Efficacy of Bortezomib for Treating Anti-Interferon-Gamma Autoantibody-Associated Adult-Onset Immunodeficiency Syndrome.

BACKGROUND: Currently, there is no effective treatment for adult-onset immunodeficiency (AOID) syndrome with anti-interferon-gamma autoantibodies (anti-IFN-γ-auto-Abs). This study aimed to investigate the effectiveness of bortezomib (BTZ) for decreasing anti-IFN-γ-auto-Abs. METHODS: A pre- and post-intervention study was conducted from February 2017 through June 2019 at Siriraj Hospital (Bangkok, Thailand). Five patients were invited to receive once-weekly BTZ (1.3 mg/m2 body surface area) subcutaneously for 8 weeks followed by oral cyclophosphamide (1 mg/kg/d) for 4 months. The primary outcomes were the difference in antibody level at 8 and 48 weeks compared with baseline and the incidence of serious adverse events (AEs). The secondary outcome was the occurrence of opportunistic infections (OIs) during the 72 weeks after starting BTZ. RESULTS: The median patient age was 46 years (range, 34-53). All patients had 3-5 OIs prior to enrollment. All patients were receiving antimycobacterial agents for treatment of nontuberculous mycobacterial infection at enrollment. There was no significant difference in the mean optical density of auto-Abs at 8 weeks (3.73 ± 0.72) or 48 weeks (3.74 ± 0.53) compared with baseline (3.84 ± 0.49; P = .336 and P = .555, respectively). However, after serum dilution, the antibody titer nonsignificantly decreased 8-16 weeks after BTZ initiation (P = .345). Ten OIs were observed 24-72 weeks after BTZ initiation. CONCLUSIONS: Treatment with BTZ followed by cyclophosphamide yielded no significant decrease in antibody titer levels, and 10 OIs were observed during 24-72 weeks of BTZ treatment. No serious AEs were observed. Combining rituximab with BTZ is likely necessary to prevent generation of new autoantibody-producing plasma cells. Clinical Trials Registration. NCT03103555.

Overexpression of TSPAN8 in consensus molecular subtype 3 colorectal cancer.

BACKGROUND: Recently, consensus molecular subtypes (CMSs) have been proposed as a robust transcriptome-based classification system for colorectal cancer (CRC). Tetraspanins (TSPANs) are transmembrane proteins. They have been associated with the development of numerous malignancies, including CRC, through their role as "master organizers" for multi-molecular membrane complexes. No previous study has investigated the correlation between TSPANs and CMS classification. Herein, we investigated the expression of TSPANs in patient-derived primary CRC tissues and their CMS classifications. METHODS: RNA samples were derived from primary CRC tissues (n = 100 patients diagnosed with colorectal adenocarcinoma) and subjected to RNA sequencing for transcriptome-based CMS classification and TSPAN-relevant analyses. Immunohistochemistry (IHC) and immunofluorescence (IF) stains were conducted to observe the protein expression level. To evaluate the relative biological pathways, gene-set enrichment analysis was performed. RESULTS: Of the highly expressed TSPAN genes in CRC tissues (TSPAN8, TSPAN29, and TSPAN30), TSPAN8 was notably overexpressed in CMS3-classified primary tissues. The overexpression of TSPAN8 protein in CMS3 CRC was also observed by IHC and IF staining. As a result of gene-set enrichment analysis, TSPAN8 may potentially play a role in organizing signaling complexes for kinase-based metabolic deregulation in CMS3 CRC. CONCLUSIONS: The present study reports the overexpression of TSPAN8 in CMS3 CRC. This study proposes TSPAN8 as a subtype-specific biomarker for CMS3 CRC. This finding provides a foundation for future CMS-based studies of CRC, a complex disease and the second leading cause of cancer mortality worldwide.

Exploring extracellular matrix and prostaglandin pathway alterations across varying resection margin distances of right-sided colonic adenocarcinoma.

BACKGROUND: Surgical resection followed by indicated adjuvant therapy offers potential curative treatment in colonic adenocarcinoma. Beyond the well-established seed and soil theory of colon cancer progression, the 'normal-appearing' tissues near the tumor are not genuinely normal and remain as remnants in patients following surgery. Our objective was to elucidate the alteration of gene expression and pathways across various distances of resection margins in right-sided colonic adenocarcinoma. METHODS: Twenty-seven fresh samples of primary cancer and 56 matched non-tumor tissues adjacent to the tumor (NAT) were collected from patients with resectable right-sided colon cancer. NAT were systematically obtained at varying distances (1, 5, and 10 cm) on both proximal and distal sides. Comprehensive gene expression analysis was performed using 770-gene PanCancer Progression Panel, delineating distinctive pathways and functional predictions for each region. RESULTS: Distinctive gene signatures and pathways exhibited by normal-appearing tissues were discovered at varying distances from cancer. Notably, SFRP2, PTGDS, COL1A1, IL1B, THBS2, PTGIS, COL1A2, NPR1, and BGN were upregulated, while ENPEP, MMP1, and NRCAM were downregulated significantly in 1-cm tissue compared to farther distances. Substantial alterations in the extracellular matrix (ECM) and prostaglandin/thromboxane synthesis were significantly evident at the 1-cm distance. Functional analysis indicated enhanced cell viability and survival, alongside reduced cellular death and apoptosis. CONCLUSIONS: Different distances exerted a significant impact on gene alteration within the normal-looking mucosa surrounding primary cancer, influenced by various mechanisms. These findings may highlight potential therapeutic targets related to the ECM and prostaglandin/thromboxane pathways for treatment strategies.

Thai patients who fulfilled NCCN criteria for breast/ovarian cancer genetic assessment demonstrated high prevalence of germline mutations in cancer susceptibility genes: implication to Asian population testing.

BACKGROUND: Germline genetic mutation plays a significant role in breast cancer susceptibility. The strength of such predisposition varies among ethnic groups across the globe, and clinical data from Asian population to develop a strategic approach to who should undergo a genetic test are lacking. METHODS: We performed a multigene test with next generation sequencing in Thai patients whose clinical history fulfilled NCCN criteria for breast/ovarian cancer genetic assessment, consists of 306 breast cancer patients, 62 ovarian cancer patients, 14 pancreatic cancer patients and 7 prostate cancer patients. Genetic test result and clinical history were then checked with each NCCN criteria to determined detection rate for each indication. RESULTS: There were 83 pathogenic/likely pathogenic (P/LP) variants identified in 104 patients, 44 of these P/LP variants were novel. We reported a high rate of germline P/LP variants in breast cancer (24%), ovarian cancer (37%), pancreatic cancer (14%), and prostate cancer (29%). Germline P/LP variants in BRCA1 and BRCA2 accounted for 80% of P/LP variants found in breast cancer and 57% of P/LP variants found in ovarian cancer. The detection rate of patients who fulfilled NCCN 2019 guideline for genetic/familial high-risk assessment of breast and ovarian cancers was 22-40%. CONCLUSION: Overall, the data from this study strongly support the consideration of multigene panel test as a diagnostic tool for patients with inherited cancer susceptibility in Thailand and Asian population. Implementation of the NCCN guideline is applicable, some modification may be needed to be more suitable for Asian population.

Successful treatment of arrhythmia with ß-blocker and flecainide combination in pregnant patients with Andersen-Tawil syndrome: A case report and literature review.

Andersen-Tawil syndrome (ATS) is a rare disorder characterized by a triad of ventricular arrhythmia (VA), dysmorphic features, and periodic paralysis. Due to the rarity of this condition, less is known about physiologic effect of pregnancy to ATS and arrhythmia. There is no established guideline for peripartum or postpartum treatment and prevention of arrhythmia in ATS; thus, the clinical management is challenging. We reported two KCNJ2-associated ATS patients who got pregnant and underwent vaginal birth safely. Both individuals had VA, micrognathia without periodic paralysis. ß-blocker plus flecainide could be an effective treatment combination when monotherapy failed to control arrhythmia. VA of two pregnant patients with ATS could be controlled by either physiologic changes associated pregnancy or the combination treatment of ß-blocker and flecainide.

Physician awareness, preparedness, and opinions toward consumer-initiated genetic testing in Thailand: Views from a changing landscape.

Consumer-initiated genetic tests have captured public interest in recent years, including in low-to-middle-income countries (LMICs) such as Thailand. Due to limited resources and personnel, physicians will most likely bear the burden of increasing service needs from the public as consumer-initiated genetic tests become popularized. The primary objective of this study was to describe (a) awareness, (b) preparedness to provide counseling about the consumer-initiated genetic test, and (c) opinions on the usefulness of consumer-initiated genetic tests among physicians at an academic hospital in Bangkok, Thailand. The secondary objective was to describe factors that were associated with the awareness, preparedness, and opinion of the participants. Paper questionnaires were sent out to participants which included internal medicine residents, fellows, and faculty staff members. The questionnaires assessed awareness, preparedness to discuss consumer-initiated genetic test results, and opinion on the usefulness of consumer-initiated genetic tests and included both closed- and open-ended questions. Responses were anonymous. Among 308 participants, there were 223 (72.4%) residents, 14 (4.5%) fellows, and 71 (23.1%) staff members. Only 15% of participants were aware of consumer-initiated genetic tests, mostly from the internet, and only 7% were prepared to provide counseling regarding consumer-initiated genetic tests. However, 60% agreed that consumer-initiated genetic tests may be clinically useful. Many participants, including trainees, expressed concerns about the interpretation of consumer-initiated genetic test results, application into clinical practice, appropriate counseling, and patient referral to geneticists. Multivariate logistic regression revealed that years of work experience was independently associated with awareness of consumer-initiated genetic tests, while male gender and less work experience were independently associated with favorable opinion toward the usefulness of consumer-initiated genetic tests. Our results pointed to an urgent need for genetic counselors in Thailand. Also, physicians, particularly trainees, need appropriate training to prepare them for a rapidly evolving environment where consumer-initiated genetic tests become commonplace.

Precision medicine in Thailand.

Extraordinary advances in high throughput next generation sequencing (NGS) technology and bioinformatics are the main thrust that transforms the current state of healthcare into the era of precision medicine where clinical practice takes individual variability into account. Here, we summarize the current status of the infrastructure we have and the adoption of precision medicine in Thailand in four spheres: rare diseases, oncology, pharmacogenomics, and noncommunicable diseases. Moreover, we provide our perspectives to the future of precision medicine in Thailand, especially the manpower and ethical, legal, and social issues. We believe that with decreasing costs of NGS, increasing ability to interpret the genomic data, a greater number of actionable and available treatments, implementation of precision medicine at the public health level is not a matter of if but when.

Revised Ghent Criteria is Comparable to Original Diagnostic Criteria for Marfan Syndrome with Increased Ability to Clinically Diagnose Related Disorders.

BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with major features in cardiovascular ocular and skeletal systems. Due to its genetic heterogeneity and variable expressivity, Ghent nosology was established for clinical diagnosis of MFS. In 2010, Ghent diagnostic criteria were revised to better diagnose MS and categorize its related disorders. There is no previous clinical comparison between the original and revised Ghent criteria for diagnosis of MFS in Thai patients. OBJECTIVE: To compare application and efficacy of Ghent and revised Ghent criteria in adult Thai patients with clinical suspicion of MFS. MATERIAL AND METHOD: This study was a retrospective analysis of patients with clinical suspicion of MFS who attended the Medical Genetics Clinic, Siriraj Hospital between January 2003 and December 2013. Patients were clinically examined for diagnosis of MFS using both the Ghent and revised Ghent criteria. Multidisciplinary data, including physical examination, echocardiography, slit-lamp examination, and genetic testing, were analyzed. RESULTS: Clinical and genetic data of 138 (77 males and 61 females) individuals with clinical suspicion of MFS were reviewed The most common presentation was cardiovascular manifestation. Of 92 patients diagnosed as MFS by original Ghent nosology 70 of those patients (76.1%) were also diagnosed as MFS by revised Ghent criteria. Forty-eight of 138 patients (34.8%) had undergone genetic testing, with FBN1 mutations detected in 23 patients. Twenty-two patients with detectable FBN1 mutations fulfilled both the Ghent and revised Ghent criteria. Of 22 patients whose diagnoses were not fulfilled by revised Ghent nosology, most were due to inadequate systemic score (SS). The use of revised Ghent nosology also facilitated improved diagnosis of MFS-related disorders. CONCLUSION: Revised Ghent nosology has further differentiated MFS from other MFS-related disorders and has further expanded the classification of MFS-related disorders. Genetic testing of FBN1 helps physicians to more accurately diagnose patients with MFS and related disorders.

GLIMMERS: glioma molecular markers exploration using long-read sequencing.

Summary: The revised WHO guidelines for classifying and grading brain tumors include several copy number variation (CNV) markers. The turnaround time for detecting CNVs and alterations throughout the entire genome is drastically reduced with the customized read incremental approach on the nanopore platform. However, this approach is challenging for non-bioinformaticians due to the need to use multiple software tools, extract CNV markers and interpret results, which creates barriers due to the time and specialized resources that are necessary. To address this problem and help clinicians classify and grade brain tumors, we developed GLIMMERS: glioma molecular markers exploration using long-read sequencing, an open-access tool that automatically analyzes nanopore-based CNV data and generates simplified reports. Availability and implementation: GLIMMERS is available at https://gitlab.com/silol_public/glimmers under the terms of the MIT license.

HLA variants and their association with IgE-Mediated banana allergy: A cross-sectional study.

Background: Banana allergy is on the rise in tropical regions. Advances in genomics and candidate gene identification have increased interest in genetic factors in food allergies. However, the genetic basis of IgE-mediated banana allergy is underexplored. Objective: To characterize HLA variants and their association with IgE-mediated banana allergy. Methods: This cross-sectional study recruited banana-allergic adults, confirmed by allergology tests, with non-allergic individuals as controls. Genomic DNA extraction and sequencing BAM files for HLA typing were conducted. Allele frequency was calculated using the direct counting method, and odds ratio (OR) with 95 % confidence interval (CI) were determined. Fisher's exact or chi-square tests were used to assess associations with Bonferroni's correction for multiple tests. The allele frequency of the Thai population from The Allele Frequency Net Database was used to compute the allele enrichment ratio (ER). Results: A total of 59 cases and 64 controls were recruited. HLA genotyping indicated potential associations of HLA-B*15:25 (OR 11.872; p-value 0.027), HLA-C*04:03 (OR 7.636; p-value 0.033), and HLA-DQB1*06:09 (OR 11.558; p-value 0.039) with banana allergy. However, after Bonferroni correction, none of these associations reached statistical significance. Comparing allele frequency with the general population from The Allele Frequency Net Database, our ER analysis revealed a higher prevalence in the banana allergy group for B*15:25 (ER 1.849), C*04:03 (ER 1.332), and DQB1*06:09 (ER 6.602) alleles. Conclusions: This study provides initial genetic insights into banana allergy, suggesting potential links with specific HLA alleles. Despite 12 initially identifying alleles, none were statistically significant after multiple testing correction. Larger studies are needed to detect possible significant correlations.

Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand.

Multi-gene panel testing has led to the detection of pathogenic/likely pathogenic (P/LP) variants in many cancer susceptibility genes in patients with breast-ovarian cancer spectrum. However, the clinical and genomic data of Asian populations, including Thai cancer patients, was underrepresented, and the clinical significance of multi-gene panel testing in Thailand remains undetermined. In this study, we collected the clinical and genetic data from 4567 Thai patients with cancer in the hereditary breast-ovarian cancer (HBOC) spectrum who underwent multi-gene panel testing. Six hundred and ten individuals (13.4%) had germline P/LP variants. Detection rates of germline P/LP variants in breast, ovarian, pancreatic, and prostate cancer were 11.8%, 19.8%, 14.0%, and 7.1%, respectively. Non-BRCA gene mutations accounted for 35% of patients with germline P/LP variants. ATM was the most common non-BRCA gene mutation. Four hundred and thirty-two breast cancer patients with germline P/LP variants (80.4%) met the current NCCN genetic testing criteria. The most common indication was early-onset breast cancer. Ten patients harbored double pathogenic variants in this cohort. Our result showed that a significant proportion of non-BRCA P/LP variants were identified in patients with HBOC-related cancers. These findings support the benefit of multi-gene panel testing for inherited cancer susceptibility among Thai HBOC patients. Some modifications of the testing policy may be appropriate for implementation in diverse populations.

STK11 Causative Variants and Copy Number Variations Identified in Thai Patients With Peutz-Jeghers Syndrome.

Introduction Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder caused by germline mutations in the serine-threonine kinase 11 (STK11) tumor suppressor gene. This syndrome is characterized by hamartomatous gastrointestinal polyps, mucocutaneous melanin pigmentation, and a higher risk of developing various cancers. Methods We summarized the clinical and molecular characteristics of five unrelated Thai patients with PJS. Denaturing high-performance liquid chromatography (DHPLC) screening, coupled with direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), were applied for the molecular analysis of STK11. Results A total of four STK11 pathogenic changeswere identified in the five PJS patients, including two frameshift variants (a novel c.199dup, p.Leu67ProfsTer96 and a known c.834_835del, p.Cys278TrpfsTer6) and two types of copy number variations (CNV), exon 1 deletion and exons 2-3 deletion. Among reported STK11 exonic deletions, exon 1 and exons 2-3 deletions were found to be the two most commonly deleted exons. Conclusion All identified STK11 mutations were null mutations that were associated with more severe PJS phenotypes and cancers. This study broadens the phenotypic and mutational spectrum of STK11 in PJS.

Ultrarapid and high-resolution HLA class I typing using transposase-based nanopore sequencing applied in pharmacogenetic testing.

Nanopore sequencing has been examined as a method for rapid and high-resolution human leukocyte antigen (HLA) typing in recent years. We aimed to apply ultrarapid nanopore-based HLA typing for HLA class I alleles associated with drug hypersensitivity, including HLA-A*31:01, HLA-B*15:02, and HLA-C*08:01. Most studies have used the Oxford Nanopore Ligation Sequencing kit for HLA typing, which requires several enzymatic reactions and remains relatively expensive, even when the samples are multiplexed. Here, we used the Oxford Nanopore Rapid Barcoding kit, which is transposase-based, with library preparation taking less than 1 h of hands-on time and requiring minimal reagents. Twenty DNA samples were genotyped for HLA-A, -B, and -C; 11 samples were from individuals of different ethnicity and nine were from Thai individuals. Two primer sets, a commercial set and a published set, were used to amplify the HLA-A, -B, and -C genes. HLA-typing tools that used different algorithms were applied and compared. We found that without using several third-party reagents, the transposase-based method reduced the hands-on time from approximately 9 h to 4 h, making this a viable approach for obtaining same-day results from 2 to 24 samples. However, an imbalance in the PCR amplification of different haplotypes could affect the accuracy of typing results. This work demonstrates the ability of transposase-based sequencing to report 3-field HLA alleles and its potential for race- and population-independent testing at considerably decreased time and cost.

Identification of Genomic Alterations in Thai Patients With Colorectal Cancer Using Next-Generation Sequencing-Based Multigene Cancer Panel.

Introduction Colorectal cancer (CRC) is one of the leading causes of death and illness in the general population. Although the incidence of CRC is steadily decreasing worldwide, it is being diagnosed more in individuals under 50 years of age. Multiple disease-causing variants have been reported to be involved in the development of CRC. This study aimed to investigate the molecular and clinical characteristics of Thai patients with CRC. Methods NGS-based multigene cancer panel testing was performed on 21 unrelated patients. Target enrichment was performed using a custom-designed Ion AmpliSeq on-demand panel. Thirty-six genes associated with CRC and other cancer were analyzed for variant detection. Results Sixteen variants (five nonsense, eight missense, two deletions, and one duplication) in nine genes were identified in 12 patients. Eight (66.7%) patients harboring disease-causing deleterious variants in genes APC, ATM, BRCA2, MSH2, and MUTYH. One of the eight patients also carried additional heterozygous variants in genes ATM, BMPR1A, and MUTYH. In addition, four patients carried variants of uncertain significance in genes APC, MLH1, MSH2, STK11, and TP53. Among all detected genes, APC was the most frequent causative gene observed in CRC patients, which is consistent with previous reports. Conclusion This study demonstrated the comprehensive molecular and clinical characterization of CRC patients. These findings showed the benefits of using multigene cancer panel sequencing for pathogenic gene detection and showed the prevalence of genetic aberrations in Thai patients with CRC.

A cost-utility analysis of BRCA1 and BRCA2 testing in high-risk breast cancer patients and family members in Thailand: a cost-effective policy in resource-limited settings.

Background: Screening for germline pathogenic BRCA1 or BRCA2 variants (gBRCA) in high-risk breast cancer patients is known to be cost-effective in high-income countries. Nationwide adoption of genetics testing in high-risk breast cancer population remains poor. Our study aimed to assess gBRCA health economics data in the middle-income country setting of Thailand. Methods: Decision tree and Markov model were utilized to assess cost-utility between the testing vs. no-testing groups from a societal and lifetime perspective and lifetime. We interviewed 264 patients with breast/ovarian cancer and their family members to assess relevant costs and quality of life using EQ-5D-5L. One-way sensitivity, probabilistic sensitivity (Monte Carlo simulation), and budget impact analyses were done to estimate the outcome under Thailand's Universal Health Coverage scheme. Results: The predicted lifetime cost and Quality-adjusted Life Years (QALY) for those with breast cancer were $13,788 and 10.22 in the testing group and $13,702 and 10.07 in the no-testing group. The incremental cost-effectiveness ratio for gBRCA testing in high-risk breast cancer patients was $573/QALY. The lifetime cost for the family members of those with gBRCA was $14,035 (QALY 9.99), while the no-testing family members group was $14,077 (QALY 9.98). Performing gBRCA testing in family members was cost-saving. Conclusion: Cost-utility analysis demonstrated a cost-effective result of gBRCA testing in high-risk breast cancer patients and cost-saving in familial cascade testing. The result was endorsed in the national health benefits package in 2022. Other middle-income countries may observe the cost-effective/cost-saving aspects in common genetic diseases under their national health schemes.

The KRAS-Mutant Consensus Molecular Subtype 3 Reveals an Immunosuppressive Tumor Microenvironment in Colorectal Cancer.

Colorectal cancers (CRC) with KRAS mutations (KRASmut) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRASmut, focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRASmut in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS (KRASwt). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRASmut and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRASmut in the TME regions of CMS3-classified CRC tissues. CRC patients with KRASmut were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFß signaling by KRASmut was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRASmut CMS3-classified tissues suggested up-regulated genes, CD40, CTLA4, ARG1, STAT3, IDO, and CD274, that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRASmut in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRASmut should consider these transcriptional landscapes.

Whole exome sequencing and rare variant association study to identify genetic modifiers, KLF1 mutations, and a novel double mutation in Thai patients with hemoglobin E/beta-thalassemia.

OBJECTIVES: Clinical manifestations of patients with Hemoglobin E/beta-thalassemia vary from mild to severe phenotypes despite exhibiting the same genotype. Studies have partially identified genetic modifiers. We aimed to study the association between rare variants in protein-coding regions and clinical severity in Thai patients. METHODS: From April to November 2018, a case-control study was conducted based on clinical information and DNA samples collected from Thai patients with hemoglobin E/beta-thalassemia over the age of four years. Cases were patients with severe symptoms, while patients with mild symptoms acted as controls. Whole exome sequencing and rare variant association study were used to analyze the data. RESULTS: All 338 unrelated patients were classified into 165 severe and 173 mild cases. Genotypes comprised 81.4% of hemoglobin E/beta-thalassemia, 2.7% of homozygous or compound heterozygous beta-thalassemia, and 0.3% of (뫧)0 thalassemia Hb E while 15.7% of samples were not classified as beta-thalassemia. A novel cis heterozygotes of IVS I-7 (A > T) and codon 26 (G > A) was identified. Six genes (COL4A3, DLK1, FAM186A, PZP, THPO, and TRIM51) showed the strongest associations with severity (observed p-values of <0.05; significance lost after correction for multiplicity). Among known modifiers, KLF1 variants were found in four mild patients and one severe patient. CONCLUSION: No rare variants were identified as contributors to the clinical heterogeneity of hemoglobin E/beta-thalassemia. KLF1 mutations are potential genetic modifiers. Studies to identify genetic factors are still important and helpful for predicting severity and developing targeted therapy.

Unusual presentation as an adult onset painful myopathy in a Thai patient with Becker muscular dystrophy.

A Thai 37-years-old man presented with adult onset progressive proximal muscle weakness and generalized myalgia. Family history showed similar symptoms in several male relatives, compatible with X-linked recessive inheritance. Electromyography suggested myopathic process. Serum creatine kinase was highly elevated. Diagnosis of Becker muscular dystrophy (BMD) was confirmed by genetic testing. His symptoms responded well to steroid treatment. This report is of the first Thai patient with atypical presentation of BMD.

Genetic polymorphism of low-density lipoprotein receptor did not affect treatment outcome of chronic hepatitis C genotype 3.

BACKGROUND: The low-density lipoprotein receptor (LDL-R) has been proposed to function as a receptor for the hepatitis C virus (HCV) entry. Polymorphism of LDL-R gene may influence the clearance of virus and response to treatment. This study was conducted to evaluate the association of LDL-R gene polymorphism and the response to antiviral treatment in patients with chronic HCV infection. MATERIAL AND METHOD: A total of 112 naïve patients with HCV genotype 3 were enrolled in the study. All patients were treated with a combination of pegylated interferon and ribavirin for 24 weeks. Polymerase chain reaction combined with restriction fragment length polymorphism was used to detect the polymorphism at the LDL-R gene intron 11 loci, including intron1, intron 3.1, intron 3.2, intron 4, intron 6, exon 8, intron 11, intron 13, intron 14 and 3'UTR-2 SNPs in intron 16 region. Comparisons of genotype and allele frequency between responders and nonresponders were analyzed. RESULTS: Patients had a mean age of 54 years and 43% were male. Mean HCVRNA viral load and alanine aminotransferase level were 6.3 log, IU/mL and 100 IU/L, respectively. Sustained virological response, relapse and no response were documented in 68.7%, 17.9% and 13.4%, respectively. Baseline characteristics including age, sex, body weight, aminotransferase levels and HCV RNA viral load were similar between responders and nonresponders. No statistical difference was found for either genotype distribution or allele frequency among responders and nonresponders. CONCLUSION: This study did not provide the evidence for a role of LDL-R polymorphism the response to antiviral treatment in patients with HCV genotype 3. This indicates that a genetic component via the LDL-R may not control HCV treatment outcome in HCV genotype 3

Can we predict final outcome of internal medicine residents with in-training evaluation.

OBJECTIVE: To assess the predictive value of in-training evaluation for determining future success in the internal medicine board certifying examination. MATERIAL AND METHOD: Ninety-seven internal medicine residents from Faculty of Medicine Siriraj Hospital who undertake the Thai Board examination during the academic year 2006-2008 were enrolled. Correlation between the scores during internal medicine rotation and final scores in board examination were then examined. RESULTS: Significant positive linear correlation was found between scores from both written and clinical parts of board certifying examination and scores from the first-year summative written and clinical examinations and also the second-year formative written examination (r = 0.43-0.68, p < 0.001). Monthly evaluation by attending staffs was less well correlated (r = 0.29-0.36) and the evaluation by nurses or medical students demonstrated inverse relationship (r = -0.2, p = 0.27 and r = -0.13, p = 0.48). CONCLUSION: Some methods of in-training evaluation can predict successful outcome of board certifying examination. Multisource assessments cannot well extrapolate some aspects of professional competences and qualities.