Sleep-Related Breathing Disorders: When CPAP Is Not Enough

Three decades ago, continuous positive airway pressure (CPAP) was introduced to treat obstructive sleep apnea (OSA). Shortly after, bilevel positive airway pressure devices (BPAP) that independently adjusted inspiratory and expiratory positive airway pressure were developed to treat complex sleep-related breathing disorders unresponsive to CPAP. Based on the bilevel positive airway pressure platform (hardware) governed by propriety algorithms (software), advanced modes of noninvasive ventilation (NIV) were developed to address complex cardiorespiratory pathophysiology beyond OSA. This review summarizes key aspects of different bilevel PAP therapies (BPAP with/without backup rate, adaptive servoventilation, and volume-assured pressure support) to treat common sleep-related hypoventilation disorders, treatment-emergent central sleep apnea, and central sleep apnea syndromes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00955-x.Key Words: Bilevel positive airway pressure (BPAP), Adaptive servoventilation (ASV), Volume-assured pressure support (VAPS), Sleep-related hypoventilation, Treatment-emergent central apnea, Central sleep apnea     

Evaluation of beta defensin 2 production by chicken heterophils using direct MALDI mass spectrometry

Beta defensins (BD) are cysteine rich, cationic antimicrobial peptides (AMP) produced mainly by epithelial and myeloid cells such as neutrophils. In birds, the neutrophil equivalent heterophils produce avian beta defensins (AvBD) of which AvBD2 is the major isoform. Heterophils recognize pathogens or their derived products through a series of pattern recognition receptors called toll-like receptors (TLR) leading to their antimicrobial activities. This work is the first report of TLR modulation of AvBD2 expression in chickens. To measure the effect of TLR activation on AvBD2 production, the heterophils were cultured with different TLR agonists for 6 h. Modulation of AvBD2 levels by TLR activation was measured using direct MALDI mass spectrometry without stable isotopic labeling or chromatographic separation. Chemical modification of the conditioned media was performed using reduction/alkylation with dithiothreitol/iodoacetamide to distinguish TLR treated AvBD2 (reduced/alkylated) from controls (non-reduced). Changes in corrected ion intensity ratios were assumed to reflect AvBD2 modulation in heterophils upon activation with different TLR agonists. In general, TLR agonists increased AvBD2 production with LPS showing the greatest induction and CpG-ODN showing little or no effect. These data show that the direct MALDI-MS coupled with reduction/alkylation may provide a rapid relative quantitative approach to the measurement of agonist-induced differential expression of AvBD2.     

Prevalence and short-term mortality of acute-on-chronic liver failure: A national cohort study from the USA

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Hemophilia A: role of FVIIIC/vWF Ag in assisting linkage analysis for carrier detection.

Carrier detection for hemophilia A was carried out in 52 females from 30 families presenting to the Haematology Department AIIMS, using linkage analysis and factor VIIIC (FVIIIC)-von Willebrand factor (vWF) antigen assay. The allelic frequency for the marker Bcl 1 and Xba 1 was 0.58 and 0.54, respectively, for the positive alleles and 0.42 and 0.46, respectively, for the negative alleles. The heterozygosity frequency of Bcl I and Xba 1 was 0.65 and 0.55, respectively. Of the 52 females, 30 were mothers of hemophilic patients and 22 were sisters of hemophilic patients. Of the 30 mothers, positive family history was present in 14. In these patients, the defective X chromosome was tracked in 10, and in four the defective X chromosome could not be tracked because the mothers were homozygous for the marker used. Of the 16 mothers without a family history of disease, three were observed to be carriers based on linkage analysis and reduced factor VIII levels in mother/sister. Possible defective X chromosome was tracked in 11 mothers and five were noninformative because they did not show heterozygosity for the markers used. Using linkage analysis, nine of the 22 sisters were found to be definite carriers, 10 noncarriers, and three were noninformative. It is thus concluded that using Bcl 1 and Xba 1 linkage analysis, carrier status can be definitely ascertained in 50% females and this level of information can be increased to 61.5% by measuring FVIIIC/vWF antigen levels in them.     

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.