Pharmacological interventions for preventing acute mountain sickness: a network meta-analysis and trial sequential analysis of randomized clinical trials

Background: Individuals ascending to high altitude are at a risk of getting acute mountain sickness (AMS). The present study is a network meta-analysis comparing all the interventions available to prevent AMS.

Methods: Electronic databases were searched for randomized clinical trials evaluating the use of drugs to prevent AMS. Incidence of AMS was the primary outcome and incidence of severe AMS, paraesthesia (as side effect of acetazolamide use), headache and severe headache, and oxygen saturation were the secondary outcomes. Odds ratio [95% confidence interval] was the effect estimate for categorical outcomes and weighted mean difference for oxygen saturation. Random effects model was used to derive the direct and mixed treatment comparison pooled estimates. Trial sequential analysis and grading of the evidence for key comparisons were carried out.

Results: A total of 24 studies were included. Acetazolamide at 125, 250 and 375?mg twice daily, dexamethasone and ibuprofen had statistically significant lower incidence of AMS compared to placebo. All the above agents except ibuprofen were also observed to significantly reduce the incidence of severe AMS. Acetazolamide alone or in combination with Ginkgo biloba were associated with lower incidence of headache, but higher risk of paraesthesia. Acetazolamide at 125?mg and 375?mg twice daily significantly reduce the incidence of severe headache as like ibuprofen. Trial sequential analysis indicates that the current evidence is adequate for the incidence of AMS only for acetazolamide 125 and 250?mg twice daily. Similarly, the strength of evidence for acetazolamide 125 and 250?mg twice daily was moderate while it was either low or very low for all other comparisons.

Conclusions: Acetazolamide at 125, 250 and 375?mg twice daily, ibuprofen and dexamethasone significantly reduce the incidence of AMS of which adequate evidence exists only for acetazolamide 125 and 250?mg twice daily therapy. Acetazolamide 125?mg twice daily could be the best in the pool considering the presence of enough evidence for preventing AMS and associated with lower incidence of paraesthesia.

• Key messages

• Acetazolamide 125, 250 and 375?mg twice daily, dexamethasone and ibuprofen reduce the incidence of AMS in high altitudes.

• Adequate evidence exists supporting the use of acetazolamide 125?mg and 250?mg twice daily for preventing AMS of which acetazolamide 125?mg twice daily could be the best.

     

Intronic sequence elements impede exon ligation and trigger a discard pathway that yields functional telomerase RNA in fission yeast

The fission yeast telomerase RNA (TER1) precursor harbors an intron immediately downstream from its mature 3′ end. Unlike most introns, which are removed from precursor RNAs by the spliceosome in two sequential but tightly coupled transesterification reactions, TER1 only undergoes the first cleavage reaction during telomerase RNA maturation. The mechanism underlying spliceosome-mediated 3′ end processing has remained unclear. We now demonstrate that a strong branch site (BS), a long distance to the 3′ splice site (3′ SS), and a weak polypyrimidine (Py) tract act synergistically to attenuate the transition from the first to the second step of splicing. The observation that a strong BS antagonizes the second step of splicing in the context of TER1 suggests that the BS–U2 snRNA interaction is disrupted after the first step and thus much earlier than previously thought. The slow transition from first to second step triggers the Prp22 DExD/H-box helicase-dependent rejection of the cleaved products and Prp43-dependent “discard” of the splicing intermediates. Our findings explain how the spliceosome can function in 3′ end processing and provide new insights into the mechanism of splicing.     

Pharmacokinetics of First-Line Antituberculosis Drugs in HIV-Infected Children with Tuberculosis Treated with Intermittent Regimens in India

The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (C_max) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median C_max and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC_0–8]) of INH (C_max, 2.5 versus 5.1 μg/ml, respectively [P = 0.016]; AUC_0–8, 11.1 versus 22.0 μg/ml · h, respectively [P = 0.047[) and PZA (C_max, 34.1 versus 42.3 μg/ml, respectively [P = 0.055]; AUC_0–8, 177.9 versus 221.7 μg/ml · h, respectively [P = 0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median C_max of RMP (1.0 versus 2.8 μg/ml, respectively; P = 0.002) and PZA (31.9 versus 44.4 μg/ml, respectively; P = 0.045) were significantly lower. Among all factors studied, the PZA C_max influenced TB treatment outcome (P = 0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP C_max. The PZA C_max significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.     

Reentrant para‐Hisian ventricular tachycardia eliminated from the noncoronary cusp: Importance of regional anatomy for vantage‐point ablation

We present a rare case of reentrant ventricular tachycardia proven by entrainment maneuvers that was successfully ablated from the noncoronary cusp. The case highlights regional anatomy, pacing maneuvers with multi‐modality images from fluoroscopy, intracardiac echo, and electroanatomical mapping.     

Ten-year trends in the incidence,clinical profile and outcomes of acute-onset endophthalmitis following combined pars plana vitrectomy and sutureless,glueless and flapless scleral fixation of intraocular lenses

International Ophthalmology - To evaluate the frequency and outcomes of acute-onset endophthalmitis following combined pars plana vitrectomy and scleral fixation of intraocular lens. We evaluated...     

A comparison of using digitally assisted vitreoretinal surgery during repair of rhegmatogenous retinal detachments to the conventional analog microscope: A prospective interventional study

International Ophthalmology - To compare outcomes and complications of pars plana vitrectomy (PPV) using a three-dimensional heads-up visualisation system (digitally assisted vitreoretinal system,...     

A comparative study on endothelial cell loss in nanophthalmic eyes undergoing cataract surgery by phacoemulsification

Purpose:The purpose of this study is to compare the endothelial cell loss (ECL) in nanophthalmic eyes and age-matched controls undergoing cataract surgery by phacoemulsification and also to identify the risk factors influencing the endothelial cell density (ECD). This was a prospective comparative interventional case series.Methods:We enrolled 19 nanophthalmic eyes (study group) and 42 age-matched cataract controls (control group) undergoing phacoemulsification after meeting the inclusion criteria. Ocular parameters like best-corrected visual acuity, intraocular pressure, pachymetry, specular microscopy, and slit lamp findings were noted preoperatively and at month 1 and 3 postsurgery. All nanophthalmic eyes underwent cataract surgery with concomitant prophylactic posterior sclerostomy.Results:The median percentage endothelial loss in nanophthalmic eyes was 4.0 (IQR 0–23.5), 7.4 (IQR 1.0–-22.4) at 1 and 3 months postoperatively compared to 6.3 (IQR 1.7–14.1) and 6.4 (IQR 2.6–-12.1) in age controlled normal eyes (P = 0.94, P = 0.46, respectively). Linear regression analysis showed increasing age as the only variable influencing the percentage decrease in corneal ECD in the study group (P = 0.001). Nanophthalmic eyes with ACD <2.5 mm had a significantly greater reduction in ECD at 3 months postcataract surgery compared to baseline (P = 0.039). Visual outcomes and IOP reduction in the study group with ACD >2.5 mm were significantly better postcataract surgery (P = 0.02 and P = 0.002, respectively).Conclusion:The percentage of ECL in nanophthalmic eyes undergoing phacoemulsification is equivalent to normal eyes. However, in the nanophthamic eyes with AC depth <2.5 mm, the percentage cell loss was significantly higher warranting the need for extensive intraoperative care. Increasing age was found to be the only significant risk factor influencing the ECD in short eyes.