Do Instructional Videos on Sputum Submission Result in Increased Tuberculosis Case Detection? A Randomized Controlled Trial.

OBJECTIVE We examined the effect of an instructional video about the production of diagnostic sputum on case detection of tuberculosis (TB), and evaluated the acceptance of the video. TRIAL DESIGN Randomized controlled trial. METHODS We prepared a culturally adapted instructional video for sputum submission. We analyzed 200 presumptive TB cases coughing for more than two weeks who attended the outpatient department of the governmental Municipal Hospital in Mwananyamala (Dar es Salaam, Tanzania). They were randomly assigned to either receive instructions on sputum submission using the video before submission (intervention group, n = 100) or standard of care (control group, n = 100). Sputum samples were examined for volume, quality and presence of acid-fast bacilli by experienced laboratory technicians blinded to study groups. RESULTS Median age was 39.1 years (interquartile range 37.0-50.0); 94 (47%) were females, 106 (53%) were males, and 49 (24.5%) were HIV-infected. We found that the instructional video intervention was associated with detection of a higher proportion of microscopically confirmed cases (56%, 95% confidence interval [95% CI] 45.7-65.9%, sputum smear positive patients in the intervention group versus 23%, 95% CI 15.2-32.5%, in the control group, p <0.0001), an increase in volume of specimen defined as a volume ≥3ml (78%, 95% CI 68.6-85.7%, versus 45%, 95% CI 35.0-55.3%, p <0.0001), and specimens less likely to be salivary (14%, 95% CI 7.9-22.4%, versus 39%, 95% CI 29.4-49.3%, p = 0.0001). Older age, but not the HIV status or sex, modified the effectiveness of the intervention by improving it positively. When asked how well the video instructions were understood, the majority of patients in the intervention group reported to have understood the video instructions well (97%). Most of the patients thought the video would be useful in the cultural setting of Tanzania (92%). CONCLUSIONS Sputum submission instructional videos increased the yield of tuberculosis cases through better quality of sputum samples. If confirmed in larger studies, instructional videos may have a substantial effect on the case yield using sputum microscopy and also molecular tests. This low-cost strategy should be considered as part of the efforts to control TB in resource-limited settings. TRIAL REGISTRATION Pan African Clinical Trials Registry PACTR201504001098231.

Endoscopic and Open Release Similarly Safe for the Treatment of Carpal Tunnel Syndrome. A Systematic Review and Meta-Analysis.

BACKGROUND The Endoscopic Release of Carpal Tunnel Syndrome (ECTR) is a minimal invasive approach for the treatment of Carpal Tunnel Syndrome. There is scepticism regarding the safety of this technique, based on the assumption that this is a rather "blind" procedure and on the high number of severe complications that have been reported in the literature. PURPOSE To evaluate whether there is evidence supporting a higher risk after ECTR in comparison to the conventional open release. METHODS We searched MEDLINE (January 1966 to November 2013), EMBASE (January 1980 to November 2013), the Cochrane Neuromuscular Disease Group Specialized Register (November 2013) and CENTRAL (2013, issue 11 in The Cochrane Library). We hand-searched reference lists of included studies. We included all randomized or quasi-randomized controlled trials (e.g. study using alternation, date of birth, or case record number) that compare any ECTR with any OCTR technique. Safety was assessed by the incidence of major, minor and total number of complications, recurrences, and re-operations.The total time needed before return to work or to return to daily activities was also assessed. We synthesized data using a random-effects meta-analysis in STATA. We conducted a sensitivity analysis for rare events using binomial likelihood. We judged the conclusiveness of meta-analysis calculating the conditional power of meta-analysis. CONCLUSIONS ECTR is associated with less time off work or with daily activities. The assessment of major complications, reoperations and recurrence of symptoms does not favor either of the interventions. There is an uncertain advantage of ECTR with respect to total minor complications (more transient paresthesia but fewer skin-related complications). Future studies are unlikely to alter these findings because of the rarity of the outcome. The effect of a learning curve might be responsible for reduced recurrences and reoperations with ECTR in studies that are more recent, although formal statistical analysis failed to provide evidence for such an association. LEVEL OF EVIDENCE I.

Emergence of acquired HIV-1 drug resistance has almost been stopped in Switzerland - a 15 year prospective cohort analysis

BACKGROUND  Drug resistance is a major barrier to successful antiretroviral treatment (ART). Therefore, it is important to monitor time trends at a population level. METHODS  We included 11,084 ART-experienced patients from the Swiss HIV Cohort Study (SHCS) between 1999 and 2013. The SHCS is highly representative and includes 72% of patients receiving ART in Switzerland. Drug resistance was defined as the presence of at least one major mutation in a genotypic resistance test. To estimate the prevalence of drug resistance, data for patients with no resistance test was imputed based on patient's risk of harboring drug resistant viruses. RESULTS  The emergence of new drug resistance mutations declined dramatically from 401 to 23 patients between 1999 and 2013. The upper estimated prevalence limit of drug resistance among ART-experienced patients decreased from 57.0% in 1999 to 37.1% in 2013. The prevalence of three-class resistance decreased from 9.0% to 4.4% and was always <0.4% for patients who initiated ART after 2006. Most patients actively participating in the SHCS in 2013 with drug resistant viruses initiated ART before 1999 (59.8%). Nevertheless, in 2013, 94.5% of patients who initiated ART before 1999 had good remaining treatment options based on Stanford algorithm. CONCLUSION  HIV-1 drug resistance among ART-experienced patients in Switzerland is a well-controlled relic from the pre-combination ART era. Emergence of drug resistance can be virtually stopped with new potent therapies and close monitoring.

Hepatitis C in HIV-infected individuals: a systematic review and meta-analysis of estimated prevalence in Africa.

INTRODUCTION Although hepatitis C virus (HCV) screening is recommended for all HIV-infected patients initiating antiretroviral therapy, data on epidemiologic characteristics of HCV infection in resource-limited settings are scarce. METHODS We searched PubMed and EMBASE for studies assessing the prevalence of HCV infection among HIV-infected individuals in Africa and extracted data on laboratory methods used. Prevalence estimates from individual studies were combined for each country using random-effects meta-analysis. The importance of study design, population and setting as well as type of test (anti-HCV antibody tests and polymerase chain reactions) was examined with meta-regression. RESULTS Three randomized controlled trials, 28 cohort studies and 121 cross-sectional analyses with 108,180 HIV-infected individuals from 35 countries were included. The majority of data came from outpatient populations (55%), followed by blood donors (15%) and pregnant women (14%). Based on estimates from 159 study populations, anti-HCV positivity prevalence ranged between 3.3% (95% confidence interval (CI) 1.8-4.7) in Southern Africa and 42.3% (95% CI 4.1-80.5) in North Africa. Study design, type of setting and age distribution did not influence this prevalence significantly. The prevalence of replicating HCV infection, estimated from data of 29 cohorts, was 2.0% (95% CI 1.5-2.6). Ten studies from nine countries reported the HCV genotype of 74 samples, 53% were genotype 1, 24% genotype 2, 14% genotype 4 and 9% genotypes 3, 5 or 6. CONCLUSIONS The prevalence of anti-HCV antibodies is high in HIV-infected patients in Africa, but replicating HCV infection is rare and varies widely across countries.

Evaluation of the city of Houston HIV/STD prevention program in Houston Independent School District (HISD) high schools

This cross-sectional study was undertaken to evaluate the impact in terms of HIV/STD knowledge and sexual behavior that the City of Houston HIV/STD prevention program in HISD high schools has had on students who have participated in it by comparing them with their peers who have not, based on self reports. The study further evaluated the program cost-effectiveness for averting future HIV infections by computing Cost-Utility Ratios based on reported sexual behavior. ^ Mixed results were obtained, indicating a statistically significant difference in knowledge with the intervention group having scored higher (p-value 0.001) but not for any of the behaviors assessed. The knowledge score outcome's overall p-value after adjusting for each stratifying variable (age, grade, gender and ethnicity) was statistically significant. The Odds Ratio of intervention group participants aged 15 years or more scoring 70% or higher was 1.86 times; that of intervention group female participants was 2.29 times; and that of intervention group Black/African American participants was 2.47 times relative to their comparison group counterparts. The knowledge score results remained statistically significant in the logistic regression model, which controlled for age, grade level, gender and ethnicity. The Odds Ratio in this case was 1.74. ^ Three scenarios based on the difference in the risk of HIV infection between the intervention and comparison group were used for computation of Cost-Utility Ratios: Base, worst and best-case scenario. The best-case scenario yielded cost-effective results for male participants and cost-saving results for female participants when using ethnicity-adjusted HIV prevalence. The scenario remained cost-effective for female participants when using the unadjusted HIV prevalence. ^ The challenge to the program is to devise approaches that can enhance benefits for male participants. If it is a threshold problem implying that male participants require more intensive programs for behavioral change, then programs should first be piloted among boys before being implemented across the board. If it is a reflection of gender differences, then we might have to go back to the drawing board and engage boys in focus group discussions that will help formulate more effective programs. Gender-blind approaches currently in vogue do not seem to be working. ^

Evaluation of the T-SPOT(RTM).TB test in the diagnosis of latent tuberculosis infection in HIV-infected children in Uganda

Background. About a third of the world’s population is infected with tuberculosis (TB) with sub-Saharan Africa being the worst hit. Uganda is ranked 16th among the countries with the biggest TB burden. The burden in children however has not been determined. The burden of TB has been worsened by the advent of HIV and TB is the leading cause of mortality in HIV infected individuals. Development of TB disease can be prevented if TB is diagnosed during its latent stage and treated with isoniazid. For over a century, latent TB infection (LTBI) was diagnosed using the Tuberculin Skin Test (TST). New interferon gamma release assays (IGRA) have been approved by FDA for the diagnosis of LTBI and adult studies have shown that IGRAs are superior to the TST but there have been few studies in children especially in areas of high TB and HIV endemicity. ^ Objective. The objective of this study was to examine whether the IGRAs had a role in LTBI diagnosis in HIV infected children in Uganda. ^ Methods. Three hundred and eighty one (381) children were recruited at the Baylor College of Medicine-Bristol Meyers Squibb Children’s Clinical Center of Excellence at Mulago Hospital, Kampala, Uganda between March and August 2010. All the children were subjected to a TST and T-SPOT ®.TB test which was the IGRA chosen for this study. Sputum examination and chest x-rays were also done to rule out active TB. ^ Results. There was no statistically significant difference between the tests. The agreement between the two assays was 95.9% and the kappa statistic was 0.7 (95% CI: 0.55–0.85, p-value<0.05) indicating a substantial or good agreement. The TST was associated with older age and higher weight for age z-scores but the T-SPOT®. TB was not. Both tests were associated with history of taking anti-retroviral therapy (ART). ^ Conclusion. Before promoting use of IGRAs in children living in HIV/TB endemic countries, more research needs to be done. ^

The performance of interferon-gamma release assays in tuberculosis patients with type II diabetes

The sensitivity of Interferon-γ release assays for detection of Mycobacterium tuberculosis (MTB) infection or disease is affected by conditions that depress host immunity (such as HIV). It is critical to determine whether these assays are affected by diabetes and related conditions (i.e. hyperglycemia, chronic hyperglycemia, or being overweight/obese) given that immune impairment is thought to underline susceptibility to tuberculosis (TB) in people with diabetes. This is important for tuberculosis control due to the millions of type 2 diabetes patients at risk for tuberculosis worldwide.^ The objective of this study was to identify host characteristics, including diabetes, that may affect the sensitivity of two commercially available Interferon-γ (IFN-γ) release assays (IGRA), the QuantiFERON®-TB Gold (QFT-G) and the T-SPOT®.TB in active TB patients. We further explored whether IFN-γ secretion in response to MTB antigens (ESAT-6 and CFP-10) is associated with diabetes and its defining characteristics (high blood glucose, high HbA1c, high BMI). To achieve these objectives, the sensitivity of QFT-G and T-SPOT. TB assays were evaluated in newly diagnosed, tuberculosis confirmed (by positive smear for acid fast bacilli and/or positive culture for MTB) adults enrolled at Texas and Mexico study sites between March 2006 and April 2009. Univariate and multivariate models were constructed to identify host characteristics associated with IGRA result and level of IFN-γ secretion.^ QFT-G was positive in 68% of tuberculosis patients. Those with diabetes, chronic hyperglycemia or obesity were more likely to have a positive QFT-G result, and to secrete higher levels of IFN-γ in response to the mycobacterial antigens (p<0.05). Previous history of BCG vaccination was the only other host characteristic associated with QFT-G result, whereby a higher proportion of non-BCG vaccinated persons were QFT-G positive, in comparison to vaccinated persons. In a separate group of patients, the T-SPOT.TB was 94% sensitive, with similar performance in all tuberculosis patients, regardless of host characteristics.^ In summary, we have demonstrated the validity of QFT-G and T-SPOT. TB to support the diagnosis of TB in patients with a range of host characteristics, but most notably in patients with diabetes. We also confirmed that TB patients with diabetes and associated characteristics (chronic hyperglycemia or BMI) secreted higher titers of IFN-γ when stimulated with MTB specific antigens, in comparison to patients without these characteristics. Together, these findings suggest that the mechanism by which diabetes increases risk to TB may not be explained by the inability to secrete IFN-γ, a key cytokine for TB control.^

Anal warts and their predictors among HIV-infected women

Human papillomavirus (HPV) is a necessary cause of cervical cancer and is also strongly associated with anal cancer. While different factors such as CD4+ cell count, HIV RNA viral load, smoking status, and cytological screening results have been identified as risk factors for the infection of HPV high-risk types and associated cancers, much less is known about the association between those risk factors and the infection of HPV low-risk types and anogential warts. In this dissertation, a public dataset (release P09) obtained from the Women's Interagency HIV Study (WIHS) was used to examine the effects of those risk factors on the size of the largest anal warts in HIV-infected women in the United States. Linear mixed modeling was used to address this research question. ^ The prevalence of anal warts at baseline for WIHS participants was higher than other populations. Incidence of anal warts in HIV-infected women was significantly higher than that of HIV-uninfected women [4.15 cases per 100 person-years (95% CI: 3.83–4.77) vs. 1.30 cases per 100 person-years (95% CI: 1.00–1.58), respectively]. There appeared to be an inverse association between the size of the largest anal wart and CD4+ cell count at baseline visit, however it was not statistically significant. There was no association between size of the largest anal wart and CD4+ cell count or HIV RNA viral load over time among HIV-infected women. There was also no association between the size of the largest anal wart and current smoking over time in HIV-infected women, even though smokers had larger warts at baseline than non-smokers. Finally, even though a woman with Pap smear results of ASCUS/LGSIL was found to have an anal wart larger than a woman with normal cervical Pap smear results the relationship between the size of the largest anal wart with cervical Pap smear results over time remains unclear. ^ Although the associations between these risk factors and the size of the largest anal wart over time in HIV-infected women could not be firmly established, this dissertation poses several questions concerning anal wart development for further exploration: (1) the role of immune function (i.e., CD4+ cell count), (2) the role of smoking status and the interaction between smoking status with other risk factors (e.g., CD4+ cell count or HIV RNA viral load), (3) the molecular mechanism of smoking on anal warts over time, (4) the potential for development of a screening program using anal Pap smear in HIV-infected women, and (5) how cost-effective and efficacious would an anal Pap smear screening program be in this high-risk population. ^

Misoprostol in addition to routine treatment of postpartum hemorrhage: A hospital-based randomized-controlled trial in Karachi, Pakistan

Background: Postpartum hemorrhage (PPH) remains a major killer of women worldwide. Standard uterotonic treatments used to control postpartum bleeding do not always work and are not always available. Misoprostol's potential as a treatment option for PPH is increasingly known, but its use remains ad hoc and available evidence does not support the safety or efficacy of one particular regimen. This study aimed to determine the adjunct benefit of misoprostol when combined with standard oxytocics for PPH treatment. Methods: A randomized controlled trial was conducted in four Karachi hospitals from December 2005 – April 2007 to assess the benefit of a 600 mcg dose of misoprostol given sublingually in addition to standard oxytocics for postpartum hemorrhage treatment. Consenting women had their blood loss measured after normal vaginal delivery and were enrolled in the study after losing more than 500 ml of blood. Women were randomly assigned to receive either 600 mcg sublingual misoprostol or matching placebo in addition to standard PPH treatment with injectable oxytocics. Both women and providers were blinded to the treatment assignment. Blood loss was collected until active bleeding stopped and for a minimum of one hour after PPH diagnosis. Total blood loss, hemoglobin measures, and treatment outcomes were recorded for all participants. Results: Due to a much lower rate of PPH than expected (1.2%), only sixty-one patients were diagnosed and treated for their PPH in this study, and we were therefore unable to measure statistical significance in any of the primary endpoints. The addition of 600 mcg sublingual misoprostol to standard PPH treatments does, however, suggest a trend in reduced postpartum blood loss, a smaller drop in postpartum hemoglobin, and need for fewer additional interventions. Women who bled less overall had a significantly smaller drop in hemoglobin and received fewer additional interventions. There were no hysterectomies or maternal deaths among study participants. The rate of transient shivering and fever was significantly higher among women receiving misoprostol Conclusion: A 600 mcg dose of misoprostol given sublingually shows promise as an adjunct treatment for PPH and its use should continue to be explored for its life-saving potential in the care of women experiencing PPH. Trial Registration: Clinical trials.gov, Registry No. NCT00116480

Water balance measurements on Samoylov Island during campaign Lena2011

The summer water balance of a typical Siberian polygonal tundra catchment is investigated in order to identify the spatial and temporal dynamics of its main hydrological processes. The results show that, besides precipitation and evapotranspiration, lateral flow considerably influences the site-specific hydrological conditions. The prominent microtopography of the polygonal tundra strongly controls lateral flow and storage behaviour of the investigated catchment. Intact rims of low-centred polygons build hydrological barriers, which release storage water later in summer than polygons with degraded rims and troughs above degraded ice wedges. The barrier function of rims is strongly controlled by soil thaw, which opens new subsurface flow paths and increases subsurface hydrological connectivity. Therefore, soil thaw dynamics determine the magnitude and timing of subsurface outflow and the redistribution of storage within the catchment. Hydraulic conductivities in the elevated polygonal rims sharply decrease with the transition from organic to mineral layers. This interface causes a rapid shallow subsurface drainage of rainwater towards the depressed polygon centres and troughs. The re-release of storage water from the centres through deeper and less conductive layers helps maintain a high water table in the surface drainage network of troughs throughout the summer.

Voltage dependence of the pattern and frequency of discrete Ca2+ release events after brief repriming in frog skeletal muscle

Applying a brief repolarizing pre-pulse to a depolarized frog skeletal muscle fiber restores a small fraction of the transverse tubule membrane voltage sensors from the inactivated state. During a subsequent depolarizing test pulse we detected brief, highly localized elevations of myoplasmic Ca2+ concentration (Ca2+ “sparks”) initiated by restored voltage sensors in individual triads at all test pulse voltages. The latency histogram of these events gives the gating pattern of the sarcoplasmic reticulum (SR) calcium release channels controlled by the restored voltage sensors. Both event frequency and clustering of events near the start of the test pulse increase with test pulse depolarization. The macroscopic SR calcium release waveform, obtained from the spark latency histogram and the estimated open time of the channel or channels underlying a spark, exhibits an early peak and rapid marked decline during large depolarizations. For smaller depolarizations, the release waveform exhibits a smaller peak and a slower decline. However, the mean use time and mean amplitude of the individual sparks are quite similar at all test depolarizations and at all times during a given depolarization, indicating that the channel open times and conductances underlying sparks are essentially independent of voltage. Thus, the voltage dependence of SR Ca2+ release is due to changes in the frequency and pattern of occurrence of individual, voltage-independent, discrete release events.

A remarkable, precisely timed release of hyperglycemic hormone from endocrine cells in the gut is associated with ecdysis in the crab Carcinus maenas

Molting or ecdysis is the most fundamentally important process in arthropod life history, because shedding of the exoskeleton is an absolute prerequisite for growth and metamorphosis. Although the hormonal mechanisms driving ecdysis in insects have been studied extensively, nothing is known about these processes in crustaceans. During late premolt and during ecdysis in the crab Carcinus maenas, we observed a precise and reproducible surge in hemolymph hyperglycemic hormone (CHH) levels, which was over 100-fold greater than levels seen in intermolt animals. The source of this hormone surge was not from the eyestalk neurosecretory tissues but from previously undescribed endocrine cells (paraneurons), in defined areas of the foregut and hindgut. During premolt (the only time when CHH is expressed by these tissues), the gut is the largest endocrine tissue in the crab. The CHH surge, which is a result of an unusual, almost complete discharge of the contents of the gut endocrine cell, regulates water and ion uptake during molting, thus allowing the swelling necessary for successful ecdysis and the subsequent increase in size during postmolt. This study defines an endocrine brain/gut axis in the arthropods. We propose that the ionoregulatory process controlled by CHH may be common to arthropods, in that, for insects, a similar mechanism seems to be involved in antidiuresis. It also seems likely that a cascade of very precisely coordinated release of (neuro) hormones controls ecdysis.

Specific therapy regimes could lead to long-term immunological control of HIV

We use mathematical models to study the relationship between HIV and the immune system during the natural course of infection and in the context of different antiviral treatment regimes. The models suggest that an efficient cytotoxic T lymphocyte (CTL) memory response is required to control the virus. We define CTL memory as long-term persistence of CTL precursors in the absence of antigen. Infection and depletion of CD4+ T helper cells interfere with CTL memory generation, resulting in persistent viral replication and disease progression. We find that antiviral drug therapy during primary infection can enable the development of CTL memory. In chronically infected patients, specific treatment schedules, either including deliberate drug holidays or antigenic boosts of the immune system, can lead to a re-establishment of CTL memory. Whether such treatment regimes would lead to long-term immunologic control deserves investigation under carefully controlled conditions.

Polyazamacrolides from ladybird beetles: Ring-size selective oligomerization

The pupal defensive secretion of the 24-pointed ladybird beetle, Subcoccinella vigintiquatuorpunctata, consists of a mixture of macrocyclic polyamines, dominated by the three dimeric, 30-membered macrocycles 11-13, derived from the two building blocks 11-(2-hydoxyethylamino)-5-tetradecenoic acid (9) and 11-(2-hydoxyethylamino)-5,8-tetradecadienoic acid (10). Smaller amounts of the four possible cyclic trimers of 9 and 10 were also detected, corresponding to 45-membered macrocycles. Structural assignments were based on NMR-spectroscopic investigations and HPLC–MS analyses. In addition, the all-S absolute configuration of the S. vigintiquatuorpunctata macrocycles was determined by comparison of derivatives of the natural material with enantiomerically pure synthetic samples. Comparing this alkaloid mixture with that of the pupal defensive secretion in related ladybird beetle species indicates that the degree of oligomerization of the 2-hydroxyethylamino carboxylic acid building blocks can be carefully controlled by the insects.