Tewodros Eguale

Human T Cell Responses to the ESAT-6 Antigen from Mycobacterium tuberculosis

Human T cell responses to ESAT-6 and eight synthetic overlapping peptides were investigated in tuberculosis (TB) patients and control subjects from regions of high and low endemicity for TB. ESAT-6 was recognized by 65% of all tuberculin purified protein derivative-responsive TB patients, whereas only 2 of 29 bacille Calmette-Guérin-vaccinated Danish healthy donors recognized this molecule. In Ethiopia, a high frequency (58%) of healthy contacts of TB patients recognized ESAT-6. All of the peptides were recognized by some donors, indicating that the molecule holds multiple epitopes. Danish and Ethiopian patients differed in the fine specificity of their peptide responses. Recognition of the C-terminal region (aa 72-95) was predominant in Danish patients, whereas recognition of aa 42-75 was predominant in Ethiopia. The relationship of these differences to the distribution of HLA types in the two populations is discussed. This study demonstrates that ESAT-6 is frequently recognized during early infection and holds potential as a component of a future TB-specific diagnostic reagent.

Immune Responses to the Mycobacterium tuberculosis-Specific Antigen ESAT-6 Signal Subclinical Infection among Contacts of Tuberculosis Patients

ABSTRACT Diagnosis of latent Mycobacterium tuberculosis infection is considered essential for tuberculosis control but is hampered by the lack of specific reagents. We report that strong recognition of tuberculosis complex-specific antigen ESAT-6 by healthy household contacts of tuberculosis patients correlates with the subsequent development of active tuberculosis during a 2-year follow-up period.

Medication-related falls in the elderly: causative factors and preventive strategies.

People are living to older age. Falls constitute a leading cause of injuries, hospitalization and deaths among the elderly. Older people fall more often for a variety of reasons: alterations in physiology and physical functioning, and the use (and misuse) of medications needed to manage their multiple conditions. Pharmacological factors that place the elderly at greater risk of drug-related side effects include changes in body composition, serum albumin, total body water, and hepatic and renal functioning. Drug use is one of the most modifiable risk factors for falls and falls-related injuries. Fall-risk increasing drugs (FRIDs) include drugs for cardiovascular diseases (such as digoxin, type 1a anti-arrhythmics and diuretics), benzodiazepines, antidepressants, antiepileptics, antipsychotics, antiparkinsonian drugs, opioids and urological spasmolytics. Psychotropic and benzodiazepine drug use is most consistently associated with falls. Despite the promise of a more favourable side-effect profile, evidence shows that atypical antipsychotic medications and selective serotonin reuptake inhibitor antidepressants do not reduce the risk of falls and hip fractures. Despite multiple efforts with regards to managing medication-associated falls, there is no clear evidence for an effective intervention. Stopping or lowering the dose of psychotropic drugs and benzodiazepines does work, but ensuring a patient remains off these drugs is a challenge. Computer-assisted alerts coupled with electronic prescribing tools are a promising approach to lowering the risk of falls as the use of information technologies expands within healthcare.

Circulating TNF-alpha, TGF-beta, and IL-10 in tuberculosis patients and healthy contacts.

Levels of tumour necrosis factor (TNF)‐α, transforming growth factor (TGF)‐β, and interleukin (IL)‐10 in plasma of pulmonary tuberculosis (TB) patients and healthy contacts and plasma and pleural fluid of patients with tuberculous pleuritis were examined by enzyme immunoassay. Plasma TNF‐α and IL‐10 were elevated to significant levels in healthy contacts. High levels of TGF‐β and IL‐10 were also detected in plasma from TB patients and healthy contacts. Pleural fluid contained all three cytokines with the level of IL‐10 being highest followed by TGF‐β and TNF‐α. Plasma of tuberculous pleuritis patients also had detectable levels of the three cytokines. Increased levels of TNF‐α in plasma of contacts and to some extent pleural fluid of pleuritis patients, is perhaps to limit the infection, while elevated IL‐10 in plasma of TB patients and contacts and pleural fluid would perhaps modulate excess proinflammation. Elevated TGF‐β in TB patients suggests its role in the immunopathogenesis.

Drug, Patient, and Physician Characteristics Associated With Off-label Prescribing in Primary Care

BACKGROUND Off-label prescribing may lead to adverse drug events. Little is known about its prevalence and determinants resulting from challenges in documenting treatment indication. METHODS We used the Medical Office of the XXI Century electronic health record network in Quebec, Canada, where documentation of treatment indication is mandatory. One hundred thirteen primary care physicians wrote 253 347 electronic prescriptions for 50 823 patients from January 2005 through December 2009. Each drug indication was classified as on-label or off-label according to the Health Canada drug database. We identified off-label uses lacking strong scientific evidence. Alternating logistic regression was used to estimate the association between off-label use and drug, patient, and physician characteristics. RESULTS The prevalence of off-label use was 11.0%; of the off-label prescriptions, 79.0% lacked strong scientific evidence. Off-label use was highest for central nervous system drugs (26.3%), including anticonvulsants (66.6%), antipsychotics (43.8%), and antidepressants (33.4%). Drugs with 3 or 4 approved indications were associated with less off-label use compared with drugs with 1 or 2 approved indications (6.7% vs 15.7%; adjusted odds ratio [AOR], 0.44; 95% CI, 0.41-0.48). Drugs approved after 1995 were prescribed off-label less often than were drugs approved before 1981 (8.0% vs 17.0%; AOR, 0.46; 95% CI, 0.42-0.50). Patients with a Charlson Comorbidity Index of 1 or higher had lower off-label use than did patients with an index of 0 (9.6% vs 11.7%; AOR, 0.94; 95% CI, 0.91-0.97). Physicians with evidence-based orientation were less likely to prescribe off-label (AOR, 0.93; 95% CI, 0.88-0.99), a 7% reduction per 5 points in the evidence section of the Evidence-Practicality-Conformity Scale. CONCLUSIONS Off-label prescribing is common and varies by drug, patient, and physician characteristics. Electronic prescribing should document treatment indication to monitor off-label use.

Association of Off-label Drug Use and Adverse Drug Events in an Adult Population

IMPORTANCE Off-label use of prescription drugs has been identified as an important contributor to preventable adverse drug events (ADEs) in children. Despite concerns regarding adverse outcomes, to date, no systematic investigation of the effects of off-label drug use in adult populations has been performed. OBJECTIVE To monitor and evaluate off-label use of prescription drugs and its effect on ADEs in an adult population. DESIGN, SETTING, AND PARTICIPANTS A cohort of 46,021 patients who received 151,305 incident prescribed drugs was assembled from primary care clinics in Quebec, Canada, using the Medical Office of the XXIst Century electronic health record, which supports documentation of treatment indications and treatment outcomes. Prescriptions dispensed from January 1, 2005, through December 30, 2009, were followed up from the date of the prescription to the date the drug use was discontinued, the end of treatment, or the end of follow-up (December 30, 2010). Data were analyzed from January 5, 2012, to March 15, 2015. EXPOSURES Off-label prescription drug use with and without strong scientific evidence. MAIN OUTCOMES AND MEASURES Adverse drug events in off-label use with and without strong scientific evidence. Analysis used multivariate marginal Cox proportional hazards regression for clustered data with the drug as the unit of analysis. RESULTS A total of 3484 ADEs were found in the 46,021 study patients, with an incidence rate of 13.2 per 10,000 person-months. The rate of ADEs for off-label use (19.7 per 10,000 person-months) was higher than that for on-label use (12.5 per 10,000 person-months) (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.30-1.60). Off-label use lacking strong scientific evidence had a higher ADE rate (21.7 per 10,000 person-months) compared with on-label use (AHR, 1.54; 95% CI, 1.37-1.72). However, off-label use with strong scientific evidence had the same risk for ADEs as on-label use (AHR, 1.10; 95% CI, 0.88-1.38). The risks for ADEs were higher for drugs approved from 1981 to 1995 (14.4 per 10,000 person-months; AHR, 1.62; 95% CI, 1.45-1.80) and for those used by women (14.3 per 10,000 person-months; AHR, 1.17; 95% CI, 1.06-1.28), patients receiving 5 to 7 drugs (12.1 per 10,000 person-months; AHR, 3.23; 95% CI, 2.66-3.92), and patients receiving cardiovascular drugs (15.9 per 10,000 person-months; AHR, 3.30; 95% CI, 2.67-4.08) and anti-infectives (66.2 per 10,000 person-months; AHR, 6.33; 95% CI, 4.58-8.76). Patients with a 1-unit increase in the continuity of care index had a 19% increase in ADEs (AHR, 1.19; 95% CI, 1.12-1.26). CONCLUSIONS AND RELEVANCE Off-label use of prescription drugs is associated with ADEs. Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence. Future electronic health records should be designed to enable postmarket surveillance of treatment indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs.

Computerised physician order entry-related medication errors: analysis of reported errors and vulnerability testing of current systems

Importance Medication computerised provider order entry (CPOE) has been shown to decrease errors and is being widely adopted. However, CPOE also has potential for introducing or contributing to errors. Objectives The objectives of this study are to (a) analyse medication error reports where CPOE was reported as a ‘contributing cause’ and (b) develop ‘use cases’ based on these reports to test vulnerability of current CPOE systems to these errors. Methods A review of medication errors reported to United States Pharmacopeia MEDMARX reporting system was made, and a taxonomy was developed for CPOE-related errors. For each error we evaluated what went wrong and why and identified potential prevention strategies and recurring error scenarios. These scenarios were then used to test vulnerability of leading CPOE systems, asking typical users to enter these erroneous orders to assess the degree to which these problematic orders could be entered. Results Between 2003 and 2010, 1.04 million medication errors were reported to MEDMARX, of which 63 040 were reported as CPOE related. A review of 10 060 CPOE-related cases was used to derive 101 codes describing what went wrong, 67 codes describing reasons why errors occurred, 73 codes describing potential prevention strategies and 21 codes describing recurring error scenarios. Ability to enter these erroneous order scenarios was tested on 13 CPOE systems at 16 sites. Overall, 298 (79.5%) of the erroneous orders were able to be entered including 100 (28.0%) being ‘easily’ placed, another 101 (28.3%) with only minor workarounds and no warnings. Conclusions and relevance Medication error reports provide valuable information for understanding CPOE-related errors. Reports were useful for developing taxonomy and identifying recurring errors to which current CPOE systems are vulnerable. Enhanced monitoring, reporting and testing of CPOE systems are important to improve CPOE safety.

Influence of Physicians' Management and Communication Ability on Patients' Persistence With Antihypertensive Medication

BACKGROUND Less than 75% of people prescribed antihypertensive medication are still using treatment after 6 months. Physicians determine treatment, educate patients, manage side effects, and influence patient knowledge and motivation. Although physician communication ability likely influences persistence, little is known about the importance of medical management skills, even though these abilities can be enhanced through educational and practice interventions. The purpose of this study was to determine whether a physicians medical management and communication ability influence persistence with antihypertensive treatment. METHODS This was a population-based study of 13,205 hypertensive patients who started antihypertensive medication prescribed by a cohort of 645 physicians entering practice in Quebec, Canada, between 1993 and 2007. Medical Council of Canada licensing examination scores were used to assess medical management and communication ability. Population-based prescription and medical services databases were used to assess starting therapy, treatment changes, comorbidity, and persistence with antihypertensive treatment in the first 6 months. RESULTS Within 6 months after starting treatment, 2926 patients (22.2%) had discontinued all antihypertensive medication. The risk of nonpersistence was reduced for patients who were treated by physicians with better medical management (odds ratio per 2-SD increase in score, 0.74; 95% confidence interval, 0.63-0.87) and communication (0.88; 0.78-1.00) ability and with early therapy changes (odds ratio, 0.45; 95% confidence interval, 0.37-0.54), more follow-up visits, and nondiuretics as the initial choice of therapy. Medical management ability was responsible for preventing 15.8% (95% confidence interval, 7.5%-23.3%) of nonpersistence. CONCLUSION Better clinical decision-making and data collection skills and early modifications in therapy improve persistence with antihypertensive therapy.

The effectiveness of a new generation of computerized drug alerts in reducing the risk of injury from drug side effects: a cluster randomized trial

Context Computerized drug alerts for psychotropic drugs are expected to reduce fall-related injuries in older adults. However, physicians over-ride most alerts because they believe the benefit of the drugs exceeds the risk. Objective To determine whether computerized prescribing decision support with patient-specific risk estimates would increase physician response to psychotropic drug alerts and reduce injury risk in older people. Design Cluster randomized controlled trial of 81 family physicians and 5628 of their patients aged 65 and older who were prescribed psychotropic medication. Intervention Intervention physicians received information about patient-specific risk of injury computed at the time of each visit using statistical models of non-modifiable risk factors and psychotropic drug doses. Risk thermometers presented changes in absolute and relative risk with each change in drug treatment. Control physicians received commercial drug alerts. Main outcome measures Injury risk at the end of follow-up based on psychotropic drug doses and non-modifiable risk factors. Electronic health records and provincial insurance administrative data were used to measure outcomes. Results Mean patient age was 75.2 years. Baseline risk of injury was 3.94 per 100 patients per year. Intermediate-acting benzodiazepines (56.2%) were the most common psychotropic drug. Intervention physicians reviewed therapy in 83.3% of visits and modified therapy in 24.6%. The intervention reduced the risk of injury by 1.7 injuries per 1000 patients (95% CI 0.2/1000 to 3.2/1000; p=0.02). The effect of the intervention was greater for patients with higher baseline risks of injury (p<0.03). Conclusion Patient-specific risk estimates provide an effective method of reducing the risk of injury for high-risk older people. Trial registration number clinicaltrials.gov Identifier: NCT00818285.

Variants of the SFTPA1 and SFTPA2 genes and susceptibility to tuberculosis in Ethiopia

Lungs are the central organ affected and targeted by Mycobacterium tuberculosis and immune processes in the lung are of critical importance in the pathogenesis of tuberculosis. A major lung defense against invading pathogens is provided by surfactant protein A, a multi-chain protein encoded by the SFTPA1 and SFTPA2 genes. Here, we investigated polymorphisms in the SFTPA1 and SFTPA2 genes for association with tuberculosis in 181 Ethiopian families comprising 226 tuberculosis cases. Four polymorphisms, SFTPA1 307A, SFTPA1 776T, SFTPA2 355C, and SFTPA2 751C, were associated with tuberculosis (P=0.00008; P=0.019, P=0.029 and P=0.042, respectively). Additional subgroup analysis in male, female and more severely affected patients provided evidence for SFTPA1/2-covariate interaction. Finally, out of five intragenic haplotypes identified in the SFTPA1 gene and nine identified in the SFTPA2 gene, 1A3 was most significantly associated with tuberculosis susceptibility (P=0.026). These findings suggest that SFTPA1 and SFTPA2 modify the risk of tuberculosis susceptibility and that this risk is influenced by additional covariates.