A scoping review of interventions to mitigate common non-communicable diseases among people with TB.

BACKGROUND: Recommendations have been made to integrate screening for common non-communicable diseases (NCDs) within TB programs. However, we must ensure screening is tied to evidence-based interventions before scale-up. We aimed to map the existing evidence regarding interventions that address NCDs that most commonly affect people with TB.METHODS: We systematically searched PubMed, Medline, and Embase for studies that evaluated interventions to mitigate respiratory disease, cardiovascular disease, alcohol and substance use disorder, and mental health disorders among people with TB. We excluded studies that only screened for comorbidity but resulted in no further intervention. We also excluded studies focusing on smoking cessation interventions for which evidence-based guidelines are well established.RESULTS: The search identified 20 studies that met our inclusion criteria. The most commonly evaluated intervention was referral for diabetes care (6 studies). Other interventions included pulmonary rehabilitation (5 studies), care programs for alcohol use disorder (4 studies), and psychosocial support or individual counselling (5 studies).CONCLUSION: There is limited robust evidence to support identified interventions in changing individual outcomes, and a significant knowledge gap remains on the long-term durability of the interventions´ clinical benefit, reach, and effectiveness. Implementation research demonstrating feasibility and effectiveness is needed before scaling up.

Active case-finding in contacts of people with TB.

BACKGROUND: Exposure to people with TB substantially elevates a person's risk of tuberculous infection and TB disease. Systematic screening of TB contacts enables the early detection and treatment of co-prevalent disease, and the opportunity to prevent future TB disease. However, scale-up of contact investigation in high TB transmission settings remains limited.METHODS: We undertook a narrative review to evaluate the evidence for contact investigation and identify strategies that TB programmes may consider when introducing contact investigation and management.RESULTS: Selection of contacts for priority screening depends upon their proximity and duration of exposure, along with their susceptibility to develop TB. Screening algorithms can be tailored to the target population, the availability of diagnostic tests and preventive therapy, and healthcare worker expertise. Contact investigation may be performed in the household or at communal locations. Local contact investigation policies should support vulnerable patients, and ensure that drop-out during screening can be mitigated. Ethical issues should be anticipated and addressed in each setting.CONCLUSION: Contact investigation is an important strategy for TB elimination. While its epidemiological impact will be greatest in lower-transmission settings, the early detection and prevention of TB have important benefits for contacts and their communities.

Resource implications of the latent tuberculosis cascade of care: a time and motion study in five countries.

BACKGROUND: The End TB Strategy calls for global scale-up of preventive treatment for latent tuberculosis infection (LTBI), but little information is available about the associated human resource requirements. Our study aimed to quantify the healthcare worker (HCW) time needed to perform the tasks associated with each step along the LTBI cascade of care for household contacts of TB patients. METHODS: We conducted a time and motion (TAM) study between January 2018 and March 2019, in which consenting HCWs were observed throughout a typical workday. The precise time spent was recorded in pre-specified categories of work activities for each step along the cascade. A linear mixed model was fit to estimate the time at each step. RESULTS: A total of 173 HCWs in Benin, Canada, Ghana, Indonesia, and Vietnam participated. The greatest amount of time was spent for the medical evaluation (median: 11 min; IQR: 6-16), while the least time was spent on reading a tuberculin skin test (TST) (median: 4 min; IQR: 2-9). The greatest variability was seen in the time spent for each medical evaluation, while TST placement and reading showed the least variability. The total time required to complete all steps along the LTBI cascade, from identification of household contacts (HHC) through to treatment initiation ranged from 1.8 h per index TB patient in Vietnam to 5.2 h in Ghana. CONCLUSIONS: Our findings suggest that the time requirements are very modest to perform each step in the latent TB cascade of care, but to achieve full identification and management of all household contacts will require additional human resources in many settings.

Introduction of spirometry into clinical practice in Georgetown, Guyana: quality and diagnostic outcomes.

SETTING: Georgetown Public Hospital Corporation (GPHC), a 600-bed publicly funded referral hospital in Georgetown, Guyana. OBJECTIVE: To assess spirometry quality and diagnostic outcomes 2 years after the introduction of spirometry into routine clinical practice at GPHC. DESIGN: We performed a retrospective review of 476 consecutive spirometry assessments performed from November 2013 to November 2015. We assessed the proportion and trend of spirometry tests meeting acceptability criteria, along with diagnostic interpretations and spirometry laboratory referral patterns. RESULTS: Overall, 80.4% of the 454 initial spirometry measurements on unique patients met the acceptability criteria, with no significant change in the proportion of acceptable spirometry over the study period (P = 0.450). Of the 369 (81.3%) first tests considered interpretable, 139 (30.6%) were normal, 151 (33.3%) were obstructive, 54 (11.9%) were suggestive of a restrictive pattern, 25 (5.5%) were suggestive of a mixed disorder and 119 (26.2%) tests met the definition of reversibility. CONCLUSION: Over a 2-year period, high-quality spirometry was performed in GPHC, a publicly funded hospital in a middle-income country with no pre-existing specialised respiratory service.

Spatio-temporal analysis of tuberculous infection risk among clients of a homeless shelter during an outbreak.

SETTING: British Columbia (BC) has a low incidence of tuberculosis (TB), with the burden of endogenously acquired disease concentrated among vulnerable populations, including the homeless. In May 2008, a TB outbreak began in a BC homeless shelter, with a single index case seeding multiple secondary cases within the shelter. OBJECTIVE: To use nightly shelter records to quantify the risk of latent tuberculous infection (LTBI) among shelter clients as a function of their sleeping distance from and duration of exposure to the index case. DESIGN: Distance and duration of exposure were visualised and assessed using logistic regression with LTBI status as outcome. We used a novel machine learning approach to establish exposure thresholds that optimally separated infected and non-infected individuals. RESULTS: Of 161 exposed shelter clients, 58 had a recorded outcome of infected (n = 39) or non-infected (n = 19). Only duration of exposure to the index was associated with increased odds of infection (OR 1.26); stays of ⩾ 5 nights put shelter clients at higher odds of infection (OR 4.97). CONCLUSION: The unique data set and analytical approach suggested that, in a shelter environment, long-term clients are at highest risk of LTBI and should be prioritised for screening during an outbreak investigation.

Chest radiography for active tuberculosis case finding in the homeless: a systematic review and meta-analysis.

SETTING: In low-incidence regions, tuberculosis (TB) often affects vulnerable populations. Guidelines recommend active case finding (ACF) in homeless populations, but there is no consensus on a preferred screening method. OBJECTIVE: We performed a systematic review and meta-analysis to evaluate the use of chest X-ray (CXR) screening in ACF for TB in homeless populations. DESIGN: Articles were identified through EMBASE, Medline and the Cochrane Library. Studies using symptom screens, CXRs, sputum sweeps, tuberculin skin tests and/or interferon-gamma release assays to detect active TB in homeless populations were sought. Data were extracted using a standardised method by two reviewers and validated with an objective tool. RESULTS: Sixteen studies addressing CXR screening of homeless populations for active TB in low-incidence regions were analysed. The pooled prevalence of active TB in the 16 study cohorts was 931 per 100 000 population screened (95%CI 565-1534) and 782/100 000 CXR performed (95%CI 566-1079). Six of seven longitudinal screening programs reported a reduction in regional TB incidence after implementation of the CXR-based ACF programme. CONCLUSION: Our data suggest that CXR screening is a good tool for ACF in homeless populations in low-incidence regions.

Targeting adipose tissue via systemic gene therapy.

Adipose tissue has a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing cytomegalovirus promoter-regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver-specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8 and administered intravenously to 9- to 10-week-old ob/ob mice. Phenotypic changes were measured over an 8-week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose.

Therapeutic drug monitoring in the treatment of tuberculosis: a retrospective analysis.

SETTING: Tuberculosis (TB) in-patient treatment unit in Vancouver, Canada. OBJECTIVE: To examine the results of therapeutic drug monitoring (TDM) in anti-tuberculosis treatment. DESIGN: We performed a retrospective analysis of TDM data from 2000 to 2010. All in-patients treated for TB with TDM performed during their treatment course were included. RESULTS: TDM was performed on 52 patients in 76 treatment episodes from 2000 to 2010. Overall, 103/213 (48.4%) drug levels measured were low, and 5/213 (2.3%) were high. At least one drug level was low in 47/52 (90.3%) patients. Initial serum levels were low in respectively 76.6% and 68.4% of isoniazid (INH) and rifampicin (RMP) levels. In contrast, only 2.9% of initial pyrazinamide levels were low. Five patients with a susceptible strain on initial presentation later developed drug-resistant disease, with all five patients demonstrating at least one low drug level and two demonstrating multiple low levels. Dose adjustments were made in response to 26 INH and RMP levels, with variable serum responses. CONCLUSION: In this population with high rates of treatment failure and acquired resistance, we demonstrate that most patients had low drug levels. Prospective studies are required to examine the relationship between drug levels and clinical outcomes.

A randomised controlled trial of ribavirin in Crimean Congo haemorrhagic fever: ethical considerations.

The randomised controlled trial (RCT) constitutes a quantitative, comparative, controlled study of a particular treatment, and provides invaluable evidence regarding its pharmacotherapeutic efficacy. These studies are generally predicated upon the ethical principle of clinical equipoise. However, this may be insufficient to justify withholding treatment from a control group while assessing drug therapy in a potentially fatal disease. Thus, the criteria for randomisation, informed consent methodology and timing, and consideration of treatment options in such a scenario remain the province of medical ethics. This paper addresses the need for an RCT of ribavirin in the treatment of Crimean Congo haemorrhagic fever, and highlights underlying ethical concerns in light of the current medical, virological and ethical literature.

Inhibition of adrenaline and adenosine diphosphate induced platelet aggregation by Lansberg's hognose pit viper (Porthidium lansbergii hutmanni) venom.

The haemostatic components of venom from the genus Porthidium has been poorly studied, although it is known that severe manifestations occur when humans are envenomed, which include invasive oedema and disseminated ecchymosis. The effects of venom on blood platelets are commonly studied and are normally carried out with platelet-rich plasma (PRP). A series of crude venom dilutions was used to determine the effects of adenosine diphosphate (2 microM) and adrenaline (11 microM) induced platelet aggregation. Venom of Porthidium lansbergii hutmanni was fractioned by anionic exchange chromatography, and the fractions were also used to determine the 50% inhibition of adenosine diphosphate (ADP) and adrenaline-induced platelet aggregating dose (AD50). Crude venom has more effect in inhibiting adrenaline-induced aggregation (AD50 = 0.0043 microg) followed by the adenosine diphosphate (AD50 = 17 microg). Peaks I and II obtained by chromatography also inhibited adrenaline-induced platelet aggregation with an AD50 of 3.2 and 0.013 microg, respectively, and both peaks inhibited ADP-induced platelet aggregation with an AD50 of 10 microg. The main purpose of this work was to characterise the in vitro effects caused by P. lansbergii hutmanni crude venom and its fractions on the platelet aggregation mediated by adrenaline and ADP agonists.

Why practice reduces dual-task interference.

M. A. Van Selst, E. Ruthruff, and J. C. Johnston (1999) found that practice dramatically reduced dual-task interference in a Psychological Refractory Period (PRP) paradigm with 1 vocal response and 1 manual response. Results from 3 further experiments using the highly trained participants of M. A. Van Selst et al. (1999) support 4 main conclusions: (a) A processing bottleneck exists even after extensive practice; (b) the principal cause of the reduction in PRP interference with practice is shortening of Task 1 bottleneck stages; (c) a secondary cause is that 1 or more, but not all, of the Task 2 substages that are postponed before practice are not postponed after practice (i.e., become automatized); and (d) the extent of PRP reduction with practice depends on the modalities of the 2 responses. A control experiment with 2 manual response tasks showed less PRP reduction with practice than that found by Van Selst et al.

Attention and performance.

Recent progress in the study of attention and performance is discussed, focusing on the nature of attentional control and the effects of practice. Generally speaking, the effects of mental set are proving more pervasive than was previously suspected, whereas automaticity is proving less robust. Stimulus attributes (e.g. onsets, transients) thought to have a "wired-in" ability to capture attention automatically have been shown to capture attention only as a consequence of voluntarily adopted task sets. Recent research suggests that practice does not have as dramatic effects as is commonly believed. While it may turn out that some mental operations are automatized in the strongest sense, this may be uncommon. Recent work on task switching is also described; optimal engagement in a task set is proving to be intimately tied to learning operations triggered by the actual performance of a new task, not merely the anticipation of such performance.

A probabilistic approach to space-group determination from powder diffraction data.

An algorithm for the determination of the space-group symmetry of a crystal from powder diffraction data, based upon probability theory, is described. Specifically, the relative probabilities of different extinction symbols are assessed within a particular crystal system. In general, only a small number of extinction symbols are relatively highly probable and a single extinction symbol is often significantly more probable than any other. Several examples are presented to illustrate this approach.

Switching between simple cognitive tasks: the interaction of top-down and bottom-up factors.

How do top-down factors (e.g., task expectancy) and bottom-up factors (e.g., task recency) interact to produce an overall level of task readiness? This question was addressed by factorially manipulating task expectancy and task repetition in a task-switching paradigm. The effects of expectancy and repetition on response time tended to interact underadditively, but only because the traditional binary task-repetition variable lumps together all switch trials, ignoring variation in task lag. When the task-recency variable was scaled continuously, all 4 experiments instead showed additivity between expectancy and recency. The results indicated that expectancy and recency influence different stages of mental processing. One specific possibility (the configuration-execution model) is that task expectancy affects the time required to configure upcoming central operations, whereas task recency affects the time required to actually execute those central operations.

Visual search in complex displays: factors affecting conflict detection by air traffic controllers.

Recent free flight proposals to relax airspace constraints and give greater autonomy to aircraft have raised concerns about their impact on controller performance. Relaxing route and altitude restrictions would reduce the regularity of traffic through individual sectors, possibly impairing controller situation awareness. We examined the impact of this reduced regularity in four visual search experiments that tested controllers' detection of traffic conflicts in the four conditions created by factorial manipulation of fixed routes (present vs. absent) and altitude restrictions (present vs. absent). These four conditions were tested under varying levels of traffic load and conflict geometry (conflict time and conflict angle). Traffic load and conflict geometry showed strong and consistent effects in all experiments. Color coding altitude also substantially improved detection times. In contrast, removing altitude restrictions had only a small negative impact, and removing route restrictions had virtually no negative impact. In some cases conflict detection was actually better without fixed routes. The implications and limitations of these results for the feasibility of free flight are discussed. Actual or potential applications include providing guidance in the selection of free flight operational concepts.

Feline immunodeficiency virus vectors persistently transduce nondividing airway epithelia and correct the cystic fibrosis defect.

Several problems limit the application of gene transfer to correct the cystic fibrosis (CF) Cl(-) transport defect in airway epithelia. These include inefficient transduction with vectors applied to the apical surface, a low rate of division by airway epithelial cells, failure of transgene expression to persist, and immune responses to vectors or vector-encoded proteins. To address these issues, we used a feline immunodeficiency virus-based (FIV-based) vector. FIV vector formulated with a calcium chelator transduced fully differentiated, nondividing human airway epithelia when applied to the apical surface. FIV-based vector encoding the cystic fibrosis transmembrane conductance regulator cDNA corrected the Cl(-) transport defect in differentiated CF airway epithelia for the life of the culture (>3 months). When this approach was applied in vivo, FIV vector expressing beta-galactosidase transduced 1-14% of adult rabbit airway epithelia. Transduced cells were present in the conducting airways, bronchioles, and alveoli. Importantly, gene expression persisted, and cells with progenitor capacity were targeted. FIV-based lentiviral vectors may be useful for the treatment of genetic lung diseases such as CF. This article may have been published online in advance of the print edition.

Classification of small cell lung cancer and pulmonary carcinoid by gene expression profiles.

Small cell lung cancer is a common type of lung cancer that is generally classified within the spectrum of neuroendocrine lung neoplasms. Using high-density cDNA arrays, we profiled gene expression of small cell lung cancers and compared these expression profiles to those of normal bronchial epithelial cells and pulmonary carcinoids, which are classified as benign neuroendocrine tumors. We found the overall expression profiles of two small cell lung cancer cell lines, two microdissected tissue samples of primary small cell lung cancer, and cultured bronchial epithelial cells to be relatively similar to one another, with an average Pearson correlation coefficient for these comparisons of 0.63. However, we found the expression profiles of small cell lung cancers (and bronchial epithelial cells) to be surprisingly dissimilar to those of two samples of pulmonary carcinoid tumors, with an average correlation coefficient for these comparisons of 0.20. We then compared the pulmonary carcinoid expression profiles to those of two samples of infiltrating astrocytic brain cancers (oligodendroglioma and high-grade astrocytoma) and found similarity of gene expression among these four samples (average correlation coefficient, 0.57). These gene expression profiles suggest that small cell lung cancers are closely related to (and possibly derived from) epithelial cells, and that pulmonary carcinoids are related to neural crest-derived brain tumors. More generally, our results suggest that broad profiles of gene expression may reveal similarities and differences between tumors that are not apparent by traditional morphological criteria.