Novel compounds targeting InhA for TB therapy

Tuberculosis (TB) is described as lethal disease in the world. Resistant to TB drugs is the main reason to have unfavourable outcomes in the treatment of TB. Therefore, new agents to replace existing drugs are urgently needed. Previous reports suggested that InhA inhibitors, an enoyl-ACP-reductase, might provide auspicious candidates which can be developed into novel antitubercular agents. In this review, we explain the role of InhA in the resistance of isoniazid. Furthermore, five classes of InhA inhibitors, which display novel binding modes and deliver evidence of their prosperous target engagement, have been debated.     

Peripheral blood leukocyte telomere length is associated with age but not renal function: A cross-sectional follow-up study

Objectives

We aimed to evaluate the relationship between baseline renal function and changes in telomere length in Han Chinese.

Methods

The telomere restriction fragment (TRF) length of leukocytes in the peripheral blood was measured in healthy volunteers recruited in 2014. The estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine (Scr) and serum cystatin C (CysC)-eGFRcys and eGFRScr-cys through the Cockcroft-Gault formula (eGFRC-G) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI / eGFRCKD-EPI) equation. The correlation between telomere length changes over time and renal function was analyzed.

Results

Leukocyte TRF lengths were negatively correlated to age (r = -0.393, p < 0.001) and serum CysC (r = -0.180, p < 0.01), while positively associated with eGFRCKD-EPI, eGFRC-G, eGFRcys, and eGFRScr-cys (r = 0.182, 0.122, 0.290, and 0.254 respectively, p < 0.01). The 3-year change of telomere length was 46 bp/years. When adjusted for age, the associations between telomere length changes and baseline, subsequent TRF lengths, and serum CysC were no longer present. No association was observed between TRF length changes and renal function.

Conclusion

The rate of telomere length changes was affected by age and baseline telomere length. The telomere length changes might be important markers for aging.

     

Initial Validation of the Toulouse St. Louis University Mini Falls Assessment in Older Adults

Background/Objectives

Falls are one of the most prevalent health issues facing older adults. This study examines the validity of the Toulouse-St. Louis University Mini Falls Assessment (TSLUMFA). Objectives were to validate the TSLUMFA by testing if it differentiates between prior non fallers (n=80) and fallers (n=23), and predicts future falls as well as or better than the gold standard Tinetti Gait and Balance Instrument (TGBI). Examine if the subset of FRAIL Scale items on the TSLUMFA distinguishes between previous non fallers (n=75) and fallers (n=20), and predicts future falls as well as or better than the TGBI. Identify TSLUMFA cut offs scores for fall risk.

Design

Prospective validation study.

Setting

Participants were ambulatory patients presenting to the SLU Geriatrics Clinic.

Participants

103 ambulatory older adults.

Measurements

Fall risk was assessed using the three assessments. Outcome measures were previous falls and follow up falls.

Results

TSLUMFA, FRAIL, and TGBI differentiated between previous fallers and non fallers. A TSLUMFA score <23 stratified patients as moderate risk (Sensitivity=0.806 Specificity=0.776) and a score <21 stratified patients as high risk (Sensitivity=0.929 Specificity=0.897). 78% of patients (n=80) participated in follow up and 20% (n=16) of these patients fell during follow up. TSLUMFA and TGBI absolute scores were lower among patients who fell during the follow up period versus non fallers but the observed differences were not statistically significant (TSLUMFA P=0.123 and TGBI P=0.074).

Conclusion

This study validated the TSLUMFA and FRAIL. No test predicted falls with statistical significance (most likely due to the low follow up participation) but a positive trend was seen. Clinical recommendations from this study are to use the FRAIL as an initial fall screen and patients scoring > 3 should be analyzed by TSLUMFA. The TSLUMFA’s advantage is that it pinpoints areas that will directly benefit from therapy to reduce falls.

     

The risk of neurodevelopmental disorders following Thimerosal-containing Hib vaccine in comparison to Thimerosal-free Hib vaccine administered from 1995 to 1999 in the United States

Investigators postulated that early-life exposure to organic mercury (Hg) significantly increases the risk of childhood neurodevelopmental disorders (NDs). The Vaccine Adverse Event Reporting System database was utilized to conduct a hypothesis testing case-control study by evaluating 3486 total adverse event reports reported following Haemophilus influenza type b (Hib) vaccination. Exposed subjects received a Thimerosal-containing formulation (HIBTITER?, Wyeth-Lederle), while unexposed subjects received a Thimerosal-free formulation (PEDVAXHIB?, Merck). Subjects were included if they received either of these two Hib vaccine formulations between 1995 and 1999. Cases were defined as adverse event reports with a reported outcome of autism, developmental delay, psychomotor delay, or NDs in general. Cases with reported outcomes of febrile convulsions, pyrexia, or injection site pain, all of which have no biologically plausible relation to Hg exposure, were also examined. Controls were defined as adverse event reports without any mention of the specific case outcome examined. Cases of reported autism (odds ratio (OR)?=?2.75, p?<?0.02), developmental delay (OR?=?5.39, p?<?0.01), psychomotor disorder (OR?=?2.38, p?<?0.03), and neurodevelopmental disorder in general (OR?=?2.70, p?<?0.001) were each significantly more likely than their respective controls to receive Thimerosal-containing Hib vaccine than Thimerosal-free Hib vaccine. Significant effects for neurodevelopmental disorder in general were observed for males (OR?=?2.52, p?<?0.005), but not females when separated by gender. For the outcomes that had no biologically plausible relation to Hg exposure, the cases were no more likely than their respective controls to receive Thimerosal-containing Hib vaccine than Thimerosal-free Hib vaccine. This study provides suggestive evidence of an association between Thimerosal and neurodevelopmental outcomes and provides support for carrying out additional well-designed studies examining the association between Thimerosal-containing vaccines and a wide range of neurodevelopmental outcomes.     

Economic evaluation of telephone-based weight loss support for patients with knee osteoarthritis: a randomised controlled trial

Background

The prevalence of knee osteoarthritis is increasing worldwide. Obesity is an important modifiable risk factor for both the incidence and progression of knee osteoarthritis. Consequently, international guidelines recommend all patients with knee osteoarthritis who are overweight receive support to lose weight. However, few overweight patients with this condition receive care to support weight loss. Telephone-based interventions are one potential solution to provide scalable care to the many patients with knee osteoarthritis. The objective of this study is to evaluate, from a societal perspective, the cost-utility and cost-effectiveness of a telephone-based weight management and healthy lifestyle service for patients with knee osteoarthritis, who are overweight or obese.

Methods

An economic evaluation was undertaken alongside a pragmatic randomised controlled trial. Between May 19 and June 30, 2015, 120 patients with knee osteoarthritis were randomly assigned to an intervention or usual care control group in a 1:1 ratio. Participants in the intervention group received a referral to an existing non-disease specific 6-month telephone-based weight management and healthy lifestyle service. Quality-adjusted life years (QALYs) was the utility measure and knee pain intensity, disability, weight, and body mass index (BMI) were the clinical measures of effect. Costs included intervention costs, healthcare utilisation costs (healthcare services and medication use) and absenteeism costs due to knee pain. Data was collected at baseline, 6?weeks and 26?weeks. The primary cost-effectiveness analysis was performed from the societal perspective.

Results

Mean cost differences between groups (intervention minus control) were $493 (95%CI: -3513 to 5363) for healthcare costs, $-32 (95%CI: -73 to 13) for medication costs, and $125 (95%CI: -151 to 486) for absenteeism costs. The total mean difference in societal costs was $1197 (95%CI: -2887 to 6106). For QALYs and all clinical measures of effect, the probability of the intervention being cost-effective compared with usual care was less than 0.36 at all willingness-to-pay values.

Conclusions

From a societal perspective, telephone-based weight loss support, provided using an existing non-disease specific 6-month weight management and healthy lifestyle service was not cost-effective in comparison with usual care for overweight and obese patients with knee osteoarthritis.

Trial registration number

ACTRN12615000490572, registered 18th May 2015