Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise.

The current active-latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies.

Beyond latent and active tuberculosis: a scoping review of conceptual frameworks.

There is growing recognition that tuberculosis (TB) infection and disease exists as a spectrum of states beyond the current binary classification of latent and active TB. Our aim was to systematically map and synthesize published conceptual frameworks for TB states. We searched MEDLINE, Embase and EMcare for review articles from 1946 to September 2023. We included 40 articles that explicitly described greater than two states for TB. We identified that terminology, definitions and diagnostic criteria for additional TB states within these articles were inconsistent. Eight broad conceptual themes were identified that were used to categorize TB states: State 0: Mycobacterium tuberculosis (Mtb) elimination with innate immune response (n = 25/40, 63%); State I: Mtb elimination by acquired immune response (n = 31/40, 78%); State II: Mtb infection not eliminated but controlled (n = 37/40, 93%); State III: Mtb infection not controlled (n = 24/40, 60%); State IV: bacteriologically positive without symptoms (n = 26/40, 65%); State V: signs or symptoms associated with TB (n = 39/40, 98%); State VI: severe or disseminated TB disease (n = 11/40, 28%); and State VII: previous history of TB (n = 5/40, 13%). Consensus on a non-binary framework that includes additional TB states is required to standardize scientific communication and to inform advancements in research, clinical and public health practice.

Operationalization of bi-directional screening for tuberculosis and diabetes in private sector healthcare clinics in Karachi, Pakistan.

BACKGROUND: Many countries are facing overlapping epidemics of tuberculosis (TB) and diabetes mellitus (DM). Diabetes increases the overall risk of developing Tuberculosis (TB) and contributes to adverse treatment outcomes. Active screening for both diseases can reduce TB transmission and prevent the development of complications of DM. We investigated bi-directional TB-DM screening in Karachi, Pakistan, a country that ranks fifth among high TB burden countries, and has the seventh highest country burden for DM. METHODS: Between February to November 2014, community-based screeners identified presumptive TB and DM through verbal screening at private health clinics. Individuals with presumptive TB were referred for a chest X-ray and Xpert MTB/RIF. Presumptive DM cases had random blood glucose (RBS) tested. All individuals with bacteriologically positive TB were referred for diabetes testing (RBS). All pre-diabetics and diabetics were referred for a chest X-ray and Xpert MTB/RIF test. The primary outcomes of this study were uptake of TB and DM testing. RESULTS: A total of 450,385 individuals were screened, of whom 18,109 had presumptive DM and 90,137 had presumptive TB. 14,550 of these individuals were presumptive for both DM and TB. The uptake of DM testing among those with presumptive diabetes was 26.1% while the uptake of TB testing among presumptive TB cases was 5.9%. Despite efforts to promote bi-directional screening of TB and DM, the uptake of TB testing among pre-diabetes and diabetes cases was only 4.7%, while the uptake of DM testing among MTB positive cases was 21.8%. CONCLUSION: While a high yield for TB was identified among pre-diabetics and diabetics along with a high yield of DM among individuals diagnosed with TB, there was a low uptake of TB testing amongst presumptive TB patients who were recorded as pre-diabetic or diabetic. Bi-directional screening for TB and DM which includes the integration of TB diagnostics, DM screening and TB-DM treatment within existing health care programs will need to address the operational challenges identified before implementing this as a strategy in public health programs.

Factors associated with month 2 smear non-conversion among Category 1 tuberculosis patients in Karachi, Pakistan.

Predictors of smear non-conversion at baseline can help identify cases at risk for failure of tuberculosis treatment. Retrospective data for smear-positive Category 1 patients in Karachi, Pakistan, was analyzed. Predictors of sputum conversion were determined using multiple logistic regression with sputum conversion as outcome variable and patient demographics, baseline weight, baseline sputum smear grade, case-finding approach as explanatory variables. Age ≥35 years, baseline sputum grade of 3+ were significantly associated with predicting sputum smear positivity at month 2 of treatment. Monitoring compliance to TB treatment should be considered amongst older patients and those with a high sputum grade at baseline.

Perceptions of anti-smoking messages amongst high school students in Pakistan.

BACKGROUND: Surveys have provided evidence that tobacco use is widely prevalent amongst the youth in Pakistan. Several reviews have evaluated the effectiveness of various tobacco control programs, however, few have taken into account the perceptions of students themselves regarding these measures. The aim of this study was to determine the most effective anti-smoking messages that can be delivered to high-school students in Pakistan, based on their self-rated perceptions. It also aimed to assess the impact of pictorial/multi-media messages compared with written health warnings and to discover differences in perceptions of smokers to those of non-smokers to health warning messages. METHODS: This study was carried out in five major cities of Pakistan in private English-medium schools. A presentation was delivered at each school that highlighted the well-established health consequences of smoking using both written health warnings and pictorial/multi-media health messages. Following the presentation, the participants filled out a graded questionnaire form, using which they rated the risk-factors and messages that they thought were most effective in stopping or preventing them from smoking. The Friedman test was used to rank responses to each of the questions in the form. The Wilcoxon Signed Rank test used to analyze the impact of pictorial/multi-media messages over written statements. The Mann Whitney U test was used to compare responses of smokers with those of non-smokers. RESULTS: Picture of an oral cavity cancer, videos of a cancer patient using an electronic voice box and a patient on a ventilator, were perceived to be the most effective anti-smoking messages by students. Addiction, harming others through passive smoking and impact of smoking on disposable incomes were perceived to be less effective messages. Pictorial/multi-media messages were perceived to be more effective than written health warnings. Health warnings were perceived as less effective amongst smokers compared to non-smokers. CONCLUSION: Graphic pictorial/multi-media health warnings that depict cosmetic and functional distortions were perceived as effective anti-smoking messages by English-medium high school students in Pakistan. Smokers demonstrated greater resistance to health promotion messages compared with non-smokers. Targeted interventions for high school students may be beneficial.

Stability-indicating ultra-performance liquid chromatography method for the estimation of thymoquinone and its application in biopharmaceutical studies.

Thymoquinone (THQ) is known for its neuroprotective and anti-convulsant properties in preclinical studies. We herewith describe a simple, rapid, selective, sensitive and stability-indicating UPLC method for the estimation of THQ and its application to biopharmaceutical studies such as in vitro release from nanoparticulate system and in vivo pharmacokinetic study. The method employed gradient elution using a Waters Acquity HSS-T3 C(18) (100 × 2.1 mm, 1.8 µm) UPLC column. The mobile phase consisted of water and acetonitrile, pumped at a flow rate of 0.5 mL/min. The injection volume was 5 µL and THQ was monitored at 294 nm wavelength with a total run time of 6 min. In solution as well as in plasma, the method was found to be linear (r ≥ 0.998), precise (CV ≤ 2.45%) and accurate (recovery ≥ 84.8%) in the selected concentration range of 0.1-0.8 µg/mL. Forced degradation studies revealed that THQ undergoes degradation under acidic, basic, oxidation and UV light stress conditions. However, the developed UPLC method could effectively resolve degradation product peaks from THQ. Further, no interference was found at the retention time of THQ from any plasma components, indicating selectivity of the developed method. For solutions, the limits of detection and quantitation of the method were found to be 0.001 and 0.0033 µg/mL, respectively; while in plasma they were 0.006 and 0.02 µg/mL, respectively. The validated method was successfully applied to quantify THQ in dissolution medium as well as oral in vivo pharmacokinetic study of THQ suspension and THQ- solid lipid nanoparticle (THQ-SLN) formulation. A 2-fold increase in the relative bioavailability was observed with the THQ-SLN compared with THQ. The results indicate that the SLN significantly increased plasma concentrations and retention within the systemic circulation.

Quantitative analysis of safranal in saffron extract and nanoparticle formulation by a validated high-performance thin-layer chromatographic method.

INTRODUCTION: Safranal is an effective anticonvulsant shown to act as an agonist at GABA(A) receptors. Nose to brain delivery via nanoparticle formulation might improve its brain delivery. A selective and sensitive analytical method is required for evaluation of safranal-based novel drug delivery systems. OBJECTIVE: To develop and validate a high-performance thin-layer chromatographic (HPTLC) method for the quantitative analysis of safranal as bulk, in saffron extract and in developed safranal-loaded nanoparticle formulation. METHODOLOGY: Chromatographic separation was achieved on silica gel pre-coated TLC aluminium plates 60F-254, using n-hexane:ethyl acetate (9 : 1, v/v) as the mobile phase. Quantitative analysis was carried out by densitometry at a wavelength of 310 nm. The method was validated and applied to detect related impurities, to analyse safranal in saffron extract and to evaluate safranal-loaded nanoparticles. RESULTS: Compact spots of safranal were observed at R(f) value 0.51 +/- 0.02. The method was linear (r = 0.9991) between 0.5 and 5.0 ng/spot. The intra- and inter-day precisions were 1.08-2.17 and 1. 86-3.47%, respectively. The limit of detection was 50 ng/spot and the limit of quantification was 150 ng/spot. The method proved to be accurate (recovery 97.4-102.0%) and was selective for safranal. Evaluation of safranal-loaded nanoparticle formulation demonstrated drug loading of 23.0%, encapsulation efficiency of 42.0% and sustained drug release following biphasic pattern. CONCLUSION: The present method is useful for the quantitative and qualitative analysis of safranal and safranal-loaded nanoparticle formulation. It provides significant advantages in terms of greater specificity and rapid analysis.

CNS drug delivery systems: novel approaches.

The brain is a delicate organ, and nature has very efficiently protected it. The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB). Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancers or heart diseases. The abysmally low number of potential therapeutics reaching commercial success is primarily due to the complexity of the CNS drug development. The clinical failure of many probable candidates is often, ascribable to poor delivery methods which do not pervade the unyielding BBB. It restricts the passive diffusion of many drugs into the brain and constitutes a significant obstacle in the pharmacological treatment of central nervous system (CNS) disorders. General methods that can enhance drug delivery to the brain are, therefore, of great pharmaceutical interest. Various strategies like non-invasive methods, including drug manipulation encompassing transformation into lipophilic analogues, prodrugs, chemical drug delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery and intranasal drug delivery, which exploits the olfactory and trigeminal neuronal pathways to deliver drugs to the brain, are widely used. On the other hand the invasive methods which primarily rely on disruption of the BBB integrity by osmotic or biochemical means, or direct intracranial drug delivery by intracerebroventricular, intracerebral or intrathecal administration after creating reversible openings in the head, are recognised. Extensive review pertaining specifically, to the patents relating to drug delivery across the CNS is currently available. However, many patents e.g. US63722506, US2002183683 etc., have been mentioned in a few articles. It is the objective of this article to expansively review drug delivery systems for CNS by discussing the recent patents available.