Summary
Background
Pregabalin is a calcium channel α2δ ligand that modifies visceral hypersensitivity in IBS patients. Clinical data for pregabalin in IBS are lacking.
Aim
To test the efficacy of ...pregabalin on gastrointestinal symptoms in IBS patients.
Methods
A double‐blind, placebo‐controlled trial was performed. Adults meeting IBS Rome III criteria with ≥3 pain attacks per month were randomised to pregabalin 225 mg vs placebo twice daily for 12 weeks. Questionnaires were completed weekly. The primary endpoint was average pain Bowel Symptom Scale (BSS) scores weeks 9‐12. An intention‐to‐treat analysis of covariance evaluated treatment effects on quantitative endpoints, adjusting for age and gender. Adequate relief and change in pain score were assessed using a chi‐squared test.
Results
Eighty‐five patients were recruited and randomised. Sample characteristics include: mean age 39.4 (SD = 14.6); 73 (86%) female; 37 (44%) IBS‐D, 29 (35%) IBS‐M, 18 (21%) IBS‐C. The pregabalin arm had lower average pain‐BSS scores weeks 9‐12 (25 vs 42, P = 0.008). Compared with placebo, the overall IBS BSS severity score was lower in the pregabalin arm (26 vs 42, P = 0.009). Differences were observed for the diarrhoea‐BSS and bloating‐BSS scores (P = 0.049 and 0.016, respectively). No differences between groups were seen for constipation‐BSS scores. Adequate relief was not different between the two arms (46% vs 36%, P = 0.35). 63% pregabalin vs 45% placebo had a change in pain score ≥30 at week 12 from baseline (P = 0.10). Post‐treatment IBS‐QoL scores did not differ between groups.
Conclusion
This trial suggests that pregabalin may be beneficial for IBS abdominal pain, bloating and diarrhoea.
To report the design and implementation of the Right Drug, Right Dose, Right Time-Using Genomic Data to Individualize Treatment protocol that was developed to test the concept that prescribers can ...deliver genome-guided therapy at the point of care by using preemptive pharmacogenomics (PGx) data and clinical decision support (CDS) integrated into the electronic medical record (EMR).
We used a multivariate prediction model to identify patients with a high risk of initiating statin therapy within 3 years. The model was used to target a study cohort most likely to benefit from preemptive PGx testing among the Mayo Clinic Biobank participants, with a recruitment goal of 1000 patients. We used a Cox proportional hazards model with variables selected through the Lasso shrinkage method. An operational CDS model was adapted to implement PGx rules within the EMR.
The prediction model included age, sex, race, and 6 chronic diseases categorized by the Clinical Classifications Software for International Classification of Diseases, Ninth Revision codes (dyslipidemia, diabetes, peripheral atherosclerosis, disease of the blood-forming organs, coronary atherosclerosis and other heart diseases, and hypertension). Of the 2000 Biobank participants invited, 1013 (51%) provided blood samples, 256 (13%) declined participation, 555 (28%) did not respond, and 176 (9%) consented but did not provide a blood sample within the recruitment window (October 4, 2012, through March 20, 2013). Preemptive PGx testing included CYP2D6 genotyping and targeted sequencing of 84 PGx genes. Synchronous real-time CDS was integrated into the EMR and flagged potential patient-specific drug-gene interactions and provided therapeutic guidance.
This translational project provides an opportunity to begin to evaluate the impact of preemptive sequencing and EMR-driven genome-guided therapy. These interventions will improve understanding and implementation of genomic data in clinical practice.
Approximately 10% of sudden infant death syndrome (SIDS) cases may stem from potentially lethal cardiac channelopathies, with approximately half of channelopathic SIDS involving the Na(V)1.5 cardiac ...sodium channel. Recently, Na(V) beta subunits have been implicated in various cardiac arrhythmias. Thus, the 4 genes encoding Na(V) beta subunits represent plausible candidate genes for SIDS.
This study sought to determine the spectrum, prevalence, and functional consequences of sodium channel beta-subunit mutations in a SIDS cohort.
In this institutional review board-approved study, mutational analysis of the 4 beta-subunit genes, SCN1B to 4B, was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing of DNA derived from 292 SIDS cases. Engineered mutations were coexpressed with SCN5A in HEK 293 cells and were whole-cell patch clamped. One of the putative SIDS-associated mutations was similarly studied in adenovirally transduced adult rat ventricular myocytes.
Three rare (absent in 200 to 800 reference alleles) missense mutations (beta3-V36M, beta3-V54G, and beta4-S206L) were identified in 3 of 292 SIDS cases. Compared with SCN5A+beta3-WT, beta3-V36M significantly decreased peak I(Na) and increased late I(Na), whereas beta3-V54G resulted in a marked loss of function. beta4-S206L accentuated late I(Na) and positively shifted the midpoint of inactivation compared with SCN5A+beta4-WT. In native cardiomyocytes, beta4-S206L accentuated late I(Na) and increased the ventricular action potential duration compared with beta4-WT.
This study provides the first molecular and functional evidence to implicate the Na(V) beta subunits in SIDS pathogenesis. Altered Na(V)1.5 sodium channel function due to beta-subunit mutations may account for the molecular pathogenic mechanism underlying approximately 1% of SIDS cases.
The S1103Y-SCN5A polymorphism has been implicated as a proarrhythmic, sudden death predisposing risk factor in African Americans, including one postmortem investigation of African-American infants ...with sudden infant death syndrome (SIDS).
The purpose of this study was to assess whether the relatively African-American-specific common polymorphism S1103Y in the SCN5A-encoded cardiac sodium channel is overrepresented in SIDS among African Americans.
Seventy-one cases from a population-based cohort of unexplained infant deaths among African Americans (37 females and 34 males, average age 3 +/- 2 months, age range birth to 11 months) were submitted to the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory for postmortem genetic testing. Polymerase chain reaction and a restriction digest assay were performed to genotype this cohort for S1103Y.
Targeted mutational analysis of exon 18 in SCN5A of the African-American SIDS cohort (n = 71) revealed the S1103Y polymorphism in 16 (22.5%) of 71 African-American cases of SIDS compared to 135 (11.6%) of 1,161 ostensibly healthy adult African Americans (P = .01).
This study provides an independent assessment of the prevalence of S1103Y-SCN5A among African-American infants with sudden, unexpected, unexplained death prior to their first birthday. Further scrutiny and quantification of the risk apparently associated with S1103Y appear warranted.
Patient comfort is often assessed during gastrointestinal procedures to guide sedation. There are, however, no validated scales appropriate for routine comfort assessment. This study validated a ...single-item La Crosse (WI) intra-endoscopy sedation comfort score (L-WISC) by determining interobserver agreement and correlation with patient outcomes. The study was conducted in prospective outpatient cohorts of patients undergoing outpatient esophagogastroduodenoscopy and/or colonoscopy at a regional healthcare medical center endoscopy unit. In Phase 1, independent assessments of 100 patients' intraprocedural comfort by the endoscopist and nurse determined interobserver agreement. In Phase 2, nurses assessed 200 patients, who were provided surveys to self-report their comfort 2 weeks postprocedure. In Phase 1, there was fair interobserver agreement (weighted κ = 0.36, with 95% confidence intervals CI 0.19, 0.53). After L-WISC revisions, Phase 1 was repeated with moderate agreement (weighted κ = 0.45; 95% CI 0.31, 0.60). In Phase 2, using the revised score, there was poor agreement (weighted κ = 0.098; 95% CI -0.0020, 0.20) between nurses' and patients' scores. The L-WISC is the first intraprocedural gastrointestinal comfort score appropriate for routine use to be validated with interobserver agreement and correlation with patient outcomes. It has reproducibility between endoscopists and nurses. It does not predict patient recollection of sedation comfort, but it remains unclear whether such prediction is possible with the use of amnestic sedatives. The L-WISC provides standardized levels of patient comfort to guide sedation titration routinely during outpatient endoscopy.
We examined the clinical usefulness of measurements of antimitochondrial autoantibodies (AMA) in predicting disease progression in patients with primary biliary cirrhosis (PBC). We determined the ...relationships between AMA levels measured by indirect immunofluorescence (IF) and those measured by quantitative enzyme immunoassays (EIAs) using recombinant 2‐oxo‐acid dehydrogenase complex (2‐OADC) proteins and the Mayo Risk Score, an established indicator of disease progression in primary biliary cirrhosis (PBC). Results of tests for AMA by either method correlated weakly (r = .24 to .30) with disease progression as indicated by Mayo Risk Scores. The levels of AMA to 2‐OADC proteins varied by more than 200‐fold between patients but remained relatively constant over time in individual patients. Despite being positively correlated with Mayo Risk Score results, the levels of AMA to 2‐OADC proteins were not useful for predicting disease progression in individual patients with PBC. In addition, we found no significant differences in the levels of autoantibodies to 2‐OADC proteins among patients with different histological stages of disease. Our results show that measurements of AMA by IF or by quantitative EIA methods with recombinant 2‐OADC proteins are not useful parameters for predicting disease progression in patients with PBC.
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