High-throughput next-generation RNA sequencing has matured into a viable and powerful method for detecting variations in transcript expression and regulation. Proactive quality control is of critical importance as unanticipated biases, artifacts, or errors can potentially drive false associations and lead to flawed results.We have developed the Quality of RNA-Seq Toolset, or QoRTs, a comprehensive, multifunction toolset that assists in quality control and data processing of high-throughput RNA sequencing data.http://hartleys.github.io/QoRTs.QoRTs generates an unmatched variety of quality control metrics, and can provide cross-comparisons of replicates contrasted by batch, biological sample, or experimental condition, revealing any outliers and/or systematic issues that could drive false associations or otherwise compromise downstream analyses. In addition, QoRTs simultaneously replaces the functionality of numerous other data-processing tools, and can quickly and efficiently generate quality control metrics, coverage counts , and browser tracks. These functions can all be carried out as part of a single unified data-processing/quality control run, greatly reducing both the complexity and the total runtime of the analysis pipeline. The software, source code, and documentation are available online at The online version of this article (doi:10.1186/s12859-015-0670-5) contains supplementary material, which is available to authorized users. High throughput next-generation sequencing of RNA (RNA-Seq) provides an unprecedented volume of transcriptomic information . HoweverIn most cases, major biases will be predictable and can be accounted for in downstream analyses. Many inherent biases will uniformly affect all replicates, and thus may not invalidate cross-sample or cross-condition comparisons, depending on the analysis methodology used –4. In otHowever, RNA-Seq is a complex multi-stage process with numerous potential modes of failure, both known and unknown. Mistakes or inconsistencies in sample prep, library creation, or in sequencing itself could potentially introduce unanticipated artifacts, biases, or errors that could lead to flawed results. In some cases such anomalies will be obvious, but in many cases major artifacts can be obfuscated by the sheer quantity of data involved. In these (presumably rare) instances, it is vital that such issues be detected so that they can be dealt with properly. However, as the full set of all possible problems that could ever arise with this technology is unknown, there is no comprehensive way to automatically test for data quality.Two existing tools, RSeQC and RNA-SeQC, can be used to perform some quality control on RNA-Seq datasets , 8. OtheHere we introduce QoRTs, the Quality of RNA-Seq ToolSet: a comprehensive, multifunction software package that generates a broad array of quality control metrics and allows bioinformaticians to view and compare RNA-Seq data across numerous replicates, organized and differentiated by batch, biological condition, library, read-group, and/or sample .The QoRTs software package consists of two distinct modules: a java package which performs most of the data processing and a companion R package for visualization and cross-replicate comparison. A recommended analysis pipeline is illustrated in Fig. All count files, QC statistics, and browser tracks for a given replicate can be generated using a single command and over a single pass through the alignment file, greatly streamlining the analysis pipeline. If desired, individual sub-functions can be deactivated to reduce runtime.QoRTs is both fast and efficient: it can generate a comprehensive array of quality control metrics, browser tracks, summary plots, and read counts in 3–6 min per million read-pairs. For typical genomes and annotations the QoRTs data processing utility requires less than 4 gigabytes of free memory. The companion R-package (used for generating plots and pdf reports) has much lower resource requirements and can generally run on any desktop computer that can support R.The java package was written in the Scala programming language and uses the Picard sam-jdk API . HoweverQuality control in bioinformatics is a contentious issue, and the necessity and utility of quality control metrics is often called into question. However, across the field of bioinformatics there are numerous cases where biases, artifacts, and other data quality issues have called results into question, sometimes resulting in retractions –19. In mRNA-Seq data in particular has numerous inherent sources of bias including hexamer bias, 3’ bias, GC bias, amplification bias, mapping bias, sequence-specific bias, and fragment-size bias , 6, 21. Without proactive and comprehensive quality control it is not possible to be certain that unobserved errors, biases, or artifacts do not violate the assumptions of downstream analyses.Performing quality control with QoRTs requires two steps. First the (java-based) data-processing module is run on each replicate, and then the companion R package is used for visualization and cross-comparison of replicates.Simple multi-replicate plots that differentiate each replicate individually (as offered in a limited capacity by RSeQC and RNA-SeQC) may be adequate for small sample sizes; however, with larger or more complex studies these plots may be unreadable due to multi-plotting and insufficiently distinct coloration. QoRTs offers the ability to organize and differentiate replicate groups by sample, sequencer-lane/run, or any arbitrary grouping assigned by the user . This allows easier identification of systematic biases and artifacts in large-scale datasets. By default QoRTs produces a battery of 34 plots, which are each described at length in the package user manual  being truncated Fig. , rather For most datasets these plots should not reveal anything of interest: RNA-Seq is a relatively mature technology and large-scale systematic errors should  be rare. However, when such errors do occur it is critical that they be caught before the flawed data is analyzed and the results reported.In addition to its primary function as a quality control tool, QoRTs automatically generates all input read-count files needed for use with a number of differential expression/regulation analysis tools. Gene-level read counts are generated using the same methodology specified by HTSeq and reproduced in the Bioconductor GenomicRanges package (using the default “union” rule) , 27. QoRQoRTs can also  produce a number of browser track files designed for use with the UCSC genome browser or the IGV viewer –30. QoRTQoRTs offers and improves upon many of the features offered by the two other major RNA quality control tools: RSeQC and RNA-SeQC  and RSeQC  were run on these example reads. Much of the resultant QC data generated by RSeQC was found to be inaccurate. Documentation of a subset of these inconsistencies is provided in the supplementary materials : Platform independentProgramming language: R, Java/ScalaOther requirements: Java 1.6 or higher (64-bit), R 3.0.2 or higher.License: This software is “United States Government Work” under the terms of the United States Copyright Act. It was written as part of the authors’ official duties for the United States Government and thus cannot be copyrighted. This software is freely available to the public for use without a copyright notice. Restrictions cannot be placed on its present or future use.


Gamma-hydroxybutyric acid (GHB) and its liquid precursor gamma-butyrolactone (GBL) have become increasingly popular beyond the clubbing culture resulting in daily consumption and dependence in the broader population. This case report illustrates the challenges of managing GHB-withdrawal and a possibly superior future approach of its management by titration and tapering of the addictive agent. Mrs. M. is a 36-year-old Caucasian female with severe GBL-dependence, chronic kidney disease stage V on hemodialysis, and past alcohol, cocaine, amphetamine, and cannabis abuse. The patient is very well known from numerous medical and psychiatric hospitalizations. Once again, Mrs. M. presented to the emergency room of the University Hospital Zurich in GHB-withdrawal with subsequent delirium.As she missed her hemodialysis when intoxicated, the patient was urgently hemodialyzed with no improvement in mental status. At that point, her mental status was severely impaired. She was lying on a stretcher, restless and unable to cooperate, grasping for two small brown glass bottles in her bag. Her consciousness was clouded, attention, concentration, and memory were severely impaired, and she was not able to produce a single meaningful sentence. Her thought process was incoherent as well as impoverished and no evidence for hallucinations or delusions existed. Her psychomotor behavior was restless and lacked goal direction, her affect was flat, impulsivity was nonexistent, and judgment and insight were severely impaired.Laboratory studies revealed a mild known anemia; the hemoglobin was 114 g/L and hematocrit was 31.4% and mean corpuscular hemoglobin (MCH) as well as mean corpuscular hemoglobin concentration (MCHC) was increased. Electrolytes, liver function tests, and the remaining laboratory results were within normal limits. The EKG revealed a previously documented unspecific S-T elevation, and the urine toxicology tested only positive for GHB.Mrs. M. was very well known to the hospital from previous admissions in GBL-withdrawal and associated delirium. She was managed and detoxified several times with oral and intravenous benzodiazepines. In those instances, the management course was challenging and complicated, with severe behavioral disturbances requiring intensive personal assistance in order to avert adverse outcomes. The withdrawal syndrome and delirium responded insufficiently due to the differences in pharmacodynamics between GHB and benzodiazepines. Even more, with oral and intravenous detoxification the hospitalization lasted on average more than a week resulting in significant health care costs.As the patient obviously attempted to reach for her GBL-bottles, she was assisted in self-administration of GBL. The patient was aided in administration of 2–4 mL every 5 minutes, totaling approximately 20 mL over the next half hour. In this process her mental status cleared, the disturbance of consciousness remitted, orientation and cognition recovered, thought process and psychomotor behavior normalized, and decisional capacity was restored. Then she admitted to consumption of 40 mL GBL prior to hemodialysis. Despite recommendations to consider further detoxification and rehabilitation, the patient decided to leave the hospital against medical advice and since then has not presented again over the next weeks.Among the admissions for GHB-withdrawal, the self-administration and titration of GBL presented the most efficient and cost effective approach.Initially GHB has been developed as an anesthetic and developed into a popular psychoactive drug in the clubbing scene . SummariB-receptor. The agonistic effect at the GHB-receptor is excitatory and the weak antagonistic effect at the GABAB-receptor is inhibitory. Activation of both receptors—GHB and GABAB—causes the addictive properties. The activation of the GHB-receptor causes the release of glutamate. The release of dopamine is biphasic: low doses stimulate dopamine release via the GHB-receptor, whereas higher concentrations then inhibit dopamine release via the GABAB-receptor and, eventually, after an initial phase of inhibition, dopamine release is again increased via the GHB-receptor.At least two distinct binding sites have been identified, the GHB-receptor and GABAB-receptor, a high affinity binding site at the inotropic αβδ-GABAA-receptor site has been identified. However, the precise role of this high-affinity binding site still remains elusive [More recently, in addition to the action at the low-affinity metabotropic GABA elusive , 6.B-receptor, benzodiazepines are indirect GABAA-agonists explaining the requirement for high doses of benzodiazepines [Addiction occurs when prolonged and repeated GHB use disrupts the balance of brain transmitters and circuits controlling reward, memory, and cognition leading to compulsive use. The duration of clinical effects is dose-dependent and ranges from 2.5 to 4 hours. The early GHB-withdrawal syndrome resembles the alcohol withdrawal syndrome which is associated with autonomic instability, tremor, restlessness, anxiety, and sleeping disorders. GHB-withdrawal usually lasts 3 to 21 days. Severe withdrawal syndromes can also produce acute delirium requiring hospitalization, often leading to intensive care management and possible fatal outcome. Important differential diagnoses for GHB-withdrawal syndrome include alcohol or benzodiazepine withdrawal, delirium caused by somatic conditions, neuroleptic malignant syndrome, and serotonin syndrome [azepines . To dateazepines .B-receptor in the case of GHB and the GABAA-receptor in the case of benzodiazepines, very high doses of benzodiazepine administered over several days may be required without fully achieving symptom control, causing distress for patient and staff as well as a potentially fatal outcome. The exact contribution of activity of the high-affinity αβδ-GABAA-receptor site of GHB still remains elusive in the withdrawal process.The case of Mrs. M. illustrates the challenges of managing GHB-withdrawal and potentially life-threatening complications such as rhabdomyolysis, seizures, bradycardia, and cardiac arrest. Due to the different pharmacodynamic mechanisms involving the GABAThe administration of related compounds such as the use of benzodiazepine in alcohol withdrawal indicates that the administration of GHB could be a superior management approach reducing distress, length of hospitalization, and health care costs. Even further, similar to methadone maintenance, the controlled administration of GHB could be a future perspective for these patients.In summary, in this case, self-administration of GBL represented the superior management approach for GHB-dependence, GHB-withdrawal, and delirium exceeding the effectiveness of benzodiazepine administered orally or intravenously. Although the administration of GBL—which is illegal in most legislatures—cannot be a routine approach, the administration of GHB, the metabolite of GBL, represents a viable option. The administration of GHB could be the future approach for the management of GHB-dependence, GHB-withdrawal, and GHB-induced delirium. The implications on length of stay and health care cost have not yet been assessed and merited further investigation.


In the present study, we investigated the association between Non-Suicidal Self-Injury (NSSI) and the UPPS-P impulsivity facets in eating disorder patients and healthy controls. The prevalence of NSSI in eating disorder (ED) patients ranged from 17% in restrictive anorexia nervosa (AN-R) patients to 43% in patients with bulimia nervosa (BN). In healthy controls (HC), the prevalence of NSSI was 19%. Eating disorder patients from the binge eating/purging type showed significantly more NSSI compared to restrictive ED and HC participants. Binge-eating/purging ED patients also scored significantly higher on Negative/Positive Urgency, Lack of Premeditation and Lack of Perseverance compared to HC and restrictive ED patients. Comparable findings were found between ED patients and HC with and without NSSI; ED patients and HC with NSSI scored significantly higher in four of the five UPPS-P dimensions compared to participants without NSSI; Sensation Seeking was the exception. Finally, the presence of NSSI in HC/ED patients was particularly predicted by low levels of Perseverance. Therefore, the treatment of ED patients with NSSI certainly needs to focus on the training of effortful control. Non-suicidal self-injury (NSSI) refers to the deliberate and direct injury of one’s own body tissue without suicidal intent , such asIn recent years, several studies have investigated the association between eating disorder symptoms and the UPPS(-P) dimensions in community and clinical samples. In a review paper of Fischer et al. ,12, NegaSimilarly, several studies have investigated the association between the presence/absence of NSSI and the UPPS-P dimensions in community and clinical samples. Glenn and Klonsky , showed The aim of the present study was to integrate these two lines of research into one study. First, we wanted to investigate the prevalence of NSSI in different subtypes of ED patients and healthy controls. Based on the literature we expected prevalence rates between 25.4% and 55.2%, with a slightly higher prevalence of binge-eating/purging ED patients . Second,The sample was recruited between January 2012 and July 2014. The total sample consisted of 481 participants: 113 healthy controls  and 368  ED patients. Given the small number of male participants, they were removed from our sample, leaving a total of 438 female participants. Additionally, 43 ED patients with Binge Eating Disorder (BED) were removed, due to the fact that they were significantly older  and weighed significantly more  compared to other ED patients and that the relevant literature did not pertain to BED. Finally, from the remaining 395 participants, 57  were removed due to missing data on the variable Non-Suicidal Self-Injury. The final sample consisted of 338 female participants: 84 HC and 254 ED patients.SD = 8.38), and statistical differences appeared in an ANOVA comparison : significant pairwise comparisons were obtained for AN-R versus AN-BP patients  and AN-R vs BN patients . Mean age was 28.15 (SD = 9.47) in ED and 21.33 (SD = 6.63) in HC . Between the groups there were no significant differences found in mean BMI . Within the ED subtypes, no significant differences for age were found  = 0.89, p =. 449). However, within ED subtypes as expected, significant results were obtained in the ANOVA for the BMI mean comparison  = 36,71, p <. 001): pairwise comparisons showed significant contrasts for AN-R compared to BN , AN-R compared to EDNOS , AN-BP compared to BN , AN-BP compared to EDNOS  and BN compared to EDNOS .The ED patients were consecutive referrals for assessment and treatment at the Department of Psychiatry of the University Hospital of Bellvitge in Barcelona. All participants were diagnosed according to the DSM-IV-TR diagnostic criteria  by meansThe final sample of female HC consisted of 84 participants. Healthy controls were recruited via advertisements in the Health Sciences Bellvitge Campus of the University of Barcelona. All HC were from the same catchment areas as the ED patients. Prior to questionnaire assessment, HC were interviewed about their lifetime history of health or mental diseases (including EDs) by means of the General Health Questionnaire-28 (GHQ-28)  and specAll participants were informed about the research procedures and gave informed consent in writing and signed. Procedures were approved by the Ethical Committee of the University Hospital of Bellvitge.Information concerning socio-demographic variables  and ED characteristics  was assessed by means of a semi-structured clinical interview.The presence/absence of NSSI was investigated by a 1-item question asking, “Have you ever engaged in self-injury without the intent to die?” Using a single-item measure of NSSI is common in NSSI research and has been shown to render consistent estimates of prevalence .To assess impulsivity facets the Spanish version of the UPPS-P Impulsivity Scale ,23 was u2 test statistic was used. Differences in UPPS-P impulsivity facet scores in function of the presence/absence of NSSI, HC/ED subtypes  and their interaction were investigated by means of a multivariate analysis of variance (ANOVA) controlled for the participants’ age. For non-significant interaction NSSI*Group, main effects were estimated and interpreted, while single effects were obtained and interpreted for significant interaction parameters. One independent ANOVA procedure was conducted for each UPPS-P scale and the Simes-Bonferroni method was used to control Type-I error due to multiple comparisons . Post-hoc comparison between diagnostic subtypes indicated that prevalence of NSSI in the HC group was not significantly different from the AN-R group , but the NSSI prevalence was lower in HC when compared to AN-BP , BN  and EDNOS . Among the ED subtypes, AN-R showed lower prevalence than AN-BP , BN  and EDNOS , while equal prevalence rates were obtained for AN-BP, BN and EDNOS.p =. 020)  see .In the present study, we investigated the association between NSSI and the UPPS-P model of impulsivity in a sample of eating disorder patients and healthy controls. The prevalence rates of NSSI in ED patients ranged from 17% (in AN-R) to 43% (in BN), and was situated around 19% in HC, hereby confirming international prevalence rates of NSSI in ED patients and healthy controls [One of the possible explanations of the higher frequency of NSSI in binge-eating/purging ED patients, is the hypothesis that binge-eating/purging ED patients are more impulsive than restrictive AN patients and healthy controls –28. The Similar results were found when we compared participants with and without NSSI. Participants with NSSI scored significantly higher on negative/positive urgency, lack of premeditation and lack of perseverance, confirming previous findings on the association between NSSI and impulsivity in ED patients ,28. The Finally, taking into account all UPPS-P dimensions while predicting NSSI, Lack of Perseverance was the most important predictor. Problems in continuing a difficult task, such as resisting the temptation to engage in NSSI (lack of perseverance) make ED patients and healthy controls vulnerable to engagement in NSSI. Treatment of these patients and healthy controls should therefore focus on impulse regulation to resist the urge to injure (as described previously ). Given By training impulse (and related emotion) regulation to prevent people from engaging in NSSI, these skills can hopefully be transferred to the domain of ED symptoms, such as binging and purging, which are driven by the same impulsivity dimensions. The fact that both NSSI and BN/BED symptoms share some common impulsivity pathways can also explain the balance between these symptoms while treating them . When thSome limitations of the present study warrant discussion. First, the sample consists of female HC/ED participants, who represent only a subset of self-injurious individuals. Second, our study was based on self-report measures, which can increase the association between variables due to shared method variance. Finally, due to the cross-sectional design of the study, the temporal relationship of UPPS-dimensions and NSSI is unclear. For example, the performance of NSSI may dispose individuals to rate themselves as having impulsive characteristics. Therefore, future studies should include an equal ratio of male/female HC/ED individuals who are assessed by means of self-report and additional assessment techniques (e.g. performance-based measures of NSSI and impulsivity) and should investigate the association between the UPPS-P dimensions and NSSI over time to draw conclusions about the directionality of the relationship.In sum, our study showed that binge-eating purging ED individuals showed an increased probability of engaging in NSSI which appears to be related to heightened levels of Lack of Premeditation (i.e. the inability to ignore distracting stimuli or to remain focused on particular tasks). Therefore, the treatment of both NSSI as well as eating disorders may benefit from impulse- (and related emotion) regulation interventions.


Chitosan, which is derived from a deacetylation reaction of chitin, has attractive antimicrobial activity. However, chitosan applications as a biocide are only effective in acidic medium due to its low solubility in neutral and basic conditions. Also, the positive charges carried by the protonated amine groups of chitosan (in acidic conditions) that are the driving force for its solubilization are also associated with its antimicrobial activity. Therefore, chemical modifications of chitosan are required to enhance its solubility and broaden the spectrum of its applications, including as biocide. Quaternization on the nitrogen atom of chitosan is the most used route to render water-soluble chitosan-derivatives, especially at physiological pH conditions. Recent reports in the literature demonstrate that such chitosan-derivatives present excellent antimicrobial activity due to permanent positive charge on nitrogen atoms side-bonded to the polymer backbone. This review presents some relevant work regarding the use of quaternized chitosan-derivatives obtained by different synthetic paths in applications as antimicrobial agents. The diseases caused by these microorganisms provoke serious health problems that in severe cases lead to death. Diseases related to the proliferation of microorganisms are particularly significant in hospitals where the risk of infection by microorganisms is a major concern, mainly when complicated surgical procedures are conducted. However, illnesses caused by poor personal hygiene and rotten or contaminated food should also be considered an important issue . Ot. OtN-hyde (EDAC) . In thisobtained . Li eta  from 6.0% to 30% were prepared by reacting amino groups of chitosan with arginine . These cronments .etal.  in its structure . Un. UnN-monted to 8   chitosan chloride (HTACC) exhibits antibacterial activity, as soluble in liquid (solution) and in solid, and as coated onto others materials [etal. [E.coli and S.aureus [operties ,91. Foll [etal.  developet pH 7.4 . Therefot pH 7.4 . N-[(2-hE.coli) and gram-positive bacteria (S.aureus) [etal. [S.aureus (ATCC 749). Thus, the nanofibers coated with TMC (polycationic polymer) mats are promising for wound-healing applications [Electrospinning is an ideal technique for producing polymer fibers with diameters down to nanoscale range and micro- and nanofibrous materials are appropriate for obtaining wound dressings ,92,93. Betal. [etal. [Chitosan is: (i) Obtained through deacetylation from chitin, the most abundant polysaccharide in the world after cellulose and thus obtainable from renewable sources; (ii) Capable of being modified using multiple alternatives for chitosan-chemical modifications that provide different desirable properties, such as good solubility at neutral and basic media; and (iii) Often, along with chitosan-derivatives, capable of significant antimicrobial activity, most of them often biocompatible; this makes chitosan, chitosan-derivatives and materials based on chitosan or chitosan derivatives excellent material alternatives for application as antimicrobial agents in different developed fields such as the food , medicaletal.  publisheetal. . Consume [etal.  provided [etal. . Modific [etal. , supportGiven its doubtless potential in the field, the following can be stated: systems based on “release on command”, in which an antimicrobial agent is released at the same time as the microbial growth occurs, will be disseminated in the future on antimicrobial materials associated to high technology. The concept of this technology is that when any change in the medium such as pH, temperature or UV light occurs , the antimicrobial system responds promptly and accordingly. Therefore, such a system turns active only in response to very specific conditions. This type of system is based on bioactive compounds, where release is triggered at the time and place where needed. In the case of antimicrobial agents, the consensus is that they will be released if one or more type of bacterial growth occurs, thus inhibiting growth of the emerging bacteria. This would, of course, enable a decrease in the active agent concentrations needed for effective effects.N-quaternization and/or O,N-quaternization are the most used ways to modify chitosan resulting in a water-soluble chitosan-derivative in a wide pH range including neutral and basic conditions. Such chitosan-derivatives present excellent antimicrobial activity due to permanent positive charges on the polymer backbone. The antimicrobial activity provided by chitosan, chitosan derivatives and chitosan-based materials is especially relevant. Various wide-ranging antimicrobial chitosan, chitosan-derivatives and chitosan-based materials exhibiting potent antimicrobial activity through membrane-lysis mechanisms have been described in this review. The uses of antimicrobial agents such as chitosan and chitosan-derivatives are likely to grow steadily in the future because of greater consumer demands for materials  with minimal possibility of microbial infections. New studies to enlarge the number of chitosan-derivatives with still higher antimicrobial effects are needed. In summary, this review is an attempt to show that chitosan, chitosan-derivatives and chitosan-based materials are value-added if the target is the developing of antimicrobial agents for use in different technological fields, providing modern society with new prospects for healthy aging and a higher quality of life.


The prevalence of obesity is disproportionately higher among African-Americans and Hispanics as compared to whites. We investigated the role of biogeographic ancestry (BGA) on adiposity and changes in adiposity in the Boston Area Community Health Survey.We evaluated associations between BGA, assessed via Ancestry Informative Markers, and adiposity (body mass index (BMI), percent body fat (PBF), and waist-to-hip ratio (WHR)) and changes in adiposity over 7 years for BMI and WHR and 2.5 years for PBF, per 10% greater proportion of BGA using multivariable linear regression. We also examined effect-modification by demographic and socio-behavioral variables.p-interaction: <0.002) with a substantially greater association in women. We observed no main associations between Native-American ancestry and adiposity but observed significant effect-modification of the association with BMI by diet (p-interaction: <0.003) with inverse associations among participants with higher Healthy Eating Scores. No associations were observed between BGA and changes in adiposity over time.We observed positive associations between West-African ancestry and cross-sectional BMI , and PBF . We also observed significant effect-modification of the association between West-African ancestry and BMI by gender (Findings support that West-African ancestry may contribute to high prevalence of total body adiposity among African-Americans, particularly African-American women. Obesity is a major public health concern which significantly increases one’s risk for adverse health including type II diabetes, cardiovascular disease, musculoskeletal disorders  and deprThe genetic basis for racial/ethnic disparities in adiposity and metabolic disease could be explained by the thrifty gene hypothesis which was first proposed in 1960’s . AccordiAncestral Informative Markers (AIMs), i.e., genetic markers unique to people of a homogenous BGA, are often used as correlates of self-identified race in studies performed in admixed populations –7, 12–19Given these contradictory findings, we sought to further evaluate the relationship between BGA and adiposity using different measures of adiposity, i.e., BMI, percent body fat (PBF), and WHR, including changes in these measures over time, in the Boston Area Community Health (BACH) Survey. A previous study performed on the BACH I cohort 2000–2002) found a positive association between African-American race and obesity as well as significant effect-modification of this association by gender 00–2002 f, 21–23, The Boston Area Community Health (BACH) Survey is a population-based prospective cohort study that has recruited approximately equal proportions of non-Hispanic white, non-Hispanic black, and Hispanic-American participants from Boston, MA, using multistage stratified cluster sampling. As detailed elsewhere , 25, thiDuring all three waves, study participants were interviewed in their homes in English or Spanish, and anthropomorphic measurements including height, weight, waist circumference, and hip circumference were taken by trained interviewers. PBF was also assessed during BACH II and BACH III. In addition, data on multiple socio-economic and behavioral factors, co-morbidities, and medication use were collected. During BACH III, investigators also obtained blood samples from participants to determine the proportion of allelic markers. Of the 3,155 participants who participated in the third follow-up survey (BACH III), we excluded participants who reported weight loss in the absence of decreased food intake or increased exercise (n = 409), who were pregnant (n = 1), had diagnosed or undiagnosed diabetes (n = 980), ever had congestive heart failure (n = 142) at the BACH III survey, or reported ever having had a diagnosis of AIDS (n = 19), cancer (n = 283), chronic lung disease (n = 235), or Alzheimer’s disease (n = 12) at the BACH I survey, as these conditions could result in weight change. Even though we were unable to exclude individuals with end-stage renal disease due to lack of information, few, if any, such individuals would have been sufficiently healthy to have been recruited to the BACH study. We were left with 1,726 participants for the analyses. Of these, 654 were self-identified non-Hispanic white participants, while 531 and 541 were self-identified black and Hispanic-Americans, respectively. All participants provided written informed consent. This study was approved by the New England Research Institutes’ Institutional Review Board.http://www.genetics.ucla.edu/software/admixture/).A total of 63 allelic markers, i.e., single nucleotide polymorphisms (SNPs) selected on their ability to estimate percent West-African and Native-American BGA, were genotyped by the Genetic Analysis Platform at the Broad Institute in Cambridge, MA using iPLEX (Sequenom). Ancestry percentages were estimated for each participant using ADMIXTURE software (v. 1.12 2). WHR was calculated by dividing waist circumference (cm) by hip circumference (cm). At BACH II and III PBF was measured via bioelectrical impedance using the Tanita scale. We calculated the percent changes in BMI and WHR between waves I and III of the BACH Survey over a mean duration of approximately seven years, and percent changes in PBF between waves II and III over a mean duration of approximately 2.5 years.At BACH I and III, BMI was calculated by dividing weight (kg) by height squared , occupation , and education  using cut-offs based on prior studies [Data on socio-economic and behavioral factors for this analysis were obtained from the BACH III assessment. For socio-economic variables, we grouped participants into categories of  studies .nutritional intake, we administered the Block Food Frequency Questionnaire (FFQ) in English or Spanish, and rated each participant’s dietary intake on a scale from 0 to 7. The FFQ Score was determined by summing up points assigned to participants based on the average daily intake of sodium , fiber , saturated fat , and the average number of daily servings of vegetables , fruits , meat , and grain . The cutoff values were based on United States Department of Agriculture [In order to assess each participant’s iculture  and Americulture . As mostphysical activity by using the Physical Activity Scale for the Elderly (PHASE) [We measured  (PHASE) . This 12In order to minimize potential biases and reduction in precision due to missing data, we performed multiple imputations using Multivariate Imputation by Chained Equations (MICE)  in R . The data were weighted by the inverse of the probability of being sampled at baseline (BACH I) to account for oversampling of minority groups. We observed greater attrition among men and participants in the lower socio-economic strata. Thus, the analyses were also adjusted for non-response and loss-to-follow-up using the propensity cell adjustment approach , and posWe assessed all outcomes per 10% rather than 1% greater proportion of genetic ancestry to avoid reporting small effect-estimates. We log-transformed cross-sectional BMI and presented the effects as a percent difference per 10% greater proportion of BGA, as the distribution of its residuals deviated from normality. All other outcome residuals were normally distributed. We performed univariable and multivariable linear regressions to assess outcomes associated with West-African and Native-American ancestry. We also evaluated for effect-modification by age, gender, diet, physical activity, income, and education by including interaction terms between these variables and the exposures in separate models.p <0.05 using a two-tailed test. In order to account for multiple comparison complexities resulting from examining six different adiposity outcomes in the overall population and different sub-populations, we also assessed our results applying more stringent criteria of p<0.008 for statistical significance .Statistical significance for all analyses was initially set at 2 vs. 27 kg/m2), PBF (36–38% vs. 33%), and slightly higher WHR (0.90 vs. 0.89) among African-Americans and Hispanic-Americans compared to non-Hispanic whites. Hispanic participants had larger increases in all longitudinal measures of adiposity  than did African-American or white participants, who had approximately equal median percent increases in BMI (0.8–0.9%) and WHR (3.6–3.7%), and no increase in PBF.At BACH I, 76.6% and 69.2% of blacks and Hispanics were overweight or obese, respectively, compared to 61.5% of whites. A greater proportion of Hispanics compared to white or black participants moved from normal to overweight/obese BMI categories between BACH I and III, with 80.7%, 80.6%, and 67.1% of Hispanic, black, and white participants overweight or obese at BACH III. In the unweighted cross-sectional data, we observed a higher median BMI (29 kg/mp<0.0005). The strength and significance of this association remained after adjusting for age and gender. However, additionally adjusting for socio-economic and behavioral variables reduced the difference to 0.62% (p = 0.04), which failed to reach the level of statistical significance required to account for multiple comparisons (p<0.008). This reduction was mostly due to adjustment for educational level and income. We observed no association between BMI and Native-American ancestry. In the multivariable analyses for cross-sectional BMI, approximately 8% of the total variance was attributable to West-African ancestry and approximately 8% to Native-American ancestry.p<0.004). No associations were observed between Native-American ancestry and PBF in the unadjusted or adjusted analyses.We also observed positive associations between PBF and West-African ancestry in the unadjusted and adjusted analyses . The attenuation of the effect estimate in the multivariable analysis was mostly due to adjustment for educational level which was inversely associated with the outcome  (p<0.004). Of note, West-African and Native-American BGA were inversely associated with a higher educational level  and higher income  in this study population.Among socio-economic and behavioral variables associated with higher cross-sectional measures of adiposity, we observed significant inverse associations with higher educational status for BMI (p<0.01)  and PBF The strengths of positive associations were somewhat diminished when analyses were repeated in the entire cohort without applying exclusion criteria. However, the directionality and significance of the results remained unchanged. Similarly, when analyses were repeated including participants with type II diabetes, the effect estimates were slightly diminished but the overall results were essentially unchanged.p-interaction = 0.0019). Similar, albeit less significant, interactions were observed when PBF (p-interaction = 0.04) or WHR (p-interaction = 0.02) were used as the measure of adiposity. In the analyses stratified by gender  and gender and income . We observed a positive association between West-African genetic ancestry and BMI among women without a college degree , while no such association was observed among women of a higher educational level  or among men of any educational level . Similar patterns were observed for associations between West-African ancestry and PBF for analyses stratified by gender and educational level, and for West-African ancestry and BMI for analyses stratified by gender and income level.p-interaction = 0.0023). However, interactions between Native-American ancestry and diet were significant only at the p<0.05 level when PBF (p-interaction = 0.04) or WHR (p-interaction = 0.01) were used as the measures of adiposity , or with PBF over a mean follow-up duration of approximately 2.5 years (median percent change of 0.00%). However, we are unable to rule out the possibility of detecting such associations over longer periods of follow-up.We observed evidence of effect modification by gender for associations between West-African ancestry and cross-sectional measures of adiposity with greater risk among women. Furthermore, this effect was restricted to women of a lower socio-economic status. These findings indicate that West-African ancestry confers higher risk of adiposity among women of West-African descent as compared to men of the same ancestral background despite a similar prevalence of adiposity genes across both groups, perhaps due to biological differences between men and women; access to education and other resources may counteract this effect. Given the greater difference in the proportions of African-American women as compared to African-American men in the lower vs. higher income categories  and lower vs. higher educational categories , it is also likely that these results reflect the differential distribution of socio-economic variables strongly associated with adiposity among men and women of West-African descent.These data concur with recent patterns of obesity prevalence in the U.S. The NHANES 2011–2012 Survey report described a substantially greater prevalence of obesity among African-American women compared to African-American men (56.6% vs. 37.1%) [We also observed evidence of effect-modification of associations between Native-American ancestry and adiposity by diet despite the relatively low proportion of Native-American ancestral markers in this population. Individuals with a Native-American ancestry who had relatively high Healthy Eating Scores, but not low scores, had negative associations with all cross-sectional measures of adiposity, albeit not all results achieved statistical significance. Further research should investigate the impact of diet on associations between Native-American ancestry and adiposity. The relatively low threshold used (FFQ Score ≥2) in our study to define healthy eating, would suggest that even a small-moderate improvement in diet may be beneficial in this subpopulation.p<0.008).Our study is not without limitations. First, the BACH study population consisted of no self-identified Native-American participants and thus, had a low prevalence of Native-American AIMs. This may have precluded us from detecting possible associations between Native-American ancestry and adiposity as were observed in other study populations , 32. SecThe strengths of this study include evaluation of multiple measures of adiposity specifically BMI, WHR, and PBF assessed cross-sectionally and over time. While the clinical meaning and utility of the different measures of adiposity likely differ by race/ethnicity, consistent patterns across different measures, as were observed in regard to BMI and PBF among participants of West-African descent in our study population, strengthen the hypothesis that West-African ancestry is associated with increased total body adiposity. In addition, to our knowledge, this was the first study to report on interactions between BGA and non-genetic factors that contribute to adiposity and which could help explain the high prevalence of adiposity in distinct populations.We observed elevated risk of overall adiposity among participants with West-African ancestry which was stronger among female participants. Our results also suggested greater protective effects of healthy eating on adiposity for participants of Native-American descent. However, these analyses should be repeated in cohorts with a greater proportion of participants of Native-American BGA in order to confirm our findings. These results also call for the evaluation of longitudinal outcomes of adiposity in cohorts with longer follow-up.S1 TableThis table presents the associations between variables included in the multivariable model and BMI.(PDF)Click here for additional data file.


Pre-operative imaging techniques are essential for tumor detection and diagnosis, but offer limited help during surgery. Recently, the applicability of imaging during oncologic surgery has been recognized, using near-infrared fluorescent dyes conjugated to targeting antibodies, peptides, or other vehicles. Image-guided oncologic surgery (IGOS) assists the surgeFon to distinguish tumor from normal tissue during operation, and can aid in recognizing vital structures. IGOS relies on an optimized combination of a dedicated fluorescent camera system and specific probes for targeting. IGOS probes for clinical use are not widely available yet, but numerous pre-clinical studies have been published and clinical trials are being established or prepared. Most of the investigated probes are based on antibodies or peptides against proteins on the membranes of malignant cells, whereas others are directed against stromal cells. Targeting stroma cells for IGOS has several advantages. Besides the high stromal content in more aggressive tumor types, the stroma is often primarily located at the periphery/invasive front of the tumor, which makes stromal targets particularly suited for imaging purposes. Moreover, because stroma up-regulation is a physiological reaction, most proteins to be targeted on these cells are “universal” and not derived from a specific genetic variation, as is the case with many upregulated proteins on malignant cancer cells. Diagnosis, staging, and surgical planning of cancer patients increasingly rely on non-invasive pre-operative imaging techniques that provide information about tumor biology and anatomical structures –3. PreseIn contrast to SPECT and PET, near-infrared fluorescence-guided oncologic surgery (NIRF-IGOS) is a real-time intraoperative imaging technique. NIRF-IGOS is introduced and validated in the clinic for sentinel lymph node mapping and biliary imaging and has the potential to significantly revolutionize image-guided surgery due to its key principles –16: firswww.transparencymarketresearch.com). The first open NIRF camera systems mentioned in the literature are the SPY (2003)  , PhotodyY (2003) ; all witY (2003) . The priY (2003) . BesidesY (2003) , head-anY (2003) , brain, Y (2003) . MoreoveY (2003) , 29, detY (2003) –32. AlsoY (2003) .NIRF-IGOSome tumor types over-express specific membranous proteins, like Her2/Neu for Her2 positive breast cancers and PMSA receptor or folate receptor-α as present in the majority of prostate and ovarian cancers, respectively. These targets are particularly suited for selective targeting –36. UnfoOur survival studies in which breast, colon, and esophageal tumors were stratified as stroma-poor (≤50%) and stroma-rich (>50%), not only indicated a strong impact of the stromal contribution to tumor behavior, but also revealed that many tumor (types) consist for a substantial part of stroma –42. Withvβ3 integrin and matrix metalloproteinase MMP-2 and MMP-9. The αvβ3 integrin has been successfully targeted in many pre-clinical and clinical imaging studies using the peptide sequence arginine–glycine–aspartic acid (RGD), conjugated with nuclear as well as (NIR) fluorescent labels . Another promising candidate target against tumor endothelium is endoglin or CD105. Pre-clinical studies in mice models have shown positive results with antibodies conjugated with PET and NIRF labels , 4847, 4t labels –54. First labels . ClinicaF labels , 57. DosNext to endothelial cells, the tumor microenvironment consists mainly of immune cells and fibroblasts, both with their own intra-tumoral distribution as schematically shown in Figure Fibroblasts, in particular, the cancer-associated fibroblasts or CAFs, are the most abundant non-immune cell type in the tumor microenvironment. CAFs are believed to develop from various origin cells and have similar characteristics as myofibroblasts , 70. Thein vitro validation of the affinity/efficiency of anti-stroma cell NIRF probes can very well be established using cultures of human stromal cells. But the use of relatively simple xenograft models of human tumor cells in immunocompromised mice, as the ultimate in vivo proof before clinical studies, is not easily applicable for stromal cells protein will be targeted and what kind of targeting vehicle will be used to target with. As indicated above, the selection of the target seems of key importance, but also for the format of the targeting vehicle and the conjugated NIRF dye are many options available, each with their own (dis)advantages. Various types of vehicles can be used, ranging from relatively large monoclonal antibodies and antibody fragments to small peptides or RNA/DNA aptamers. Next to conventional monoclonal antibodies, a whole range of recombinant antibodies and antibody fragments are available due to advanced recombinant protein technologies. In fact, because there is no need for the Fc part of antibodies for the purpose of imaging, the antibody format has become completely dispensable, leading to a range of over 20 different non-IgG-based scaffolds such as Affimers, DARPins, and Centyrins , 83. Theintegrin , 50, 86.integrin , 88. Butpolarity , 90.An interesting development is the engineering of targeting vehicles that can be equipped with multiple labels. A powerful synergy can be achieved when nuclear and fluorescent imaging methods are combined, extending the pre-operative nuclear diagnostic images with real-time intraoperative imaging, leading to improved diagnosis and patient management. A number of pre-clinical studies have indicated the versatility of this concept , 91. Cliin vivo animal models to evaluate newly developed targeting probes seems to become the most crucial step.Within the next years, NIRF-based imaging will develop into one of the most valuable tools for oncologic surgeons. The evolution of the technique relies on the development of camera systems and specific targeting probes and several hurdles still have to be taken. The rapid technical developments considering LED-technology, optics, and camera systems, combined with the latest advances in image processing, warrants a prosperous contribution of the hardware. The quest for the best target(s), however, is only just begun, and also the most optimal targeting vehicle still has to be determined. The development of proper MB and CS drafted the outlines of the review. MB designed the Figures and all authors contributed to the writing and approved the final version.The authors declare the absence of any commercial or financial relationships that could be construed as potential conflict of interest.


Extracellular vesicles (EVs) play important roles in intercellular communications via their content molecules, and mimic, at least in part, the roles that are played by their originating cells. Consistent with this notion, an increasing number of reports have suggested that EVs derived from mesenchymal stem cells (MSCs), which are therapeutically beneficial to a wide range of diseases, can serve as drugs to treat multiple diseases. EVs contain a variety of molecules, including proteins, microRNAs, and mRNAs, and are associated with biological processes in a content molecule-dependent manner. In this article, we review the latest reports regarding the therapeutic potential of MSC-EVs by focusing on the underlying molecular mechanisms of their effects. Specifically, we feature the effects of MSC-EVs in terms of their content molecules and of the tissue recovery processes endowed by these molecules. Interest in extracellular vesicles (EVs), lipid-bilayered vesicles that are secreted by various types of cells, as novel carriers for drug delivery systems has increased. In a broad sense, EVs include all types of vesicles that exist in the extracellular space. In particular, 50–200 nm EVs, usually termed exosomes  and shedExtracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have therapeutic benefits against multiple diseases –5. MesenIn this article, we review the latest reports regarding the therapeutic potential of MSC-EVs from the point of view of their content molecules. To this end, we classify their content molecules into three groups: proteins, RNAs, and undefined molecules. The possible molecular mechanisms underlying MSC-EV-mediated therapeutic effects are discussed Fig. . We alsoEvidence for biological functions of EV proteins was first provided by immunology studies in the late 1990s –10. TherMSC-EVs primarily seem to support the proliferation and apoptosis avoidance of surviving tissue cells by modulating intracellular signaling pathways. The earliest studies found that the therapeutic effect of MSC-derived paracrine factors on myocardial ischemia/reperfusion injury (MIR) is largely ascribed to EV fractions , 19. AltEVs allow MSC-derived membrane enzymes with therapeutic potential to have a unique functional mode. Our group reported that adipose tissue-derived mesenchymal stem cell (ADSC)-EVs contain enzymatically active neprilysin , the rate-limiting amyloid beta (Aβ)-degrading enzyme in the brain . CocultuOne of the most attractive characteristics of EVs is their ability to transfer RNAs from one cell to another, thereby allowing the transferred RNAs to affect the recipient cells. Between 2006 and 2007, a sensational finding demonstrated that EV cargo mRNAs can be transferred and translated to proteins in recipient cells , 25. FurAlthough more precise analyses are required, MSC-EV mRNAs are regarded as therapeutically beneficial in injured tissue recovery. The first evidence for the therapeutic effects of MSC-EVs was provided for kidney injury. Intriguingly, the therapeutic effects of MSC-EVs were partly mediated by the packaged mRNAs, which were suggested to be associated with proliferation, transcription regulation, and immunomodulation –31. AnotmiRNAs are also proposed to be key molecules that are responsible for MSC-EV-mediated therapeutic potential. miR-133b, a regulator of tyrosine hydroxylase production and a dopamine transporter, is the best characterized MSC-EV miRNA with therapeutic effects on cerebral injury. This miRNA was transferred from BM-MSCs to injured neurons and then induced neurite outgrowth and promoted neural plasticity . AlthougDespite the rapidly increasing number of reports regarding the therapeutic effects of MSC-EVs, many lack detailed investigations identifying the molecule(s) responsible for these effects. As summarized in Table +CD25+FoxP3+ regulatory T cells (Tregs) [Because the primary focus of this article is the molecular mechanisms underlying the therapeutic effects of MSC-EVs from the point of view of their content molecules, we do not provide a detailed review of those reports that have not elucidated the responsible molecules. Nevertheless, considering that these reports provide much insight, we will highlight some of them here. In a mouse model of allogeneic skin grafts, MSC-EVs contributed to immunosuppression by increasing the number of CD4 (Tregs) . This im (Tregs) . These t (Tregs)  reported (Tregs) . Islam e (Tregs)  claim th (Tregs)  identifi (Tregs) , 52, 53.In the next few years, exploring and understanding more comprehensively the therapeutic effects of MSC-EVs by taking advantage of omics data will be important. Specifically, we can expect to be able to predict the beneficial characteristics of MSC-EVs. An earlier study by Kim et al.  performeSecond, we would like to emphasize the possible oncogenic risks entailed by MSC-EVs. The pro-proliferative effects of MSC-EVs on injured cells imply the possibility that MSC-EVs accelerate cancer progression. At present, whether MSC-EVs have pro-cancer or anti-cancer effects remains controversial. Some studies have claimed that MSC-EVs support cancer progression –68, wherThird, we should account for an issue regarding inter-individual variability in MSC-EV function. MSCs that are indistinguishable based on marker characterization could display strongly different capacities to produce cytokines and respond to inflammatory licensing . Donor aMSC-EVs have beneficial effects on recovery from a variety of tissue injuries. These effects are mediated by MSC-EV content molecules including proteins and RNAs, and elucidation of the underlying mechanisms of these effects is now in progress. In addition, recently available omics data suggest a possibility to further explore and understand the key molecular basis of these beneficial effects of MSC-EVs. For the realization of clinical applications of MSC-EVs, however, we should be aware of the oncogenic risks that may be associated with MSC-EVs.Extracellular vesicles and regenerative medicine edited by Jeffrey Karp, Kelvin Ng and Armand Keating. Other articles in this series can be found at http://stemcellres.com/series/EVRM.This article is part of a thematic series on


The calcineurin/NFAT signaling pathway is implicated in a wide variety of biological processes, acting as a bridge pathway between calcium signals and gene expression. Although its role as an effector of immune responses figured prominently in early studies, it forms just one part of a larger picture. Indeed calcineurin has been shown to participate in the development and function of e.g. the immune, cardiovascular, nervous and musculoskeletal systems, and dysregulation of calcineurin/NFAT signaling contributes to pathologies affecting these tissues, in particular cancer .Activation of the calcineurin/NFAT pathway was first observed in human lymphoma, as well as in mouse models of T cell acute lymphoblastic leukemia (T-ALL) and xenotransplanted human T-ALL . In T-ALA recently developed, alternative option is to identify and target molecular pathways acting downstream of calcineurin and critical to T-ALL maintenance . Our gloStrikingly, CXCR4 is also critical to leukemia initiating cell activity (LIC) in murine T-ALL and human xenografts 6], high, high6],In conclusion, the calcineurin/NFAT pathway acts as a fundamental bridge between microenvironmental-derived signals and T-ALL cells, mediating a complex crosstalk that is so far only partially dissected, but that already lead to the identification of novel targets of therapeutic relevance to T-ALL treatment.


Mycobacterium tuberculosis (M.tb) are among the most lethal human pathogens worldwide, each being responsible for around 1.5 million deaths annually. Moreover, synergy between acquired immune deficiency syndrome (AIDS) and tuberculosis (TB) has turned HIV/M.tb co-infection into a major public health threat in developing countries. In the past decade, autophagy, a lysosomal catabolic process, has emerged as a major host immune defense mechanism against infectious agents like M.tb and HIV. Nevertheless, in some instances, autophagy machinery appears to be instrumental for HIV infection. Finally, there is mounting evidence that both pathogens deploy various countermeasures to thwart autophagy. This mini-review proposes an overview of the roles and regulations of autophagy in HIV and M.tb infections with an emphasis on microbial factors. We also discuss the role of autophagy manipulation in the context of HIV/M.tb co-infection. In future, a comprehensive understanding of autophagy interaction with these pathogens will be critical for development of autophagy-based prophylactic and therapeutic interventions for AIDS and TB.Human Immunodeficiency Virus (HIV) and  The molecular mechanisms involved in this activation are just starting to be unraveled with two converging signaling pathways described so far  and cyclic-di-adenosine monophosphate (c-di-AMP) participate in STING signaling , inhibits autophagy in macrophages by an unknown mechanism , but its cytopathic effects is mainly characterized by a decline in the CD4 T-cell population , which is produced from a transcript initiating from the promoter-harboring 3′-long terminal repeat region of the viral genome, has been shown to partially co-localize with LC3 (Clerc et al., In DCs, the viral replication intermediates could be transported into the lysosome in an autophagy-dependent manner and regulate IFN-α secretion upon TLR7-mediated ssRNA recognition (Lee et al., HIV can invade the central nervous system and autophagy has been proposed to participate in HAND but the exact mechanisms of the HIV-mediated alteration of the autophagic pathway is poorly understood. Autophagic vacuoles accumulation has been observed in post-mortem brain from patients with HIV-associated encephalitis (Zhou et al., Importantly, several studies demonstrated that the ATGs can exert some effects independently of the autophagic process (Bestebroer et al., in vitro experiments. This is of particular importance considering that bystander CD4 T lymphocytes constitute the majority of dying cells during HIV infection, leading to AIDS. Because autophagy is an anti-HIV process blocked by the virus for its replication, the development of drugs inducing this process could be beneficial for the patients.In conclusion, the autophagy/HIV relationship is complex and depends mainly on the targeted cell types and their infectious status Figure . In the M.tb is a very severe problem. Each pathogen favors infection by the other. Indeed, M.tb is responsible for 26% of deaths in HIV-infected patients, and 39% of new M.tb cases concern HIV-1 positive patients (Harrington, Synergy between HIV-1 and M.tb (Anandaiah et al., M.tb (Chang et al., M.avium (Orenstein et al., M.tb (Mwandumba et al., It is largely unknown how infection by HIV-1 facilitates infection by M.tb favors the multiplication of the other pathogen. For instance, the induction of IL-10 secretion by HIV-1 (Badou et al., M.tb infection (Patel et al., M.tb (Jasenosky et al., M.tb infection was found to increase IL-8 levels (Friedland et al., More generally, it seems clear that manipulation of the immune response by HIV-1 and M.tb is vitamin D. It is produced in the skin through exposure to ultraviolet B. It is considered that half of the human population have vitamin D insufficiency and this deficiency is much more widespread and pronounced in HIV-1 infected patients (Borella et al., A key effector allowing the immune system to fight both HIV-1 and M.tb. (Deretic, M.tb multiplication in an autophagy-dependent manner (Campbell and Spector, M.tb growth by physiological levels of 1,25D3 is dependent on Beclin-1 and ATG5, and this is also the case when macrophages are infected with both pathogens (Campbell and Spector, M.tb either alone or in coinfection (Campbell and Spector, 1,25D3 is thus an important physiological inducer of autophagy, a process that is involved in cell defense against both HIV-1 and Deretic, . Indeed M.tb has been reviewed in detail elsewhere (Jo, The capacity of vitamin D to induce autophagy and inhibit the growth of HIV-1 and here Jo, . Althoughere Jo, .M.tb infections. However, despite considerable progress, our understanding of autophagy in these deadly infections remains largely incomplete. An in-depth comprehension of the intricate interplay between HIV, M.tb and autophagy, both in vitro and in vivo, will undoubtedly unveil novel strategies employed by pathogens to subvert this pathway. Furthermore, this research avenue could also lead to improved knowledge of the autophagy pathway itself and to innovative tools for autophagy manipulation, as it was recently achieved with Nef-Beclin-1 interaction (Kyei et al., Here, we have gathered compelling published data that reveal the major functions and regulation mechanisms of autophagy in HIV and The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This study examined associations between alcohol misuse and childhood maltreatment and out-of-home placement among urban lesbian, gay, and bisexual (referred to as two-spirit) American Indian and Alaska Native adults. In a multi-site study, data were obtained from 294 individuals who consumed alcohol during the past year. The results indicated that 72.3% of men and 62.4% of women engaged in hazardous and harmful alcohol use and 50.8% of men and 48.7% of women met criteria for past-year alcohol dependence. The most common types of childhood maltreatment were physical abuse among male drinkers (62.7%) and emotional abuse (71.8%) among female drinkers. Men and women reported high percentages of out-of-home placement . Logistic multiple regressions found that for male drinkers boarding school attendance and foster care placement were significant predictors of past-year alcohol dependence. For female drinkers, being adopted was significantly associated with a decreased risk of past-year drinking binge or spree. Dose-response relationships, using number of childhood exposures as a predictor, were not significant. The results highlight the need for alcohol and violence prevention and intervention strategies among urban two-spirit individuals. From 1999–2009, American Indian and Alaska Native (AI/AN) people had higher rates of alcohol-attributable death compared to Whites . Among tLittle is known about factors associated with alcohol misuse among two-spirit people. Research with general AI/AN communities and general population of sexual minorities have examined the impact of childhood exposures, including different forms of maltreatment. Studies with reservation-based  and urbaOther childhood exposures of interest to AI/AN communities are out-of-home placement, including boarding school attendance, foster care placement, and adoption. All three were used historically to remove AI/AN children from their biological families, extended families, and reservation settings . The BoaResearch on the health effects of out-of-home placement among the indigenous population is limited to a small group of studies that have produced mixed findings. For example, one study found that AI/AN men who attended boarding school were more likely to have a diagnosis of a drug use disorder compared to men who had not attended boarding school . In contBecause multiple childhood exposures have been documented among the general AI/AN population , investiThis study used data obtained from a multi-site, cross-sectional investigation of the health of two-spirit AI/AN people, referred to as the HONOR Project. Participants were recruited from seven U.S. metropolitan sites including Seattle-Tacoma, San Francisco-Oakland, Los Angeles, Denver, Tulsa-Oklahoma City, Minneapolis-St. Paul, and New York . IndividThree recruitment methods were used to maximize coverage of the heterogeneity of the population and to minimize selection bias. They included targeted, partial-network, and respondent-driven sampling techniques . TargetA total of 451 participants completed interviews during the study period between July 2005 and March 2007. Four participants were later excluded from the analytic dataset because they did not meet eligibility criteria, resulting in a sample size of 447 participants. For the current study, analyses were conducted with 294 participants who self-reported consumption of some type of drink containing alcohol during the past 12 months. Individuals who were lifetime abstainers (n = 7) and those who did not consume alcohol in the past year (n = 111) were excluded. Individuals who self-identified as transgender (n = 35) were also excluded from the analytical dataset due to the small sample size and focus on gender comparisons.Participants completed a 3–4 hour self-administered computer-assisted interview in a private location of their choice. Trained interviewers were available to answer questions and provide assistance while respecting participants’ privacy . Almost The structured interview consisted of standardized instruments, measures adapted for the AI/AN population, and instruments created for the main study. The present study analyzed sections of the interview that assessed sociodemographic characteristics, alcohol misuse, and childhood exposures.Sociodemographic characteristics. Sociodemographic variables used in the analyses included gender, age, education level, and household monthly income.Alcohol misuse. Alcohol misuse during the past year was investigated using three separate measures. Diagnoses of alcohol disorders were determined using the Mini-International Neuropsychiatric Interview (M.I.N.I. version 5.0) [ion 5.0) . Past-yeion 5.0) ,27. Hazaion 5.0) . The AUDion 5.0) . Responsion 5.0) . DrinkinChildhood exposures. Eight categories of childhood exposures were assessed. Five categories of childhood maltreatment consisted of physical abuse, physical neglect, sexual abuse, emotional abuse, and emotional neglect. They were measured using the short form of the Childhood Trauma Questionnaire (CTQ-SF) [(CTQ-SF) . The CTQ(CTQ-SF) . The cutp < 0.05) in the initial models. Dose-response analyses were conducted using number of types of childhood exposures (range 0–8) as the predictor of past-year alcohol dependence, the most severe drinking problem assessed in the study. All regression models were adjusted for education level and household income because of significant associations with alcohol variables at the bivariate level. All models were tested separately for men and women.All analyses were conducted using SPSS 20 . Percentages of past-year alcohol misuse, childhood maltreatment, and out-of-home placement were estimated and male/female gender comparisons were conducted using Chi-square tests. Separate logistic regression models were tested for each past-year alcohol outcome variable, including alcohol dependence, hazardous and harmful alcohol consumption, and drinking binge or spree for two days or more. Using bivariate analyses, each type of childhood exposure was assessed for associations with each alcohol outcome variable. Subsequent multivariate logistic regressions tested childhood exposures that were significant predictors (As indicated in p < 0.05).Among male current drinkers, 14.1% were diagnosed with past-year alcohol abuse and 50.8% were diagnosed with past-year alcohol dependence . A largep < 0.05). Both men and women reported high percentages of being placed out of the home during childhood . Women reported significantly higher percentages of foster care placement compared to men .There was a high percentage of childhood maltreatment among two-spirit AI/AN people . Among mdecreased risk of past-year drinking binge or spree for two or more days.Bivariate logistic regressions showed significant associations between childhood exposures and alcohol misuse . For menp < 0.05) identified in initial models. When both were entered in a multivariate regression model, Indian boarding school attendance  and foster care placement  remained significant predictors of past-year alcohol dependence. For women, a multivariate regression model was conducted for past-year drinking binge and spree due to multiple significant predictors identified in initial models. When three significant predictors were entered in the model, only being adopted was significantly associated with past-year drinking binge and spree .For men, a multivariate regression model was only conducted for past-year alcohol dependence. The other two alcohol variables did not have more than one significant predictor  . Two-spiHigh percentages of childhood exposures were also documented among urban two-spirit AI/AN people. Among two-spirit male current drinkers, percentages of childhood physical abuse, physical neglect, and emotional abuse were each greater than 60%. Percentages were substantially higher than those documented for men in a multi-tribal, reservation-based study . Among tTwo-spirit men and women reported high percentages of out-of-home placement , with foster care being the most common type of experience. Out-of-home placement may be associated with childhood maltreatment. Many AI/AN children who were in the child welfare system were placed because of evidence of child abuse and neglect. Previous analyses with the HONOR Project dataset showed that several participants experienced physical or sexual abuse while attending boarding schools . Future The lack of significant associations between childhood maltreatment and alcohol misuse among two-spirit AI/AN people was surprising. The findings may be due to temporal proximity to current drinking behaviors. A reservation-based study found that the effect of distal adversity, including childhood trauma, on substance dependence onset was less evident when proximal adversities were present . ProximaA noteworthy finding was that Indian boarding school attendance and foster care placement were associated with alcohol misuse among two-spirit men, but not women. Past findings with reservation-based communities have been mixed ,12,18 anAnother explanation focuses on the strengths and resiliency of the two-spirit female participants who experienced out-of-home placement, but were not at increased risk of alcohol misuse. It is known that some individuals returned to reservations afterward and embraced tribal culture, language, and community, resulting in family narratives of persistence . Researcdecreased risk of past-year drinking binge and spree among two-spirit women was based on a sample of 17 people, and thus, should be interpreted with caution. However, the result provided further evidence of the complexity of out-of-home placement experiences, and suggested that adoption might not be an adverse experience for all AI/AN people. This was consistent with findings from a study conducted in Greenland, which is largely made up of Inuit people [The finding that being adopted was significantly associated with t people . The resThe findings have several implications for public health practice. The high rates of alcohol misuse among two-spirit people highlight the need for alcohol screening and brief intervention in settings that are frequently utilized by this population. Single-question screenings are recommended as time-efficient tools that reduce barriers to utilization attributed to multiple-question screens that require scoring . A singlThe high rates of child abuse and neglect call attention to the need for violence prevention among AI/AN communities, including those located in urban areas. Urban AI/AN communities may benefit from public health strategies that have been adapted for the general AI/AN population and emphasize cultural and historical contexts at all levels of influence . InterveThe long-lasting effects of out-of-home placement among two-spirit men point to the advantages of assessment of a wider range of exposures, including out-of-home placement, other forms of historical or cultural trauma, and discrimination, to identify meaningful areas for healing and recovery . The finThe current study had some limitations. Causal relationships between childhood exposures and adult alcohol use could not be inferred due to the cross-sectional design. However, temporal relationships were examined using childhood maltreatment that occurred before age 18 and alcohol behavior during the past 12 months. The types of out-of-home placement were also specific to the experiences of children. The findings also do not generalize to two-spirit AI/AN individuals living in rural areas or other racial and sexual minority groups . Two-spiThe current findings contributed to the growing body of knowledge on alcohol misuse and childhood exposures among urban two-spirit AI/AN adults. Research is needed to examine mediators and moderators of the relationships between childhood exposures and alcohol misuse, with an emphasis on historical and contemporary cultural contexts affecting AI/AN communities. Greater attention also needs to be directed to protective factors and resiliency that may inform culturally-relevant interventions. Shifting away from deficit-focused models and embracing indigenous knowledge and decolonizing frameworks may help end the cycle of discrimination and oppression experienced by two-spirit AI/AN people.


Pneumothorax in patients with progressive systemic sclerosis (PSS) often presents as a difficult-to-treat disease. Autologous blood-patch pleurodesis has previously been used for the treatment of pneumothorax. Blood outside its own environment is an irritant; therefore, chest physicians must watch closely for an allergic reaction. The injection is simple, painless, causes no side effects, is an inexpensive treatment for pneumothorax and is available not only in patients with persistent air leak but also in those with residual air space. A case is reported here of blood-patch pleurodesis for pneumothorax in lung fibrosis due to PSS. As an alternative therapy for difficult-to-treat pneumothorax in patients with PSS with persistent air leak and residual air space, autologous blood-patch pleurodesis would be one of the treatment options. Pneumothorax is not a rare complication of lung fibrosis due to progressive systemic sclerosis (PSS); however, a number of patients with PSS who have extensive pulmonary fibrosis with enlarged sub-pleural blebs and honeycomb lungs have been shown to develop pneumothorax. Various treatment options have been described . SurgeryA 69-year-old female was admitted to the Mito Medical Center  due to dyspnea on exertion and right chest pain lasting all day. Three years previously she was diagnosed as having PSS with lung fibrosis . Since tPhysical examination on admission revealed decreased respiratory sound in the right lung and diffuse fine crackles in both lungs. Skin thickening and tightness were observed on the fingers of both hands. Laboratory data on admission were as follows: White blood cell, 4,900/μl; C-reactive protein, 3.77 mg/dl; anti-nuclear antibody, 1:640; anti-centromere antibody, 1:640; rheumatoid factor, 4 U/ml. Tests for anti-neutrophil cytoplasmic antibodies to proteinase 3 and myeloperoxidase and anti-ribonucleoprotein and -topoisomerase 1 antibodies were negative. A chest radiograph revealed pneumothorax in the right lung, and reticulonodular opacities predominant in the bilateral lower lungs . A 20 FrPSS is a systemic disease that sometimes affects the lungs, resulting in lung fibrosis . DiffuseIn conclusion, as an alternative therapy for difficult-to-treat pneumothorax in patients with PSS with persistent air leak and residual air space, autologous blood-patch pleurodesis would be one of the treatment options.


Antiplatelet agents are commonly used for cardiovascular diseases, but their pleiotropic effects in critically ill patients are controversial. We therefore performed a meta-analysis of cohort studies to investigate the effect of antiplatelet therapy in the critically ill.Nine cohort studies, retrieved from PubMed and Embase before November 2015, involving 14,612 critically ill patients and 4765 cases of antiplatelet users, were meta-analysed. The main outcome was hospital or 30-day mortality. Secondary outcome was acute respiratory distress syndrome (ARDS) or acute lung injury (ALI). Random- or fixed-effect models were taken for quantitative synthesis of the data.2 = 0%; P <0. 001) and ARDS/ALI . In every stratum of subgroups, similar findings on mortality reduction were consistently observed in critically ill patients.Antiplatelet therapy was associated with decreased mortality (odds ratio (OR) 0.61; 95% confidence interval (CI), 0.52–0.71; IAntiplatelet therapy is associated with reduced mortality and lower incidence of ARDS/ALI in critically ill patients, particularly those with predisposing conditions such as high-risk surgery, trauma, pneumonia, and sepsis. However, it remains unclear whether similar findings can be observed in the unselected and broad population with critical illness. Sepsis and acute respiratory distress syndrome (ARDS) in the United States both contribute signi-ficantly to the expanding burden of critical illness. The incidence rate of sepsis or septic shock appears to be increasing , and witAntiplatelet agents are used to reduce platelet activation and their cardiovascular benefits in patients with the risk of heart disease, stroke, and peri-pheral arterial thrombosis are widely accepted in clinical practice. However, their pleiotropic effects in critically ill patients yielded controversial results. Many observational studies have demonstrated a protective effect of antiplatelet agents in critically ill patients –13, but Up to now, no syntheses of the evidence have been published to recapitulate and summarize the affect of this therapy in ICU population. Consequently, we conducted this meta-analysis to pool the available data and to explore the possible impact of anti-platelet agents on ARDS/ALI and risk of mortality in critically ill patients.This meta-analysis was performed in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . NeitherWithout language restrictions, electronic databases including Pubmed, Embase were retrieved to identify relevant studies from inception to November 10, 2015. A combination of exploded Medical Subject Headings (MESH) terms and corresponding keywords was used while searching. The search terms were as follows:  and . Additionally, We hand-searched the reference lists of each selected study, as well as previous review articles to obtain other potential relevant articles.Published cohort studies meeting the following criteria were included: (1) population: critically ill patients, or rather, it referred to ICU or emergency patients with ARDS/ALI predisposing conditions, such as sepsis, septic shock, transfusion, pancreatitis, pneumonia, trauma, aspiration, or high-risk surgery; (2) comparison intervention: with and without anti-platelet therapy; (3) one or more the following outcomes: newly developed ARDS/ALI, hospital or 30-day mortality. In the case of duplicate publication, we only included studies that were the most informative and complete.Two investigators (W. L. J. and L. H.) independently screened the abstracts or titles of the studies from the electronic search to identify all potential eligible studies and extracted data. Discrepancies were resolved by consensus or a third reviewer (G. X. F.). The following data were recorded: first author, publication year, country, study design, sample size, outcomes of the studies, and definition of anti-platelet therapy. We pooled the short-term mortality  and new development of ARDS/ALI with the adjusted data. We also checked the supplementary files and contacted the authors for available information where necessary.The study level risk of bias was evaluated using the nine-star Newcastle-Ottawa Scale (NOS) , which cp≥0.1), I2 <50%). Elsewise, a random-effects model was used. We likewise performed predefined subgroup analyses to study the effect of antiplatelet therapy in critically ill patients. To assess the effect of a single study on pooled estimate, a sensi-tivity analysis was used by omitting one study in turn. Funnel plots and Egger’s linear regression tests were taken to evaluate publication bias [P value less than 0.05 was considered to indicate statistical signi-ficance.All statistical analyses were performed using STATA, version 12.0 . A summary odds ratio (OR) was obtained on base of the adjusted OR in all analyses involved in this report. The hazard ratio (HR) and risk ratio (RR) were regarded as the eligible OR directly because all provided effect sizes of similar magnitude . To calcion bias . A P valThe main characteristics of the nine selected cohort studies in this meta-analysis are shown in 2 = 0%; P = 0.738). We also carried out a meta-analysis of the incidence rate of newly developed ARDS/ALI with four studies. Similarly, the pooled results indicated that antiplatelet therapy had a beneficial impact on reducing ARDS/ALI ; P <0. 001). There also was very low heterogeneity among the studies .Figs ’t materially alter by exclusion of any single study, with a range from 0.59  to 0.63 .To study the possibly existed heterogeneity, we performed a prespecified subgroup analysis according to predisposing conditions (sepsis/septic shock or > predisposing conditions), adjusted by propensity score (yes or no), type of mortality , type of effect size (OR or HR), antiplatelet agents exposure (current exposure or former exposure), aspirin for antiplatelet therapy only (yes or no), and sample size (≤1000 or >1000). Our subgroup analyses suggested the effect of anti-platelet therapy on decreasing the incidence rate of mortality in ICU population with critical illness was consistent. Details can be shown in ’s test. There was no evidence of publication bias based on the funnels plot . However, the low power with only six studies for mortality and four studies for ARDS/ALI confined the interpretability.The possibility of publication bias was judged by funnel plots and Eggerels plot  and EggeThe principal finding of our analysis is that antiplatelet therapy is associated with decrease in ARDS/ALI and mortality. To the best of our knowledge, this is the first meta-analysis to explore the effects of anti-platelet treatment on the risk of ARDS/ALI and mortality in critically ill patients with high-quality cohort study and adjusted data. Additionally, the beneficial effect of anti-platelet treatment on mortality was likewise present in every stratum from subgroup analyses. All this may suggest that the “plei-otropic effects” of anti-platelet therapy probably will be a novel therapeutic approach in critically ill patients in the future.Although antiplatelet treatment may decrease the risk of mortality and ARDS/ALI in critically ill patients, the reason remains unclear and can be explained by several potential mechanisms. First, activated platelets may contribute to micro-vascular thrombosis and organ failure. Anti-platelet therapy can impede platelet activation and the surface expression of adhesion molecules, a pivotal process in mi-crovascular thrombus formation . This viDespite advancements into the pathophysiology of critically ill patients, no specific or reliable intervention has currently been developed –49. AsceThe strength of this study is that there was an exhaustive search without language restrictions and PRISMA guidelines was used as our systematic review methods. Meanwhile, studies were assessed strictly for methodological quality, and only those of high quality were involved in our analysis. In addition, no significant heterogeneity between the included studies was observed in this study. However, our meta-analysis knows several limitations, the prin-cipal one being lack of randomized trials. Although more and more evidence emphasizes the potential benefit of antiplatelet therapy in critically ill patients, none of the randomized trials came out to report the relationship between the two described above. Considering the characteristics of observa-tional study, we should acknowledge selection bias and potential confounding. Actually, just like any observational study, it remains impossible to entirely exclude confounding, especially when the ob-served association is weak to some extent. Second, the definition of intensive care patients was wide and imprecise. In this study, critically ill patients was defined as the population with ALI/ARDS predisposing risk factors, involving sepsis, pancreatitis, transfusion, pneumonia, aspiration, trauma, or high-risk surgery. Nevertheless, it remains unclear whether the conclusion was fit for the unselected and board population with critical illness. Third, different definition of antiplatelet therapy in the included studies was used, and this may have a potential influence on our conclusion. Finally, unpub-lished studies or conference abstracts were not included. However, although publish bias was not found in our meta-analysis, unpublished studies or conference abstracts might be of great importance.In aggregate, our meta-analysis suggests that antiplatelet therapy is associated with decreased mortality, as well as a decreased incidence rate of ARDS/ALI in the critically ill, especially those with one or more predisposing risk factors such as high-risk surgery, trauma, pneumonia, and sepsis. However, it is also unknown whether similar results can be found in the unselected and broad population with critical illness. There is, thus, a great need for well de-signed, high-quality, large, ran-domized trials to confirm the effect of antiplatelet therapy in critically ill patients.S1 File(DOC)Click here for additional data file.S2 File(DOC)Click here for additional data file.S3 File(DOC)Click here for additional data file.S4 File(DOC)Click here for additional data file.


Background. Outcomes of laboratory-based tests for mobility are often used to infer about older adults' performance in real life; however, it is unclear whether such association exists. We hypothesized that mobility capacity, as measured in the laboratory, and mobility performance, as measured in real life, would be poorly linked. Methods. The sample consisted of 84 older adults (72.5 ± 5.9 years). Capacity was assessed via the iTUG and standard gait parameters . Performance was assessed in real life over a period of 6.95 ± 1.99 days using smartphone technology to calculate following parameters: active and gait time, number of steps, life-space, mean action-range, and maximum action-range. Correlation analyses and stepwise multiple regression analyses were applied. Results. All laboratory measures demonstrated significant associations with the real-life measures (between r = .229 and r = .461). The multiple regression analyses indicated that the laboratory measures accounted for a significant but very low proportion of variance (between 5% and 21%) in real-life measures. Conclusion. In older adults without mobility impairments, capacity-related measures of mobility bear little significance for predicting real-life performance. Hence, other factors play a role in how older people manage their daily-life mobility. This should be considered for diagnosis and treatment of mobility deficits in older people. With advancing age, it often becomes increasingly difficult to access community resources like grocery stores, doctor's offices, banks, and other essential services and to participate in sociocultural activities. Diminished independent mobility is a predictor of institutionalization , fallingMobility is often assessed with established field tests such as the Timed Up-and-Go test , 8, the Mobility in daily life depends not only on an intact sensorimotor system but also on intact cognition and psychosocial factors. For example, studies have shown that low cognitive status , reduced capacity, which is indicative of the highest possible level of functioning of an individual in a given domain at a certain moment, and real-life assessments measuring performance which is what individuals do in their own current environment ) Although the current study has the strength of presenting comprehensive mobility patterns of older adults, including long-term real-life physical activity and out-of-home movement measures, we acknowledge several limitations. In order to achieve a performance spectrum as wide as possible we strived to enlist participants living in assisted-living facilities, whose mobility is typically more restricted than this of independent-living older adults. However, only 13 persons  living in assisted-living facilities could be recruited. Though our sample does present a considerable range of performance at the laboratory measures, it mostly represents community-dwelling older adults living independently without severe mobility impairments. Hence, care should be taken when interpreting our results as they cannot be extended to other populations or adults with severe mobility impairments. Future research should examine the predictive ability of field tests for real-life mobility also in less active samples and/or samples with mobility impairments such as neurological patients or people with cognitive impairments.r = .184, p = .047) only with life-space. However, future studies should aim for a fixed mobility registration period for all the participants to avoid bias [Additionally, the real-life data registration period (6.9 ± 1.9 days) varied between participants within the total study period. One of the most important weather parameters which influence physical activity is maximum temperature . In ordeoid bias  due to sThe current study presents mobility patterns in a sample of rather active community-dwelling older adults without severe mobility impairments based on combination of capacity and performance measures and shows that standard laboratory-based tests have limited predictive ability for real-life mobility. This shows that capacity and performance represent different aspects of mobility. Therefore, comprehensive mobility assessments should include capacity measures as well as measures of real-life out-of-home mobility. Additionally, as anticipated, this study confirms that physical activity is better explained by physical functioning, when compared with life-space measures. Finally, this study highlights the utility of the iTUG and, considering its rather simple execution, it suggests that it should be preferred over simple gait measures, as it explains more aspects and higher proportion of real-life mobility.


The World Health Organization estimates that 450,000 cases of drug-resistant (DR) tuberculosis (TB) occurred worldwide in 2012. In South Africa, over 15,000 cases were diagnosed. Over half of patients in South Africa with TB are HIV co-infected. The management of drug-resistant TB is complex, prolonged, costly, associated with multiple toxicities and thus difficult for patients to complete. Disengagement from follow-up is common. Co-infection with HIV presents a number of additional challenges in DR TB management including shared drug toxicities between TB and HIV drugs, potential for increased drug toxicity due to underlying HIV-related organ disease such as nephropathy, pharmacokinetic drug–drug interactions and immune reconstitution inflammatory syndrome including manifestations at extrapulmonary sites. Mortality with multi-drug-resistant (MDR) TB is higher in HIV-positive patients. Mortality is similar for HIV-positive and uninfected patients with extremely drug-resistant (XDR) TB, given the current lack of effective therapy, with over 70% case fatality by five years. ART improves survival in patients with DR TB, and timing of ART initiation in relation to TB treatment should be similar to patients with drug-susceptible TB. New (e.g. bedaquiline and delaminid) and repurposed (e.g. linezolid and clofazamine) drugs promise to improve the prognosis of patients with DR TB. Several clinical trials of new regimens are ongoing and planned, and early data from the Bedaquiline Clinical Access Programme in South Africa suggests much improved short-term outcomes when bedaquiline +/− linezolid and/or clofazamine are included in the regimen of patients with XDR and pre-XDR TB including patients with HIV co-infection. There are important considerations with respect to QT prolongation and ART drug interactions related to bedaquiline that need to be factored in treatment decisions and monitoring plans.