laser wire system uses a single laser source to measure the horizontal and vertical profiles of a pulsed hydrogen ion (H(-)) beam along a 230 m long superconducting linac, which accelerates H(-) from 200 MeV to 1 GeV. In this paper, we describe the laser optics requirement for the system, the performance of the profile measurement, and the effects of laser parameters on the measurement reliability. The result provides a practical guideline for the development of a large-scale, operational, laser-based diagnostics in accelerator facilities.

Pu-erh tea tasting in Yunnan, China: correlation of drinkers' perceptions to phytochemistry.

AIM OF THE STUDY: Pu-erh (or pu'er) tea tasting is a social practice that emphasizes shared sensory experience, wellbeing, and alertness. The present study examines how variable production and preparation practices of pu-erh tea affect drinkers' perceptions, phytochemical profiles, and anti-oxidant activity. MATERIALS AND METHODS: One hundred semi-structured interviews were conducted in Yunnan Province to understand the cultural and environmental context of pu-erh tea tasting. The gong fu cha dao ('way of tea' with 'effort,' 'work,' or 'skill') method of brewing tea through multiple infusions was employed to evaluate green and black pu-erh samples from smallholder agro-forests and terrace plantations. Ranking interviews, High Performance Liquid Chromatography (HPLC), and the 1-1-diphenyl-2-picrylhydrazyl (DPPH) assay were conducted to characterize color and taste profiles, Total Catechin Content (TCC), Total Methylxanthine Content (TMC), and free radical scavenging capacity (IC(50)). RESULTS: Significant variation was found among pu-erh samples based on: (1) agro-ecosystem mode of production by TCC (P<0.0001) and TMC (P<0.0265), (2) processing method for TCC (P<0.0001), TMC (P<0.0027), and free radical scavenging capacity (P<0.0001), (3) infusion sequence for TMC (P<0.0013), (4) taste rankings for TCC (P<0.0001), TMC (P<0.0001), and IC(50) (P<0.0059) and, (5) color rankings for TMC (P<0.0009) and IC(50) (P<0.0001). Samples rated as bitter and bitter-sweet contained the greatest TCC and free radical scavenging capacity. CONCLUSIONS: This research demonstrated that production environment, processing methods, and infusion sequence in preparing tea are related to the phytochemical profile, free radical scavenging activity, and flavor of tea. Findings contribute to the ethnomedical literature by supporting previous studies that have hypothesized that the taste of plants, particularly bitterness, may guide societies in the search for medicinal plants and beneficial phytochemicals.

Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders.

Inherited metabolic disorders (IMD) or inborn errors of metabolism are a diverse group of diseases arising from genetic defects in lysosomal enzymes or peroxisomal function. These diseases are characterized by devastating systemic processes affecting neurologic and cognitive function, growth and development, and cardiopulmonary status. Onset in infancy or early childhood is typically accompanied by rapid deterioration. Early death is a common outcome. Timely diagnosis and immediate referral to an IMD specialist are essential steps in management of these disorders. Treatment recommendations are based on the disorder, its phenotype including age at onset and rate of progression, severity of clinical signs and symptoms, family values and expectations, and the risks and benefits associated with available therapies such as allogeneic hematopoietic stem cell transplantation (HSCT). This review discusses indications for HSCT and outcomes of HSCT for selected IMD. An international perspective on progress, limitations, and future directions in the field is provided.

Predictive factors for vision loss after hematopoietic cell transplant for X-linked adrenoleukodystrophy.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by cerebral demyelination, adrenal insufficiency, and progressive neurological deterioration. Hematopoietic cell transplantation (HCT) is the only effective treatment. Visual dysfunction is a common component of the disease and may continue to progress in patients after HCT. This study was designed to determine prognostic factors predictive of vision loss after HCT. SUBJECTS AND METHODS: A retrospective chart review was performed for all boys who had HCT for cerebral X-ALD at the University of Minnesota between 1991 and 2002. Patients were included if they survived 100 days post-HCT and had pre- and post-HCT ophthalmology evaluation. Complete data were available for 14 patients. Patient characteristics examined included HLA match status, graft-versus-host disease prophylaxis, source of HCT, reason for diagnosis, age at treatment, magnetic resonance imaging (MRI) severity score, pattern of demyelination on MRI, and pretreatment performance intelligence quotient (IQ). Univariate analysis was performed for correlation with posttransplant visual acuity and optic disk pallor. RESULTS: Factors significantly correlated with loss of visual acuity after HCT included pretransplant MRI severity score >11 (p = 0.03), pretransplant performance IQ <76 (p = 0.02), and the presence of pretransplant parieto-occipital demyelination on MRI (p = 0.03). Additionally, the presence of pretransplant parieto-occipital demyelination on MRI was found to correlate with the development of new optic disk pallor after HCT (p = 0.05). CONCLUSIONS: This study identifies patient characteristics predictive of vision loss after HCT for X-ALD. Decisions about treatment for X-ALD rely heavily upon prognostic information about adverse outcomes following HCT. These findings will aid clinicians counseling patients considering HCT for X-ALD.

Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study.

BACKGROUND: Favourable outcomes have been reported for patients with childhood cerebral adrenoleukodystrophy (CCALD) who had received haematopoietic cell transplantation (HCT) at the early stage of cerebral involvement. However, comparative data for non-transplanted CCALD patients are limited. We analysed survival of CCALD patients who had not received HCT and, in a subgroup with early cerebral disease, compared survival in those who underwent HCT with those who did not. METHODS: Retrospective survival analyses were done on 283 CCALD patients identified at the Kennedy Krieger Institute who had not received HCT, focusing on a 30-member early stage cerebral subgroup whose neurological disability and MRI severity scores matched those in a 19-member transplanted subgroup previously reported. A Kaplan-Meier survival curve and log-rank test were used for survival analysis and to estimate the difference between the survival probabilities of the groups with statistical significance set at alpha=0.05. FINDINGS: Mean age at onset of symptoms in the entire 283 non-transplanted group was 7 years (SD 2 years). 131 (46%) patients died during the mean follow-up period of 5.9 years (5.3) at a mean age of 12.3 years (4.9). 5-year survival was 66%. The 5-year survival probability of 54% in the early stage group was significantly poorer (chi(2)=7.47, p=0.006) than the 5-year survival of 95% in the transplanted group with early stage cerebral disease. INTERPRETATION: HCT done in the early and progressive stages of CCALD is beneficial, and our data support the recommendation that transplantation be offered to patients in the early stages of CCALD.

Azacitidine pharmacokinetics in an adolescent patient with renal compromise.

Azacitidine pharmacokinetic parameters in adolescent patients with renal compromise are not available from the medical literature. We describe a 14-year-old with myelodysplastic syndrome treated with subcutaneous 5-azacitidine for disease relapse 2 years after hematopoietic stem cell transplant. Because of renal compromise, malnutrition, and poor functional status, pharmacokinetic parameters were projected from existing literature data to select the patient's first azacitidine treatment course (1.5 mg/kg/d for 7 d). Posttreatment azacitidine plasma concentrations used to calculate patient-specific pharmacokinetic parameters corroborated initial estimates and systemic exposure associated with therapeutic benefit in adults and permitted individualization of treatment.

Long-term outcomes of adaptive functions for children with mucopolysaccharidosis I (Hurler syndrome) treated with hematopoietic stem cell transplantation.

Advances in medical treatment have prolonged the lives of children with Hurler syndrome or mucopolysaccharidosis I requiring increased attention to the assessment of their long-term outcomes and functional abilities. Adaptive functions are critical for understanding functional outcomes after treatment and developing focused interventions. We investigated the development of various adaptive functions in children who have had hematopoietic stem cell transplant (HSCT) for Hurler syndrome and risk factors that are associated with the development of these functions. We examined the development of 41 children who had 3 or more Vineland Adaptive Behavior Scales records assessed before and after transplant. Communication, daily living skills, socialization, and motor functions were measured. While standard scores decline over time, development of skills continue with a slower than average rate compared with peers. A cross-sectional nontransplanted comparison group showed more deficits after age 2 years than the transplanted group. In contrast to cognitive ability, age at transplant was not significantly associated with ultimate adaptive level. Baseline cognitive level before HSCT and growth of cognition after HSCT were associated with adaptive functions especially for communication and daily living skills. Socialization was predicted by cumulative medical risk factors, likely due to restricted social exposure in children with complicated transplant courses. Overall, measurement of adaptive behaviors demonstrated that HSCT allows long-term slow improvement of functional outcomes for children with Hurler syndrome. Children with Hurler syndrome with good cognitive levels before HSCT and continued growth of cognition after HSCT show good adaptive functions. Although cognitive and orthopedic problems as well as medical complications limit adaptive ability, identifying these problems early allow beneficial targeted interventions.

Inflammatory cytokines and the development of pulmonary complications after allogeneic hematopoietic cell transplantation in patients with inherited metabolic storage disorders.

Patients with inherited metabolic storage disorders are at a higher risk of developing pulmonary complications after hematopoietic cell transplantation (HCT). This single-center prospective study of 48 consecutive inherited metabolic storage disorder patients was performed to identify risk factors for the development of pulmonary complications after HCT. Before HCT, subjects underwent bronchoalveolar lavage (BAL) for cell count, culture, nitrite levels, and analysis of proinflammatory cytokines and chemokines. The overall incidence of pulmonary complications was 52% (infectious, 23%; noninfectious, 29%) over a period of 4 years. Diffuse alveolar hemorrhage was the most frequent noninfectious complication and occurred in 19% of patients, all of whom had a diagnosis of mucopolysaccharidosis (Hurler and Maroteaux-Lamy syndromes). Levels of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, and granulocyte colony-stimulating factor in BAL fluid samples obtained before HCT were higher in patients with mucopolysaccharidoses than in patients with leukodystrophies. In addition, levels of IL-1beta, IL-6, IL-8, and granulocyte colony-stimulating factor were increased in the BAL fluid of patients who developed noninfectious pulmonary complications compared with those who did not develop pulmonary complications. It is interesting to note that most noninfectious pulmonary complications occurred in patients with mucopolysaccharidoses, especially diffuse alveolar hemorrhage, which occurred exclusively in patients with mucopolysaccharidoses. Higher levels of bronchial proinflammatory cytokines and chemokines may be predictive of the development of subsequent posttransplantation noninfectious complications in patients with mucopolysaccharidoses, especially those with Hurler syndrome. Larger studies will be required to further elucidate etiologic mechanisms and predictive factors.

Effect of shorter polymerization times when using the latest generation of light-emitting diodes.

INTRODUCTION: Recent studies have suggested that a 10-second cure time with a high-energy quartz-tungsten-halogen (QTH) or a light-emitting diode (LED) light might be adequate when bonding orthodontic brackets to tooth enamel. The purpose of this study was to evaluate the ability of the latest generation of QTH and LED light-curing units (LCUs) to bond orthodontic brackets to teeth at decreased polymerization times. METHODS: Two LED LCUs (Ortholux LED, 3M Unitek, Monrovia, Calif; UltraLume LED 5, Ultradent Products, South Jordan, Utah) and a QTH LCU (Optilux 501, Demetron, Danbury, Conn) were evaluated. One hundred eighty metal orthodontic brackets were bonded to extracted human molars. The specimens were divided into 9 groups (3 lights and 3 curing times) of 20 teeth each. Each group was cured with 1 of the 3 lights for 20, 10, or 6 seconds. Thirty minutes after polymerization, the specimens were subjected to shear force on a universal testing machine until bracket failure. RESULTS: Two-way ANOVA detected significant differences among the main effects of light type and cure time. Tukey post-hoc tests determined that brackets bonded by all light types had lower bond strengths with the 6-second cure than the 20-second cure (P < .001). The highest bond strengths were obtained with the Optilux 501 QTH LCU and the UltraLume LED 5 LCU at the longest cure time of 20 seconds. CONCLUSIONS: It is recommended that orthodontic brackets be photopolymerized for at least 20 seconds with the QTH or the LED LCU before the archwires are engaged.

Reconstitution of lymphocyte subpopulations in children with inherited metabolic storage diseases after haematopoietic cell transplantation.

We prospectively evaluated the reconstitution of lymphocyte subpopulations in nine children with lysosomal diseases who underwent 11 allogeneic haematopoietic cell transplants (HCTs) following CD34(+) immunomagnetic enrichment, limited T-cell addback and in vivo B-cell depletion. Absolute lymphocyte count recovery was slow to cross the 5th percentile, occurring at a median of 10 months after HCT in patients with full chimaerism. Natural killer cells represented up to 90% of the total lymphoid population during the first 3 months. CD4(+) lymphocyte recovery occurred 9-18 months after HCT. In most patients, CD8(+) lymphocyte recovery was slow and comparable with that of CD4(+) lymphocytes. The CD4(+)/CD8(+) ratio normalised by 3-7 months after HCT in 50% of the patients. CD8(+) lymphocyte recovery was enhanced in patients with viral reactivation. Reconstitution of B-lymphocytes was particularly delayed in patients treated with rituximab. Declining chimaerism, rejection and viral reactivation were the most common problems in our series. Because of the unique graft manipulation, the pace of lymphocyte reconstitution was particularly slow, suggesting that these patients are at a significantly increased risk of infections for up to 2 years after HCT.

Functional abnormalities of heparan sulfate in mucopolysaccharidosis-I are associated with defective biologic activity of FGF-2 on human multipotent progenitor cells.

In mucopolysaccharidosis-I (MPS-I), alpha-L-iduronidase deficiency leads to progressive heparan sulfate (HS) and dermatan sulfate (DS) glycosaminoglycan (GAG) accumulation. The functional consequences of these accumulated molecules are unknown. HS critically influences tissue morphogenesis by binding to and modulating the activity of several cytokines (eg, fibroblast growth factors [FGFs]) involved in developmental patterning. We recently isolated a multipotent progenitor cell from postnatal human bone marrow, which differentiates into cells of all 3 embryonic lineages. The availability of multipotent progenitor cells from healthy volunteers and patients with MPS-I (Hurler syndrome) provides a unique opportunity to directly examine the functional effects of abnormal HS on cytokine-mediated stem-cell proliferation and survival. We demonstrate here that abnormally sulfated HS in Hurler multipotent progenitor cells perturb critical FGF-2-FGFR1-HS interactions, resulting in defective FGF-2-induced proliferation and survival of Hurler multipotent progenitor cells. Both the mitogenic and survival-promoting activities of FGF-2 were restored by substitution of Hurler HS by normal HS. This perturbation of critical HS-cytokine receptor interactions may represent a mechanism by which accumulated HS contributes to the developmental pathophysiology of Hurler syndrome. Similar mechanisms may operate in the pathogenesis of other diseases where structurally abnormal GAGs accumulate.

Africa's wild C4 plant foods and possible early hominid diets.

A small minority of Africa's wild plant foods are C4. These are primarily the seeds of some of the C4 grasses, the rootstocks and stem/leaf bases of some of the C4 sedges (especially papyrus), and the leaves of some of the C4 herbaceous dicots (forbs). These wild food plants are commonly found in disturbed ground and wetlands (particularly the grasses and sedges). Multiple lines of evidence indicate that C4 grasses were present in Africa by at least the late Miocene. It is a reasonable hypothesis that the prehistory of the C4 sedges parallels that of the C4 grasses, but the C4 forbs may not have become common until the late Pleistocene. CAM plants may have a more ancient history, but offer few opportunities for an additional C4-like dietary signal. The environmental reconstructions available for the early South African hominid sites do not indicate the presence of large wetlands, and therefore probably the absence of a strong potential for a C4 plant food diet. However, carbon isotope analyses of tooth enamel from three species of early South African hominids have shown that there was a significant but not dominant contribution of C4 biomass in their diets. Since it appears unlikely that this C4 component could have come predominantly from C4 plant foods, a broad range of potential animal contributors is briefly considered, namely invertebrates, reptiles, birds, and small mammals. It is concluded that the similar average C4 dietary intake seen in the three South African hominid species could have been acquired by differing contributions from the various sources, without the need to assume scavenging or hunting of medium to large grazing ungulates. Effectively similar dominantly dryland paleo-environments may also be part of the explanation. Theoretically, elsewhere in southern and eastern Africa, large wetlands would have offered early hominids greater opportunities for a C4 plant diet.

Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome.

PURPOSE: Hurler syndrome is a debilitating genetic disease with a typical life span of 5 to 8 years. Early hematopoietic stem cell transplantation (HSCT) mitigates disease symptoms and improves survival. However, morbidity and mortality associated with HSCT can limit its success. We describe the initial experience with combined use of enzyme replacement therapy (ERT, laronidase) and HSCT in Hurler syndrome. METHODS: Thirteen transplants were performed in 12 patients. ERT was given at a standard dose of 0.58 mg/kg per week. Transplant conditioning regimen and donor graft source were determined by institutional protocol. RESULTS: The median age at initiation of ERT was 12 months (range, 8 to 18 months). The median duration of pre-HSCT ERT was 12 weeks (range, 4 to 28). All but 1 patient tested showed decrease in urinary GAG excretion during ERT. ERT infusion-related toxicity was limited to mild reactions. Development of antibodies to laronidase did not correlate with infusion reactions or responses in urinary GAG excretion. ERT was given for a median of 7 weeks (range, 3 to 20) after HSCT. After transplantation, eight patients demonstrated complete donor engraftment and four suffered graft failure. Two patients required ventilator support and three developed acute GVHD. Eleven of the 12 patients are surviving with a median follow-up of 3 months (range, 1 to 7 months). CONCLUSIONS: In children with Hurler syndrome, ERT with HSCT is feasible and well tolerated. Development of antibodies against exogenous enzyme does not appear to correlate with infusion reactions or response to ERT. A prospective study is needed to determine the effect of concomitant ERT on transplant outcomes.