Nevin Manimala

JAMA Netw Open. 2022 Nov 1;5(11):e2243215. doi: 10.1001/jamanetworkopen.2022.43215.

ABSTRACT

IMPORTANCE: Benzodiazepines are prescribed for the treatment of adolescent sleep disorders; however, benzodiazepine overdoses occur, often in combination with opioids.

OBJECTIVE: To evaluate whether benzodiazepine treatment for sleep disorders, compared with alternative pharmacologic treatments (trazodone, hydroxyzine, zolpidem, zaleplon, and eszopiclone), is associated with increased risk of drug overdose for young people.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included privately insured people 10 to 29 years of age identified from a US commercial claims database (MarketScan), from January 1, 2009, to December 31, 2018. Young people with a sleep disorder diagnosis initiating benzodiazepine (n = 23 084) or comparator pharmacologic treatments (n = 66 706) were included in the study. Statistical analysis was performed from November 1, 2021, to May 16, 2022.

EXPOSURES: New use of benzodiazepine treatment or comparator pharmacologic treatments (defined as ≥1 year without a prescription for benzodiazepine or comparator medications).

MAIN OUTCOMES AND MEASURES: Incident diagnosed drug overdoses were identified from inpatient and emergency department records within 6 months of treatment initiation. The propensity score-adjusted cumulative incidence of overdose and hazard ratios (HRs) were estimated with intention-to-treat (analyzed based on initial treatment) and as-treated analyses (added censoring at treatment discontinuation). Results were stratified by prior prescription opioid fill.

RESULTS: The cohort included 23 084 young people initiating benzodiazepine treatment (14 444 female participants [62.6%]; mean [SD] age, 23 [4.1] years) and 66 706 initiating a comparator treatment (38 446 female participants [57.6%]; mean [SD] age, 22 [4.4] years). Six months after treatment initiation, 9.7% (95% CI, 9.3%-10.1%) of benzodiazepine users and 12.3% (95% CI, 12.1%-12.6%) of the comparator group were still receiving treatment. The crude incidence of drug overdose at 6 months was 0.9% for benzodiazepine initiators and 0.8% for comparator treatment initiators. In adjusted analyses, an increased risk of drug overdose was associated with benzodiazepines vs comparator treatments (intention-to-treat analysis: HR, 1.25 [95% CI, 1.03-1.51]; as-treated analysis: HR, 1.44 [95% CI, 1.14-1.80]). This association was stronger among young people with a recent prescription opioid fill vs those without a recent prescription opioid fill (as-treated analysis: adjusted HR, 2.01 [95% CI, 1.24-3.25] vs adjusted HR, 1.31 [95% CI, 1.00-1.70]).

CONCLUSIONS AND RELEVANCE: The findings of this study suggest that benzodiazepines, compared with alternative pharmacologic treatments for common sleep disorders, were associated with an increased risk of drug overdose among young people during the following 6-month period, especially among those with a recent opioid prescription. Drug overdose is an important safety consideration when treating young people with benzodiazepines.

PMID:36413369 | DOI:10.1001/jamanetworkopen.2022.43215

JAMA Netw Open. 2022 Nov 1;5(11):e2243232. doi: 10.1001/jamanetworkopen.2022.43232.

ABSTRACT

IMPORTANCE: Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear.

OBJECTIVES: To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden.

DESIGN, SETTING, AND PARTICIPANTS: This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-β 42 (Aβ42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022.

MAIN OUTCOMES AND MEASURES: Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels.

RESULTS: A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; β = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; β = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aβ42 burden (β = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: β = -0.884; 95% CI, 0.223 to -0.395; P < .001; CSF phosphorylated tau levels: β = -0.672; 95% CI, -1.022 to -0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001).

CONCLUSIONS AND RELEVANCE: The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.

PMID:36413367 | DOI:10.1001/jamanetworkopen.2022.43232

Proteomics. 2022 Nov 22:e2200176. doi: 10.1002/pmic.202200176. Online ahead of print.

ABSTRACT

It is challenging to study regulatory genetic variants as gene expression is affected by both genetic polymorphisms and non-genetic regulators. The mRNA allele-specific expression (ASE) assay has been increasingly used for the study of cis-acting regulatory variants because cis-acting variants affect gene expression in an allele-specific manner. However, poor correlations between mRNA and protein expressions were observed for many genes, highlighting the importance of studying gene expression regulation at the protein level. In the present study, we conducted a proof-of-concept study to utilize a recently developed allele-specific protein expression (ASPE) assay to identify the cis-acting regulatory variants of CES1 using a large set of human liver samples. The CES1 gene encodes for carboxylesterase 1 (CES1), the most abundant hepatic hydrolase in humans. Two cis-acting regulatory variants were found to be significantly associated with CES1 ASPE, CES1 protein expression, and its catalytic activity on enalapril hydrolysis in human livers. Compared to conventional gene expression-based approaches, ASPE demonstrated an improved statistical power to detect regulatory variants with small effect sizes since allelic protein expression ratios are less prone to the influence of non-genetic regulators (e.g., diseases and inducers). This study suggests that the ASPE approach is a powerful tool for identifying cis-regulatory variants. This article is protected by copyright. All rights reserved.

PMID:36413357 | DOI:10.1002/pmic.202200176

J Bone Joint Surg Am. 2022 Sep 28. doi: 10.2106/JBJS.21.01556. Online ahead of print.

ABSTRACT

BACKGROUND: The aim of the present study was to evaluate the complications associated with conventional methods of cast removal and to compare them with the complications associated with a novel method involving the use of externally guided aids for skin protection.

METHODS: Two hundred and eight cooperative patients ≥5 years of age who had no experience with cast removal were included in the study. Patients were selected arbitrarily and were divided into 2 groups. In Group 1 (106 patients [115 casts]; 60% male; average age, 20 years), conventional protection methods were used. In Group 2 (102 patients [108 casts]; 62% male; average age, 26 years), tong-shaped, externally guided, steel plate aids were used for skin protection. After the insertion of the protective part between the skin and the cast materials, the outer portion of the aid guided the operator to stay in a safe cutting line. The cast removal procedures in each group were documented, and skin injuries, burns, patient anxiety, operator anxiety, and processing time were noted.

RESULTS: In Group 1, the skin mark/scratch rate was 18%, the full-thickness skin laceration rate was 0.9%, the burn sensation rate was 22%, and the rate of first/second-degree burns was 2.5%. Anxiety was classified as moderate by 57% of the patients and as severe by 8%. Moderate anxiety was reported by 20% of the cast operators. In Group 2, only 6% of the patients experienced moderate anxiety and the removal time was reduced by >25%. When the groups were compared with regard to severe complications such as skin laceration (resulting in bleeding), visible burn, and severe anxiety, the former 2 complications were eliminated in Group 2 but the difference between the groups was statistically significant in the last category only (p = 0.325, p = 0.247, p = 0.007, respectively).

CONCLUSIONS: Eliminating saw blade-to-skin contact with a tong-like, externally guided flexible steel aid provides a high level of safety, decreases removal time by 5 to 10 minutes (depending on cast length), and makes cast removal a better experience for both patients and operators.

LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

PMID:36413353 | DOI:10.2106/JBJS.21.01556

Cannabis Cannabinoid Res. 2022 Nov 22. doi: 10.1089/can.2022.0136. Online ahead of print.

ABSTRACT

Context: Retrospective study of 36 individuals with sickle cell disease (SCD) certified for medical cannabis. Objective: We sought to examine whether medical cannabis certification was associated with a change in utilization of acute care medical services for patients with SCD. Methods: We identified patients with SCD certified for medical cannabis use between July 2014 and December 2021 using the New York State Prescription Monitoring Program (NYS PMP) and cross-matching to our electronic medical record. We estimated the mean incidences of Emergency Department (ED) visits, hospital admissions, inpatient days, and total acute encounters for SCD-related pain per month pre- and post-medical cannabis certification and used paired t-tests to assess the statistical significance of changes in hospital use. We stratified incidence based on whether patients had received a bone marrow transplant (BMT) at any point before or during the research period, since BMT is potentially an important covariate. Recertification rates and patients’ reasons for choosing to recertify were qualitatively investigated through retrospective chart review. Results: The incidence of ED visits, hospital admissions, and total acute encounters per month for SCD-related pain decreased pre- to post-certification (p=0.02; p=0.02; p=0.01). These decreases lost statistical significance after stratifying patients based on BMT history. There was no statistically significant change in the number of days per month patients spent hospitalized in either the primary analysis or after stratification by BMT status. Forty-four percent of patients chose to be recertified. Thirty-six percent of patients cited concerns regarding the cost of medical cannabis. Conclusion: Our study did not show a statistically significant relationship between certification for medical cannabis and hospital use after addressing BMT history as a potentially important covariate. However, we were likely underpowered to detect any existing difference after patient data were stratified due to our small sample size. Regardless, 44% of patients chose to be recertified, indicating a perceived benefit and utility in further investigation of medical cannabis for this population with a larger analytic sample. Patient-reported benefits were improvement of pain and other symptoms, decreased opiate requirements, and decreased side effects compared to opiates.

PMID:36413342 | DOI:10.1089/can.2022.0136

Methods Mol Biol. 2023;2581:149-176. doi: 10.1007/978-1-0716-2784-6_12.

ABSTRACT

Isothermal titration calorimetry (ITC) is the gold standard for providing quantitative and thermodynamic understanding of the interaction mechanisms between core autophagy machinery, autophagy receptors, and ATG8. Here, we used two model peptides and Arabidopsis thaliana ATG8A to characterize ATG8-peptide interactions. We employed ITC using three different methods (direct ligand titration, displacement, and competition assays) to characterize, directly and indirectly, the interaction of the peptides with ATG8. We then analyzed the ITC data by global and statistical methods and discussed advantages, drawbacks, and negative controls for each approach. We finally provide a thorough description of all the steps, including data analysis and presentation, preparation of recombinant ATG8A from E. coli, and troubleshooting notes for technical problems that can be encountered. Although we used ATG8-peptide interactions here, these assays can be applied to any other one-to-one protein-protein and ligand-protein interactions and competitive binders.

PMID:36413317 | DOI:10.1007/978-1-0716-2784-6_12

Phlebology. 2022 Nov 22:2683555221141818. doi: 10.1177/02683555221141818. Online ahead of print.

ABSTRACT

OBJECTIVE: The study aimed to examine whether alpha-1-antitrypsin (AAT), an inhibitor of leukocyte esterase(LE), which damages the venous vessel wall, has a protective effect against chronic venous disease(CVD), and to examine the relationship between AAT levels and disease severity.

METHODS: Patients admitted with varicose vein disease and having reflux flow lasting longer than 0.5 s as determined by Doppler ultrasound were included. The informed consents were taken, and blood samples were obtained for complete blood count, C-reactive protein (CRP) level, and AAT level following anamnesis and physical examination. Clinical Etiologic Anatomic Pathologic (CEAP) classification was used to assess disease severity, and patients were divided into CEAP 1-5 groups accordingly.

RESULTS: A total of 87 patients were included in the study. There was no statistically significant difference between the groups in body weight, red blood cell counts, platelet counts, or neutrophil counts (p = 0.117, p = 0.932, p = 0.177, and p = 0.177, respectively).CRP and AAT levels were higher in patients with a CEAP clinical score of 5 compared to the other groups (p = 0.018, and p = 0.020, respectively). AAT levels were similar in the CEAP 1-3 group and decreased in the CEAP-4 group but increased again in the CEAP-5 group. The AAT level was 1.62 ± 0.3 g/L in the CEAP-1 group, 1.61 ± 0.21 g/L in the CEAP-2 group, 1.61 ± 0.27 g/L in the CEAP-3 group, 1.48 ± 0.28 g/L in the CEAP-4 group, and 1.94 ± 0.39 g/L in the CEAP-5 group. CRP levels and platelet counts were observed to affect AAT levels (p = 0.10, p = 0.017, respectively).

CONCLUSION: We believe that our hypothesis that low AAT levels play a role in the etiopathogenesis of CVD has been partially validated, at least in the CEAP-4 group. However, we believe that increased AAT levels in the CEAP-5 group may be a reactive increase in increased LE levels due to higher CRP levels of this group.

PMID:36413267 | DOI:10.1177/02683555221141818

J Gambl Stud. 2022 Nov 21. doi: 10.1007/s10899-022-10166-y. Online ahead of print.

ABSTRACT

This research empirically tests the relationship between gambling-related cognitive distortions and the development of gambling problems. In two separate studies using methodologies designed to support non-experimental causal inference, we demonstrate that holding false beliefs about gambling experiences is related to current and future risk of developing problems with gambling. In our first study, we use an instrumental variable estimation strategy on an internet sample (n = 184) and observe a statistically significant relationship between Gamblers’ Belief Questionnaire scores and measures of loss chasing, overspending, and gambling problems. These findings were robust to linear and ordinal estimation strategies and multiple model specifications. In our second study, we examine five-year prospective longitudinal data (n = 1,431) to validate our initial findings and test whether irrational thoughts are also related to future problems with gambling. While controlling for current fallacies, we find that past Gambling Fallacies Measure scores are related to present gambling problems across two survey waves. The effect size of each of the past fallacy levels is roughly half of the effect size of present levels, suggesting meaningful impacts. Our findings support the Pathways Model of Problem and Pathological Gambling.

PMID:36413263 | DOI:10.1007/s10899-022-10166-y

Cancer Chemother Pharmacol. 2022 Nov 21. doi: 10.1007/s00280-022-04489-1. Online ahead of print.

ABSTRACT

PURPOSE: Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing.

METHODS: A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated.

RESULTS: A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436).

CONCLUSION: We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing.

CLINICAL TRIAL NUMBER: Clinicaltrials.gov identifier: NCT03655821.

PMID:36413252 | DOI:10.1007/s00280-022-04489-1

Sleep. 2022 Nov 22:zsac278. doi: 10.1093/sleep/zsac278. Online ahead of print.

ABSTRACT

STUDY OBJECTIVES: International guidelines recommend using benzodiazepine receptor agonists (BZRA) for maximally four weeks. Nevertheless, long-term use for chronic insomnia disorder remains a common practice. This study aimed to test the effectiveness of blended care for discontinuing long-term BZRA use in general practice.

METHODS: A pragmatic cluster randomized controlled superiority trial compared blended care to usual care through urine toxicology screening. In the intervention, care by the general practitioner (GP) was complemented by an interactive e-learning program, based on cognitive behavioral therapy for insomnia. Adults using BZRA daily for minimally six months were eligible. Participants were clustered at the level of the GP surgery for allocation (1:1). Effectiveness was measured as the proportion of patients who had discontinued at one-year follow-up. Data analysis followed intention-to-treat principles.

RESULTS: In total, 916 patients in 86 clusters, represented by 99 GPs, were randomized. Primary outcome data was obtained from 727 patients (79%). At one-year follow-up, 82 patients (18%) in blended care, compared to 91 patients (20%) in usual care, had discontinued. There was no statistically significant effect for the intervention (OR: 0·924; 95% CI: 0·60, 1·43). No adverse events were reported to the research team.

CONCLUSIONS: The findings did not support the superiority of blended care over usual care. Both strategies showed clinical effectiveness, with an average of 19% of patients having discontinued at one-year follow-up. Further research is important to study the effect of structurally implementing digital interventions in general practice.

PMID:36413221 | DOI:10.1093/sleep/zsac278