A randomized controlled pilot study of daily intravenous ketamine over three days for treatment-resistant depression.

BACKGROUND: Studies have confirmed the rapid antidepressant action of ketamine in depressive episodes. Nevertheless, a standardized procedure for the delivery of ketamine infusion in individuals suffering from treatment-resistant depression, particularly in terms of infusion frequency and total dosage, remains undetermined. In addition, an efficacious ketamine regimen for persistent pain management involved a continuous 10-day infusion period with no notable adverse effects. Consequently, the primary objective of this study was to evaluate the antidepressant capacity of consecutive ketamine infusions spanning over three successive days, the duration of therapeutic response, and the overall safety profile of the treatment. METHODS: In this randomized controlled trial, participants aged 18-64 with treatment-resistant depression were randomized to receive either intravenous ketamine or midazolam (used as an active placebo) for 40 min daily over three consecutive days. Statistical analysis using repeated measures ANOVA was employed to assess the changes in the total score of the Montgomery-Åsberg Depression Rating Scale (MADRS) and the clinical global impression-Severity from the initial assessment to 10 and 31 days post-infusion. Additionally, the duration of response and remission was evaluated using Kaplan-Meier survival analysis. RESULTS: Out of 33 randomized participants, 20 underwent the treatment as planned. By day 10th, the ketamine group had a mean reduction in MADRS score of 12.55 (95% CI = 6.70-18.09), whereas the midazolam group had a decrease of 17.22 (95% CI = 11.09-23.36). This pattern continued to day 31, with ketamine showing a mean score decrease of 13.73 (95% CI = 7.54-19.91) and midazolam a fall of 12.44 (95% CI = 5.61-19.28). Both treatments were well tolerated, with dissociative symptoms in the ketamine group being temporary and ceasing by the end of each infusion. CONCLUSION: Intravenous ketamine given for three consecutive days did not show a notable antidepressant advantage when compared to the active placebo midazolam, highlighting the need for further research into effective treatments schedules for treatment-resistant depression. TRIAL REGISTRATION: NCT05026203, ClinicalTrials.gov, registered on 24/08/2021.

Incidence of Delayed Recovery from Femoral Nerve Block in Total Knee Arthroplasty.

OBJECTIVE: Femoral nerve block has been proven as an effective analgesia for total knee arthroplasty (TKA). Delayed recovery from nerve block can result in serious complication during postoperative period. This prospective, single-center, observational study investigated the incidence in delayed recovery from femoral nerve block more than 24 hours postoperatively. MATERIAL AND METHOD: Two hundred and forty patients with femoral nerve block as part of anesthesia plan for elective unilateral TKA were recruited into study. Participants were assessed for sensory or motor impairment lasting longer than 24 hours post operation. Factors associated with delayed recovery from femoral nerve block were analyzed. RESULTS: Five patients (incidence = 2.08%) reported sensory or motor impairment more than 24 hours post operation. All of the patients could ambulate within 4 days post operation without permanent nerve injury or serious complication. Higher dose of local anesthetic agent using for femoral nerve block showed association with the delayed recovery (p-value = 0.01). CONCLUSION: This study demonstrated 2.08% incidence in delayed recovery from femoral nerve block. High concentration and dose of local anesthetic agent may lead to fall during early ambulatory period.

A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E.

b-Thalassemia/HbE disease is clinically variable. In searching for genetic factors modifying the disease severity, patients were selected based on their disease severities, and a genome-wide association study (GWAS) was performed. Genotyping was conducted with the Illumina Human 610-Quad BeadChips array using DNAs from 618 Thai b0-thalassemia/HbE patients who were classified as 383 severe and 235 mild phenotypes by a validated scoring system. Twenty-three SNPs in three independent genes/regions were identified as being significantly associated with the disease severity. The highest association was observed with SNPs in the b-globin gene cluster (chr.11p15), and rs2071348 of the HBBP1 gene revealed the most significant association [P = 2.96 9 10(-13), odds ratio (OR) = 4.33 (95% confidence interval (CI), 2.74-6.84)]. The second was identified in the intergenic region between the HBS1L and MYB genes (chr.6q23), among which rs9376092 was the most significant [P = 2.36 9 10(-10), OR = 3.07 (95% CI, 2.16-4.38)]. The third region was located in the BCL11A gene (chr.2p16.1), and rs766432 showed the most significant association [P = 5.87 9 10-10, OR = 3.06 (95% CI, 2.15-4.37)]. All three loci were replicated in an independent cohort of 174 Indonesian patients. The associations to fetal hemoglobin levels were also observed with SNPs on these three regions. Our data indicate that several genetic loci act in concert to influence HbF levels of beta(0)-thalassemia/HbE patients. This study revealed that all the three reported loci and the alpha-globin gene locus are the best and common predictors of the disease severity in beta-thalassemia.

Genetic modifiers of Hb E/beta0 thalassemia identified by a two-stage genome-wide association study.

BACKGROUND: Patients with Hb E/beta0 thalassemia display remarkable variability in disease severity. To identify genetic modifiers influencing disease severity, we conducted a two-stage genome scan in groups of 207 mild and 305 severe unrelated patients from Thailand with Hb E/beta0 thalassemia and normal alpha-globin genes. METHODS: First, we estimated and compared the allele frequencies of approximately 110,000 gene-based single nucleotide polymorphisms (SNPs) in pooled DNAs from different severity groups. The 756 SNPs that showed reproducible allelic differences at P < 0.02 by pooling were selected for individual genotyping. RESULTS: After adjustment for age, gender and geographic region, logistic regression models showed 50 SNPs significantly associated with disease severity (P < 0.05) after Bonferroni adjustment for multiple testing. Forty-one SNPs in a large LD block within the beta-globin gene cluster had major alleles associated with severe disease. The most significant was bthal_bg200 (odds ratio (OR) = 5.56, P = 2.6 x 10(-13)). Seven SNPs in two distinct LD blocks within a region centromeric to the beta-globin gene cluster that contains many olfactory receptor genes were also associated with disease severity; rs3886223 had the strongest association (OR = 3.03, P = 3.7 x 10(-11)). Several previously unreported SNPs were also significantly associated with disease severity. CONCLUSIONS: These results suggest that there may be an additional regulatory region centromeric to the beta-globin gene cluster that affects disease severity by modulating fetal hemoglobin expression.

pHCR: a parallel haplotype configuration reduction algorithm for haplotype interaction analysis.

Finding gene interaction models is one of the most important issues in genotype-phenotype association studies. This paper presents a model-free nonparametric statistical interaction analysis known as Parallel Haplotype Configuration Reduction (pHCR). This technique extends the original Multifactor Dimensionality Reduction (MDR) algorithm by using haplotype contribution values (c-values) and a haplotype interaction scheme instead of analyzing interactions among single-nucleotide polymorphisms. The proposed algorithm uses the statistical power of haplotypes to obtain a gene-gene interaction model. pHCR computes a statistical value for each haplotype, which contributes to the phenotype, and then performs haplotype interaction analysis on the basis of the cumulative c-value of each individual haplotype. To address the high computational complexity of pHCR, this paper also presents a scalable parallel computing solution. Nine common two-locus disease models were used to evaluate the algorithm performance under different scenarios. The results from all cases showed that pHCR shows higher power to detect gene-gene interaction in comparison with the results obtained from running MDR on the same data set. We also compared pHCR with FAMHAP, which mainly considers haplotype in the association analysis. For every experiment on the simulated data set, pHCR correctly produced haplotype interactions with much fewer false positives. We also challenged pHCR with a real data set input of beta-thalassemia/Hemoglobin E (HbE) disease. The result suggested the interaction between two previously reported quantitative trait loci of the fetal hemoglobin level, which is a major modifying factor, and disease severity of beta-thalassemia/HbE disease.

A scoring system for the classification of beta-thalassemia/Hb E disease severity.

Beta-thalassemia intermediate patients show a remarkable clinical heterogeneity. We examined the phenotypic diversity of 950 beta-thalassemia/Hb E patients in an attempt to construct a system for classifying disease severity. A novel scoring system based on six independent parameters, hemoglobin level, age at disease presentation, age at receiving first blood transfusion, requirement for transfusion, spleen size, and growth and development, was able to separate patients into three distinctive severity categories: mild, moderate, and severe courses. This system, therefore, can increase the accuracy of studies of genotype-phenotype interactions and facilitate decisions for appropriate patient management.

Genetic analysis of candidate modifier polymorphisms in Hb E-beta 0-thalassemia patients.

Hemoglobin E (Hb E)-beta-thalassemia patients display a range of clinical severities, from nearly asymptomatic to transfusion-dependent thalassemia major. Given this clinical heterogeneity, additional genetic factors modifying disease severity remain to be discovered. Association studies are being conducted to elucidate the role of genetic polymorphisms as disease severity modifiers in Hb E-beta-thalassemia patients. Using strict scoring criteria, 1060 Hb E-beta-thalassemia patients were categorized into mild, moderate, and severe groups. Taking a candidate gene approach, we found no statistically significant differences between the mild and severe patients groups in allelic or genotypic frequencies for single nucleotide polymorphisms within five genes known to influence globin gene expression and erythropoiesis.