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Background: The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional alterations in severe COVID-19, defined as acute respiratory or other organ failure., Methods: We profiled 127 hospitalized patients with COVID-19 (n = 79 with severe COVID-19 and 48 with moderate) who collectively provided 241 stool samples from April 2020 to May 2021 to identify links between COVID-19 severity and gut microbial taxa, their biochemical pathways, and stool metabolites., Results: Forty-eight species were associated with severe disease after accounting for antibiotic use, age, sex, and various comorbidities. These included significant in-hospital depletions of Fusicatenibacter saccharivorans and Roseburia hominis, each previously linked to post-acute COVID syndrome or "long COVID," suggesting these microbes may serve as early biomarkers for the eventual development of long COVID. A random forest classifier achieved excellent performance when tasked with classifying whether stool was obtained from patients with severe vs. moderate COVID-19, a finding that was externally validated in an independent cohort. Dedicated network analyses demonstrated fragile microbial ecology in severe disease, characterized by fracturing of clusters and reduced negative selection. We also observed shifts in predicted stool metabolite pools, implicating perturbed bile acid metabolism in severe disease., Conclusions: Here, we show that the gut microbiome differentiates individuals with a more severe disease course after infection with COVID-19 and offer several tractable and biologically plausible mechanisms through which gut microbial communities may influence COVID-19 disease course. Further studies are needed to expand upon these observations to better leverage the gut microbiome as a potential biomarker for disease severity and as a target for therapeutic intervention., (© 2023. The Author(s).)

Background: Emery-Dreifuss Muscular Dystrophy (EDMD) is an uncommon genetic disease among the group of muscular dystrophies. EDMD is clinically heterogeneous and resembles other muscular dystrophies. Mutation of the lamin A/C (LMNA) gene, which causes EDMD, also causes many other diseases. There is inter and intrafamilial variability in clinical presentations. Precise diagnosis can help in patient surveillance, especially before they present with cardiac problems. Hence, this paper shows how a molecular work-out by next-generation sequencing can help this group of disorders., Case Presentation: A 2-year-10-month-old Javanese boy presented to our clinic with weakness in lower limbs and difficulty climbing stairs. The clinical features of the boy were Gower's sign, waddling gait and high CK level. His father presented with elbow contractures and heels, toe walking and weakness of limbs, pelvic, and peroneus muscles. Exome sequencing on this patient detected a pathogenic variant in the LMNA gene (NM_170707: c.C1357T: NP_733821: p.Arg453Trp) that has been reported to cause Autosomal Dominant Emery-Dreifuss muscular dystrophy. Further examination showed total atrioventricular block and atrial fibrillation in the father., Conclusion: EDMD is a rare disabling muscular disease that poses a diagnostic challenge. Family history work-up and thorough neuromuscular physical examinations are needed. Early diagnosis is essential to recognize orthopaedic and cardiac complications, improving the clinical management and prognosis of the disease. Exome sequencing could successfully determine pathogenic variants to provide a conclusive diagnosis., (© 2022. The Author(s).)

Background: Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) Type II is an autosomal recessive condition encompassing a heterogeneous group of disorders characterized by symmetrical growth retardation leading to dwarfism, microcephaly, and a range of multiple medical complications including neurovascular diseases. Biallelic pathogenic variants in the pericentrin gene (PCNT) have been implicated in its pathogenesis., Case Presentation: We performed whole-exome sequencing to ascertain the diagnosis of a 2 year and 6 months old boy who presented with severe failure to thrive, microcephaly, and facial gestalt suggestive of MOPD Type II which included features such as retrognathia, small ears, prominent nasal root with a large nose, microdontia, sparse scalp hair, bilateral fifth finger clinodactyly. He had a small ostium secundum atrial septal defect and bilaterally small kidneys. Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) Type II was confirmed based on a pathogenic compound heterozygous frameshift variant in the PCNT gene c.5059_5060delAA | p. Asn1687fs (novel variant) and c.9535dup (p. Val3179fs). His parents were found to be heterozygous carriers for the variants., Conclusion: We report a novel frameshift variant in the PCNT gene and a previously unreported phenotype for Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) Type II., (© 2022. The Author(s).)

Background: Congenital hemidysplasia with ichthyosiform erythroderma and limb defects also known as CHILD syndrome is an X-linked dominant, male lethal genodermatosis with a prevalence of 1 in 100,000 live births. Mutations in NSDHL gene located at Xq28 potentially impair the function of NAD(P) H steroid dehydrogenase-like protein and is responsible for its pathogenesis., Case Presentation: The proband was a 9-month-old twin (T2) girl with a healthy twin sister (T1) of Sri Lankan origin born to non-consanguineous parents. She presented with right sided continuous icthyosiform erythroderma and ipsilateral limb defects and congenital hemidysplasia since birth. Notably the child had ipsilateral hand hypoplasia and syndactyly. There were other visceral abnormalities. We performed whole exome sequencing and found a novel heterozygous variant (NSDHL, c.713C > A, p.Thr238Asn)., Conclusion: We report a novel missense variant in the NSDHL gene that resides in a highly-conserved region. This variant affects the NAD(P) H steroid dehydrogenase-like protein function via reduction in the number of active sites resulting in the CHILD syndrome phenotype and syndactyly.

An amendment to this paper has been published and can be accessed via the original article.

Objective: Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common genetic neuromuscular disease in children, resulting from a defect in the DMD gene located on Xp21.2. The new emerging treatment using exon skipping strategy is tailored to specific mutations, thus molecular diagnostics are particularly important. This study aimed to detect the DMD gene deletion in Indonesian DMD/BMD patients and analyze the potential amenability by exon skipping therapy., Results: Thirty-four male patients were enrolled in this study, 23 of them (67.6%) underwent muscle biopsy and showed the absence or partially expressed dystrophin protein in immunohistochemistry staining. All patients had very high serum CK levels (10.529 ± 9.97 IU/L). Multiplex PCR revealed the DMD gene deletions in 15 (44.1%) cases. Seventy-eight percent of deletions were clustered in the hot-spot region of exon 43 to 52. Furthermore, seven (20.5%) patients were potentially amenable to exon skipping treatment. Therefore, multiplex PCR is one feasible method to detect DMD gene deletion in Indonesian DMD/BMD patients that can further determine the potential amenability of exon skipping therapy. In addition, this study is the first report of DMD gene deletion analysis in Indonesia.

Background: Most of the global burden of pollution-related morbidity and mortality is believed to occur in resource-limited settings, where HIV serostatus and sex may influence the relationship between air pollution exposure and respiratory morbidity. The lack of air quality monitoring networks in these settings limits progress in measuring global disparities in pollution-related health. Personal carbon monoxide monitoring may identify sub-populations at heightened risk for air pollution-associated respiratory morbidity in regions of the world where the financial cost of air quality monitoring networks is prohibitive., Methods: From September 2015 through May 2017, we measured 48-h ambulatory carbon monoxide (CO) exposure in a longitudinal cohort of HIV-infected and uninfected adults in rural southwestern Uganda. We fit generalized mixed effects models to identify correlates of CO exposure exceeding international air quality thresholds, quantify the relationship between CO exposure and respiratory symptoms, and explore potential effect modification by sex and HIV serostatus., Results: Two hundred and sixty study participants completed 419 sampling periods. Personal CO exposure exceeded international thresholds for 50 (19%) participants. In covariate-adjusted models, living in a home where charcoal was the main cooking fuel was associated with CO exposure exceeding international thresholds (adjusted odds ratio [AOR] 11.3, 95% confidence interval [95%CI] 4.7-27.4). In sex-stratified models, higher CO exposure was associated with increased odds of respiratory symptoms among women (AOR 3.3, 95%CI 1.1-10.0) but not men (AOR 1.3, 95%CI 0.4-4.4). In HIV-stratified models, higher CO exposure was associated with increased odds of respiratory symptoms among HIV-infected (AOR 2.5, 95%CI 1.01-6.0) but not HIV-uninfected (AOR 1.4, 95%CI 0.1-14.4) participants., Conclusions: In a cohort in rural Uganda, personal CO exposure frequently exceeded international thresholds, correlated with biomass exposure, and was associated with respiratory symptoms among women and people living with HIV. Our results provide support for the use of ambulatory CO monitoring as a low-cost, feasible method to identify subgroups with heightened vulnerability to pollution-related respiratory morbidity in resource-limited settings and identify subgroups that may have increased susceptibility to pollution-associated respiratory morbidity.

Background: Whereas meditation training has been purported to support slower cellular aging, little work has explored the association among different facets of dispositional mindfulness, self-compassion, and cellular aging. The present study aimed to examine the relationship between leukocyte telomere length (LTL), an index of cellular aging, dispositional mindfulness, and self-compassion in a sample of Singaporean Chinese adults., Methods: One hundred and fifty-eight Chinese adults (mean age = 27.24 years; 63.3% female) were recruited from the community and completed self-report measures assessing dispositional mindfulness, self-compassion, and psychological symptoms, as well as provided blood samples for analyses of LTL. Multiple regression analyses were conducted to examine the role of trait mindfulness and self-compassion in predicting LTL, taking into consideration potential covariates such as chronological age and psychological symptoms., Results: Results showed that nonreactivity, one of the five facets of dispositional mindfulness, was significantly associated with LTL, after controlling for chronological age. There was also a trend for dispositional mindfulness, self-compassion, and their selected facets (i.e., nonjudging, common humanity, and de-identification) to each be associated with longer LTL., Conclusions: Overall, the findings provide preliminary support for the association among aspects of dispositional mindfulness, self-compassion, and aging. In particular, individuals high on nonreactivity experience slower aging at the cellular level, likely through engaging in more adaptive coping mechanisms.

Background: Several disease specific instruments have been developed to identify and assess diabetes distress. In Malaysia, the Problem Areas in Diabetes Scale has been validated in Malay, but it does not have specific domains to assess the different areas of diabetes-related distress. Hence, we decided to use the Diabetes Distress Scale instead. To date, only the Malay version of the Diabetes Distress Scale has been validated in Malaysia. However, English is widely spoken by Malaysians, and is an important second language in Malaysia. Therefore, our aim was to determine the validity and reliability of the English version of the Diabetes Distress Scale among patients with type 2 diabetes in Malaysia., Methods: The Diabetes Distress Scale was administered to 114 patients with type 2 diabetes, who could understand English, at baseline and 4 weeks later, at a primary care clinic in Malaysia. To assess for convergent validity, the Depression Anxiety Stress Scale was administered at baseline. Discriminative validity was assessed by analysing the total diabetes distress scores of participants with poor (Hb A1c  > 7.0%) and good glycaemic control (Hb A1c  ≤ 7.0%)., Results: The majority of our participants were male 65(57.0%), with a median duration of diabetes of 9.5 years. Exploratory factor analysis showed that the Diabetes Distress Scale had 4 subscales, as per the original Diabetes Distress Scale. The overall Cronbach's α was 0.920 (range = 0.784-0.859 for each subscale). The intraclass correlation ranged from 0.436 to 0.643 for test-retest. The Diabetes Distress Scale subscales were significantly correlated with the different subscales of the Depression Anxiety Stress Scale (spearman's rho range = 0.427-0.509, p < 0.001). Patients with poor glycaemic control had significantly higher diabetes distress score (1.88) compared to those with good glycaemic control (1.50) (p < 0.001)., Conclusions: The English version of the Diabetes Distress Scale was found to be a valid and reliable instrument to evaluate diabetes distress among patients with type 2 diabetes in Malaysia. It can be used in clinical practice to offer a useful indicator of the effect of diabetes-induced distress during clinic visits, especially for patients with poor glycemic control. This would ensure that these patients are provided the care that is required.

Background: Advance care planning is a voluntary process whereby individual preferences, values and beliefs are used to aid a person in planning for end-of-life care. Currently, there is no local instrument to assess an individual's awareness and attitude towards advance care planning. This study aimed to develop an Advance Care Planning Questionnaire and to determine its validity and reliability among older people in Malaysia., Methods: The Advance Care Planning Questionnaire was developed based on literature review. Face and content validity was verified by an expert panel, and piloted among 15 participants. Our study was conducted from October 2013 to February 2014, at an urban primary care clinic in Malaysia. Included were those aged >50 years, who could understand English. A retest was conducted 2 weeks after the first administration., Results: Participants from the pilot study did not encounter any problems in answering the Advance Care Planning Questionnaire. Hence, no further modifications were made. Flesch reading ease was 71. The final version of the Advance Care Planning Questionnaire consists of 66 items: 30 items were measured on a nominal scale, whilst 36 items were measured on a Likert-like scale; of which we were only able to validate 22 items, as the remaining 14 items were descriptive in nature. A total of 245 eligible participants were approached; of which 230 agreed to participate (response rate = 93.9 %). Factor analysis on the 22 items measured on a Likert-scale revealed four domains: "feelings regarding advance care planning", "justifications for advance care planning", "justifications for not having advance care planning: fate and religion", and "justifications for not having advance care planning: avoid thinking about death". The Cronbach's alpha values for items each domain ranged from 0.637-0.915. In test-retest, kappa values ranged from 0.738-0.947., Conclusions: The final Advance Care Planning Questionnaire consisted of 63 items and 4 domains. It was found to be a valid and reliable instrument to assess the awareness and attitude of older people in Malaysia towards advance care planning.

Background: Osteoporosis has significant impact on healthcare costs and quality of life. Amongst the models for collaborative disease state management services published internationally, there is sparse evidence regarding the role of community pharmacists in the provision of osteoporosis care. Hence, the aim of our study was to explore community pharmacists' opinions (including the barriers and facilitators) and scope of osteoporosis disease state management services by community pharmacists in Malaysia, informing a vision for developing these services., Methods: Semi-structured individual interviews and focus groups discussions were conducted with community pharmacists from October 2013 to July 2014. Three trained researchers interviewed the participants. Interviews were recorded and transcribed verbatim. Data were analyzed thematically using an interpretative description approach., Results: Nineteen community pharmacists with 1-23 years of experience were recruited (in depth interviews: n = 9; focus group discussions: n = 10). These participants reflected on their experience with osteoporosis-related enquiries, which included medication counseling, bone density screening and referral of at-risk patients. Key barriers were the lack of numerous factors: public awareness of osteoporosis, accurate osteoporosis screening tools for community pharmacists, pharmacists' knowledge on osteoporosis disease and medications, time to counsel patients about bone health, collaboration between pharmacists and doctors, and support from the government and professional body. The pharmacists wanted more continuing education on osteoporosis, osteoporosis awareness campaigns, a simple, unbiased osteoporosis education material, and inter-professional collaboration practices with doctors, and pharmacists' reimbursement for osteoporosis care., Conclusions: The involvement of community pharmacists in the provision of osteoporosis disease state management was minimal. Only ad-hoc counseling on osteoporosis prevention was performed by community pharmacists. Development and trial of collaborative osteoporosis disease state management services in community pharmacy could be facilitated by training, support and remuneration.

Background: Prescribing incompetence is an important factor that contributes to prescribing error, and this is often due to inadequate training during medical schools. We therefore aimed to develop and validate an instrument to assess the prescribing readiness of medical students (PROMS) in Malaysia., Methods: The PROMS comprised of 26 items with four domains: undergraduate learning opportunities; hands-on clinical skills practice; information gathering behaviour; and factors affecting the learning of prescribing skills. The first three domains were adapted from an existing questionnaire, while items from the last domain were formulated based on findings from a nominal group discussion. Face and content validity was determined by an expert panel, pilot tested in a class of final year (Year 5) medical students, and assessed using the Flesch reading ease. To assess the reliability of the PROMS, the internal consistency and test-retest (at baseline and 2 weeks later) were assessed using the Wilcoxon Signed Ranks test and Spearman's rho. The discriminative validity of the PROMS was assessed using the Mann-Whitney U-test (to assess if the PROMS could discriminate between final year medical students from a public and a private university)., Results: A total of 119 medical students were recruited. Flesch reading ease was 46.9, indicating that the instrument was suitable for use in participants undergoing tertiary education. The overall Cronbach alpha value of the PROMS was 0.695, which was satisfactory. Test-retest showed no difference for 25/26 items, indicating that our instrument was reliable. Responses from the public and private university final year medical students were significantly different in 10/26 items, indicating that the PROMS was able to discriminate between these two groups. Medical students from the private university reported fewer learning opportunities and hands-on practice compared to those from the public university. On the other hand, medical students from the private university reported more frequent use of both web based and non-web-based resources compared to their public university counterparts., Conclusions: The PROMS instrument was found to be a reliable and valid tool for assessing medical students' readiness to prescribe in Malaysia. It may also inform on the adequacy of medical programmes in training prescribing skills.

Background: The US Federal and Drug Administration (FDA) recently revised statin drug labels to include the information that increases in fasting serum glucose and glycated haemoglobin levels have been reported with the use of statins. Yet in a survey, 87% of the doctors stated that they had never or infrequently observed increases in glucose or HbA1c levels in patients on statin. In this study we would like to determine the association between the use of statins and glycaemic control in a retrospective cohort of patients with hypertension., Methods: A retrospective review of 1060 medical records of patients with hypertension at a primary care clinic was conducted. These records were selected using systematic random sampling (1:4). Data on patient socio-demographic factors; clinical profile; investigation results and prescribed medications were collected. Independent t-test was used for continuous variables while Pearson's χ2 test was used for categorical variables. Logistic regression was done to adjust for confounders., Results: 810 (76.4%) patients with hypertension were on statins, out of which 792 (97.8%) were taking simvastatin 10 mg or 20 mg daily. Analysis of the whole group regardless of diabetes status showed that the statin user group had higher HbA1c and fasting blood glucose values. The difference in HbA1c levels remained significant (adjusted OR = 1.290, p = 0.044, 95% CI 1.006, 1.654) after adjustment for diabetes, diabetic medication and fasting blood glucose. In the study population who had diabetes, statin users again had significantly higher HbA1c level compared to statin non-users. This difference remained significant (adjusted OR 1.208, p = 0.037, 95% CI 1.012, 1.441) after adjustment for age and diabetic medications., Conclusions: Statins use is associated with increased HbA1c levels among hypertensive patients and hypertensive patients with diabetes. Clinicians managing hypertensive patients on statins should consider monitoring the HbA1c level and ensure that those with diabetes have their hyperglycaemia kept under control.

Background: Traditional open surgery for gastrointestinal stromal tumors (GIST) requires a long incision. Moreover, the gas-filling laparoscopic technique used in GIST surgery still has its limitations. Therefore, we developed a gasless laparoscopic (GL) surgery for GIST and compared it with traditional open surgery., Methods: Between October 2007 and September 2009, 62 GIST patients in the National Taiwan University Hospital received wide excisions. Of these 62 patients, 30 underwent the new procedure (GL group) and 32 had open surgery (OS group). Preoperative and postoperative clinicopathologic characteristics were compared between the groups., Results: There were no significant differences in preoperative characteristics or blood loss. However, the days to first flatus, postoperative hospital stay, wound length, white blood cell count at postoperative day one, and peak daily body temperature were all significantly improved in the GL group. Usage of postoperative analgesia on postoperative days one to five was also significantly lower in the GL group., Conclusions: Wide-excision laparoscopy for gastric GIST can be performed more safely, more effectively, and with faster postoperative recovery using the gasless technique as compared with the open method. We, therefore, recommend this new surgical technique, which hybridizes the advantages of both the traditional open method and pure laparoscopic surgery.

Background: Patient's knowledge on diabetes, hypertension and hyperlipidaemia and its medications can be used as one of the outcome measures to assess the effectiveness of educational intervention. To date, no such instrument has been validated in Malaysia. Therefore, the aim of this study was to evaluate the validity and reliability of the Diabetes, Hypertension and Hyperlipidemia (DHL) knowledge instrument for assessing the knowledge of patients with type 2 diabetes in Malaysia., Methods: A 28-item instrument which comprised of 5 domains: diabetes, hypertension, hyperlipidemia, medications and general issues was designed and tested. One point was given for every correct answer, whilst zero was given for incorrect answers. Scores ranged from 0 to 28, which were then converted into percentage. This was administered to 77 patients with type 2 diabetes in a tertiary hospital, who were on medication(s) for diabetes and who could understand English (patient group), and to 40 pharmacists (professional group). The DHL knowledge instrument was administered again to the patient group after one month. Excluded were patients less than 18 years old., Results: Flesch reading ease was 60, which is satisfactory, while the mean difficulty factor(SD) was 0.74(0.21), indicating that DHL knowledge instrument was moderately easy. Internal consistency of the instrument was good, with Cronbach's α = 0.791. The test-retest scores showed no significant difference for 26 out of the 28 items, indicating that the questionnaire has achieved stable reliability. The overall mean(SD) knowledge scores was significantly different between the patient and professional groups [74.35(14.88) versus 93.84(6.47), p < 0.001]. This means that the DHL knowledge instrument could differentiate the knowledge levels of participants. The DHL knowledge instrument shows similar psychometric properties as other validated questionnaires., Conclusions: The DHL knowledge instrument shows good promise to be adopted as an instrument for assessing diabetic patients' knowledge concerning their disease conditions and medications in Malaysia.

Background: Intraluminal migration of a drain through an anastomotic site is a rare complication of gastric surgery., Case Presentation: We herein report the intraluminal migration of a drain placed after a lower esophagectomy and total gastrectomy with Roux-en-Y anastomosis for gastric small cell carcinoma. Persistent drainage was noted 1 month after surgery, and radiographic studies were consistent with drain tube migration. Endoscopy revealed the drain had migrated into the esophagojejunostomy anastomotic site. The drain was removed from outside of abdominal wound while observing the anastomotic site endoscopically. The patient was treated with suction via a nasogastric tube drain for 5 days, and thereafter had an uneventful recovery., Conclusions: Though drain tube migration is a rare occurrence, it should be considered in patients with persistent drainage who have undergone gastric surgery.

Background: One of the most common and efficient methods for detecting mutations in genes is PCR amplification followed by direct sequencing. Until recently, the process of designing PCR assays has been to focus on individual assay parameters rather than concentrating on matching conditions for a set of assays. Primers for each individual assay were selected based on location and sequence concerns. The two primer sequences were then iteratively adjusted to make the individual assays work properly. This generally resulted in groups of assays with different annealing temperatures that required the use of multiple thermal cyclers or multiple passes in a single thermal cycler making diagnostic testing time-consuming, laborious and expensive.These factors have severely hampered diagnostic testing services, leaving many families without an answer for the exact cause of a familial genetic disease. A search of GeneTests for sequencing analysis of the entire coding sequence for genes that are known to cause muscular dystrophies returns only a small list of laboratories that perform comprehensive gene panels.The hypothesis for the study was that a complete set of universal assays can be designed to amplify and sequence any gene or family of genes using computer aided design tools. If true, this would allow automation and optimization of the mutation detection process resulting in reduced cost and increased throughput., Results: An automated process has been developed for the detection of deletions, duplications/insertions and point mutations in any gene or family of genes and has been applied to ten genes known to bear mutations that cause muscular dystrophy: DMD; CAV3; CAPN3; FKRP; TRIM32; LMNA; SGCA; SGCB; SGCG; SGCD. Using this process, mutations have been found in five DMD patients and four LGMD patients (one in the FKRP gene, one in the CAV3 gene, and two likely causative heterozygous pairs of variations in the CAPN3 gene of two other patients). Methods and assay sequences are reported in this paper., Conclusion: This automated process allows laboratories to discover DNA variations in a short time and at low cost.