Use of a Molecular Diagnostic Test in AFB Smear Positive Tuberculosis Suspects Greatly Reduces Time to Detection of Multidrug Resistant Tuberculosis

Background: The WHO has recommended the implementation of rapid diagnostic tests to detect and help combat M/XDR tuberculosis (TB). There are limited data on the performance and impact of these tests in field settings. Methods: The performance of the commercially available Genotype MTBDRplus molecular assay was compared to conventional methods including AFB smear, culture and drug susceptibility testing (DST) using both an absolute concentration method on Löwenstein-Jensen media and broth-based method using the MGIT 960 system. Sputum specimens were obtained from TB suspects in the country of Georgia who received care through the National TB Program. Results: Among 500 AFB smear-positive sputum specimens, 458 (91.6%) had both a positive sputum culture for Mycobacterium tuberculosis and a valid MTBDRplus assay result. The MTBDRplus assay detected isoniazid (INH) resistanc

Clinical Deterioration during Antitubercular Treatment at a District Hospital in South Africa: The Importance of Drug Resistance and AIDS Defining Illnesses

Background: Clinical deterioration on drug therapy for tuberculosis is a common cause of hospital admission in Africa. Potential causes for clinical deterioration in settings of high HIV-1 prevalence include drug resistant Mycobacterium tuberculosis (M.tb), co-morbid illnesses, poor adherence to therapy, tuberculosis associated-immune reconstitution inflammatory syndrome (TB-IRIS) and subtherapeutic antitubercular drug levels. It is important to derive a rapid diagnostic work-up to determine the cause of clinical deterioration as well as specific management to prevent further clinical deterioration and death. We undertook this study among tuberculosis (TB) patients referred to an adult district level hospital situated in a high HIV-1 prevalence setting to determine the frequency, reasons and outcome for such clinical deterioration. Method: A prospective observational study conducted during the first quarter of 2007. We defined clinical deterioration as clinical worsening or failure to stabilise after 14 or more days of antitubercular treatment, resulting in hospital referral. We collected data on tuberculosis diagnosis and treatment, HIV-1 status and antiretroviral treatment, and investigated reasons for clinical deterioration as well as outcome. Results: During this period, 352 TB patients met inclusion criteria; 296 were admitted to hospital accounting for 17% of total medical admissions (n = 1755). Eighty three percent of TB patients (291/352) were known to be HIV-1 co-infected with a median CD4 count of 89cells/mm3 (IQR 38-157). Mortality among TB patients admitted to hospital was 16% (n = 48). The median duration of hospital admission was 9.5 days (IQR 4-18), longer than routine in this setting (4 days). Among patients in whom HIV-1 status was known (n = 324), 72% of TB patients (n = 232) had an additional illness to tuberculosis; new AIDS defining illnesses (n = 80) were the most frequent additional illnesses (n = 208) in HIV-1 co-infected patients (n = 291). Rifampin-resistant M.tb (n = 41), TB-IRIS (n = 51) and drug resistant bacterial infections (n = 12) were found in 12%, 14% and 3.4% of the 352 cases, respectively. Interpretation: In our setting, new AIDS defining illnesses, drug resistant M.tb and other drug resistant bacteria are important reasons for clinical deterioration in HIV-1 co-infected patients receiving antitubercular treatment. HIV-1 coinfected patients may be at increased risk of acquiring nosocomial drug resistant pathogens because profound immune suppression results in co-morbid illnesses that require prolonged inpatient admissions. Routine infection control is essential and needs to be strengthened in our setting. Copyright: © 2009 Pepper et al

The Prevalence and Drug Sensitivity of Tuberculosis among Patients Dying in Hospital in KwaZulu-Natal, South Africa: A Postmortem Study

A postmortem study by Ted Cohen and colleagues reveals a huge toll of tuberculosis among patients dying in hospitals in KwaZulu-Natal, South Africa

Molecular detection of rifampin and isoniazid resistance to guide chronic TB patient management in Burkina Faso

<p>Abstract</p> <p>Background</p> <p>Drug-resistant tuberculosis (DR-TB) is considered a real threat to the achievement of TB control. Testing of mycobacterial culture and testing of drug susceptibility (DST) capacity are limited in resource-poor countries, therefore inadequate treatment may occur, favouring resistance development. We evaluated the molecular assay GenoType^®MTBDR<it>plus </it>(Hain Lifescience, Germany) in order to detect DR-TB directly in clinical specimens as a means of providing a more accurate management of chronic TB patients in Burkina Faso, a country with a high TB-HIV co-infection prevalence.</p> <p>Methods</p> <p>Samples were collected in Burkina Faso where culture and DST are not currently available, and where chronic cases are therefore classified and treated based on clinical evaluation and sputum-smear microscopy results. One hundred and eight chronic TB patients (sputum smear-positive, after completing a re-treatment regimen for pulmonary TB under directly observed therapy) were enrolled in the study from December 2006 to October 2008. Two early morning sputum samples were collected from each patient, immediately frozen, and shipped to Italy in dry ice. Samples were decontaminated, processed for smear microscopy and DNA extraction. Culture was attempted on MGIT960 (Becton Dickinson, Cockeysville, USA) and decontaminated specimens were analyzed for the presence of mutations conferring resistance to rifampin and isoniazid by the molecular assay GenoType^®MTBDR<it>plus</it>.</p> <p>Results</p> <p>We obtained a valid molecular test result in 60/61 smear-positive and 47/47 smear-negative patients.</p> <p>Among 108 chronic TB cases we identified patients who (i) harboured rifampin- and isoniazid-susceptible strains (n 24), (ii) were negative for MTB complex DNA (n 24), and (iii) had non-tuberculous mycobacteria infections (n 13). The most represented mutation conferring rifampin-resistance was the D516V substitution in the hotspot region of the <it>rpoB </it>gene (43.8% of cases). Other mutations recognized were the H526D (15.6%), the H526Y (15.6%), and the S531L (9.4%).</p> <p>All isoniazid-resistant cases (n 36) identified by the molecular assay were carrying a S315T substitution in the <it>katG </it>gene. In 41.7% of cases, a mutation affecting the promoter region of the <it>inhA </it>gene was also detected.</p> <p>Conclusion</p> <p>The GenoType^®MTBDR<it>plus </it>assay performed directly on sputum specimens improves the management of chronic TB cases allowing more appropriate anti-TB regimens.</p

Quorum Decision-Making in Foraging Fish Shoals

Quorum responses provide a means for group-living animals to integrate and filter disparate social information to produce accurate and coherent group decisions. A quorum response may be defined as a steep increase in the probability of group members performing a given behaviour once a threshold minimum number of their group mates already performing that behaviour is exceeded. In a previous study we reported the use of a quorum response in group decision-making of threespine sticklebacks (Gasterosteus aculeatus) under a simulated predation threat. Here we examine the use of quorum responses by shoals of sticklebacks in first locating and then leaving a foraging patch. We show that a quorum rule explains movement decisions by threespine sticklebacks toward and then away from a food patch. Following both to and from a food patch occurred when a threshold number of initiators was exceeded, with the threshold being determined by the group size

How to promote, improve and test adherence to scientific evidence in clinical practice

BACKGROUND: Negative variation in the management of patients with the same clinical condition is frequent, and affects quality of care. Recent studies indicate that single interventions are not an effective solution. We aim to demonstrate that a multifaceted strategy can favor the introduction of research into practice, and to assess its long-term effects on a set of common medical conditions exhibiting significant negative variation at our institution. METHODS: The strategy, devised and agreed upon by a multidisciplinary group, was first applied to one relevant medical condition – cerebral ischemic stroke. To test its effectiveness a quasi-experimental study was conducted, comparing an intervention group with historical controls. After validation the strategy was extended to other pathologies, and its long-term effect measured using evidence-based quality indicators. Adherence to each indicator was determined prospectively on a six-month basis for a period of at least two consecutive years. Measures are expressed as proportions with 95% confidence intervals. RESULTS: Validation findings demonstrated that the strategy improved compliance with scientific evidence: the percentage of patients who received a CT scan within 24 hours of hospital presentation rose from 56% to 75%, (χ(2 )= 7.43 p < 0.01); admissions to selected wards increased from 45% to 64%, (χ(2 )= 7.81 p < 0.01); the number of physical medicine visits within 24 hours of the request grew from 59% to 91% (χ(2 )= 14,40 p < 0.001). Over a four-year period the program was gradually applied to 14 medical conditions. Except for 3 cases, compliance with the pathway, i.e. number of eligible patients for whom data on the care process is collected, was above the minimum requirement of 75%. Indicator adherence generally exhibited a positive trend, though variability was observed both among different conditions and between different semesters for the same pathology. CONCLUSION: According to our experience, incorporation of research into practice can be favored by systematically applying a shared, multifaceted strategy, involving multidisciplinary teams supported by central coordination. Institutions should device a tailor-made approach, should train personnel on implementation strategies, and create cultural acceptance of change. Just like for experimental trials, human and economic resources should be allocated within health care services to allow the achievement of this objective

Is HIV Infection a Risk Factor for Multi-Drug Resistant Tuberculosis? A Systematic Review

BACKGROUND:Tuberculosis (TB) is an important cause of human suffering and death. Human immunodeficiency virus (HIV), multi-drug resistant TB (MDR-TB), and extensive drug resistant tuberculosis (XDR-TB) have emerged as threats to TB control. The association between MDR-TB and HIV infection has not yet been fully investigated. We conducted a systematic review and meta-analysis to summarize the evidence on the association between HIV infection and MDR-TB. METHODS AND RESULTS:Original studies providing Mycobacterium tuberculosis resistance data stratified by HIV status were identified using MEDLINE and ISI Web of Science. Crude MDR-TB prevalence ratios were calculated and analyzed by type of TB (primary or acquired), region and study period. Heterogeneity across studies was assessed, and pooled prevalence ratios were generated if appropriate. No clear association was found between MDR-TB and HIV infection across time and geographic locations. MDR-TB prevalence ratios in the 32 eligible studies, comparing MDR-TB prevalence by HIV status, ranged from 0.21 to 41.45. Assessment by geographical region or study period did not reveal noticeable patterns. The summary prevalence ratios for acquired and primary MDR-TB were 1.17 (95% CI 0.86, 1.6) and 2.72 (95% CI 2.03, 3.66), respectively. Studies eligible for review were few considering the size of the epidemics. Most studies were not adjusted for confounders and the heterogeneity across studies precluded the calculation of a meaningful overall summary measure. CONCLUSIONS:We could not demonstrate an overall association between MDR-TB and HIV or acquired MDR-TB and HIV, but our results suggest that HIV infection is associated with primary MDR-TB. Future well-designed studies and surveillance in all regions of the world are needed to better clarify the relationship between HIV infection and MDR-TB

Impact of voluntary exercise and housing conditions on hippocampal glucocorticoid receptor, miR-124 and anxiety

Background: Lack of physical activity and increased levels of stress contribute to the development of multiple physical and mental disorders. An increasing number of studies relate voluntary exercise with greater resilience to psychological stress, a process that is highly regulated by the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanisms underlying the beneficial effects of exercise on stress resilience are still poorly understood. Here we have studied the impact of long term exercise and housing conditions on: a) hippocampal expression of glucocorticoid receptor (Nr3c1), b) epigenetic regulation of Nr3c1 (DNA methylation at the Nr3c1-1F promoter and miR-124 expression), c) anxiety (elevated plus maze, EPM), and d) adrenal gland weight and adrenocorticotropic hormone receptor (Mc2r) expression. Results: Exercise increased Nr3c1 and Nr3c1-1F expression and decreased miR-124 levels in the hippocampus in single-housed mice, suggesting enhanced resilience to stress. The opposite was found for pair-housed animals. Bisulfite sequencing showed virtually no DNA methylation in the Nr3c1-1F promoter region. Single-housing increased the time spent on stretch attend postures. Exercise decreased the time spent at the open arms of the EPM, however, the mobility of the exercise groups was significantly lower. Exercise had opposite effects on the adrenal gland weight of single and pair-housed mice, while it had no effect on adrenal Mc2r expression. Conclusions: These results suggest that exercise exerts a positive impact on stress resilience in single-housed mice that could be mediated by decreasing miR-124 and increasing Nr3c1 expression in the hippocampus. However, pair-housing reverses these effects possibly due to stress from dominance disputes between pairs

Outer membrane protein folding from an energy landscape perspective

The cell envelope is essential for the survival of Gram-negative bacteria. This specialised membrane is densely packed with outer membrane proteins (OMPs), which perform a variety of functions. How OMPs fold into this crowded environment remains an open question. Here, we review current knowledge about OFMP folding mechanisms in vitro and discuss how the need to fold to a stable native state has shaped their folding energy landscapes. We also highlight the role of chaperones and the β-barrel assembly machinery (BAM) in assisting OMP folding in vivo and discuss proposed mechanisms by which this fascinating machinery may catalyse OMP folding

Importance of patient bed pathways and length of stay differences in predicting COVID-19 hospital bed occupancy in England.

Background: Predicting bed occupancy for hospitalised patients with COVID-19 requires understanding of length of stay (LoS) in particular bed types. LoS can vary depending on the patient’s “bed pathway” - the sequence of transfers of individual patients between bed types during a hospital stay. In this study, we characterise these pathways, and their impact on predicted hospital bed occupancy. Methods: We obtained data from University College Hospital (UCH) and the ISARIC4C COVID-19 Clinical Information Network (CO-CIN) on hospitalised patients with COVID-19 who required care in general ward or critical care (CC) beds to determine possible bed pathways and LoS. We developed a discrete-time model to examine the implications of using either bed pathways or only average LoS by bed type to forecast bed occupancy. We compared model-predicted bed occupancy to publicly available bed occupancy data on COVID-19 in England between March and August 2020. Results: In both the UCH and CO-CIN datasets, 82% of hospitalised patients with COVID-19 only received care in general ward beds. We identified four other bed pathways, present in both datasets: “Ward, CC, Ward”, “Ward, CC”, “CC” and “CC, Ward”. Mean LoS varied by bed type, pathway, and dataset, between 1.78 and 13.53 days. For UCH, we found that using bed pathways improved the accuracy of bed occupancy predictions, while only using an average LoS for each bed type underestimated true bed occupancy. However, using the CO-CIN LoS dataset we were not able to replicate past data on bed occupancy in England, suggesting regional LoS heterogeneities. Conclusions: We identified five bed pathways, with substantial variation in LoS by bed type, pathway, and geography. This might be caused by local differences in patient characteristics, clinical care strategies, or resource availability, and suggests that national LoS averages may not be appropriate for local forecasts of bed occupancy for COVID-19. Trial registration: The ISARIC WHO CCP-UK study ISRCTN66726260 was retrospectively registered on 21/04/2020 and designated an Urgent Public Health Research Study by NIHR.</p