ATG16L1 rs2241880/T300A increases susceptibility to perianal Crohn's disease: An updated meta-analysis on inflammatory bowel disease risk and clinical outcomes.

BACKGROUND: ATG16L1 plays a fundamental role in the degradative intracellular pathway known as autophagy, being a mediator of inflammation and microbial homeostasis. The variant rs2241880 can diminish these capabilities, potentially contributing to inflammatory bowel disease (IBD) pathogenesis. OBJECTIVES: To perform an updated meta-analysis on the association between ATG16L1 rs2241880 and IBD susceptibility by exploring the impact of age, ethnicity, and geography. Moreover, to investigate the association between rs2241880 and clinical features. METHODS: Literature searches up until September 2022 across 7 electronic public databases were performed for all case-control studies on ATG16L1 rs2241880 and IBD. Pooled odds ratios (ORP ) and 95% CI were calculated under the random effects model. RESULTS: Our analyses included a total of 30,606 IBD patients, comprising 21,270 Crohn's disease (CD) and 9336 ulcerative colitis (UC) patients, and 33,329 controls. ATG16L1 rs2241880 was significantly associated with CD susceptibility, where the A allele was protective (ORP : 0.74, 95% CI: 0.72-0.77, p-value: <0.001), while the G allele was a risk factor (ORP : 1.23, 95% CI: 1.09-1.39, p-value: 0.001), depending on the minor allele frequencies observed in this multi-ancestry study sample. rs2241880 was predominantly relevant in Caucasians from North America and Europe, and in Latin American populations. Importantly, CD patients harbouring the G allele were significantly more predisposed to perianal disease (ORP : 1.21, 95% CI: 1.07-1.38, p-value: 0.003). CONCLUSIONS: ATG16L1 rs2241880 (G allele) is a consistent risk factor for IBD in Caucasian cohorts and influences clinical outcomes. As its role in non-Caucasian populations remains ambiguous, further studies in under-reported populations are necessary.

Etiology, outcome and prognostic indicators of acute liver failure in Asian children.

OBJECTIVE: Outcome of pediatric acute liver failure (PALF) in countries with limited availability of LT is not well described. We evaluated the outcome and prognostic indicators of PALF in Malaysia where emergency LT for ALF is limited. METHODS: In this retrospective review on children < 18 years with PALF, we compared clinical and laboratory parameters between survival after supportive treatment and after LT or succumbed without LT. The predictive values of Liver Injury Unit (LIU; peak laboratory values for international normalized ratio [INR], ammonia, total bilirubin) and upon admission (aLIU) on outcome of PALF was evaluated using receiver operator characteristic (ROC) curves. RESULTS: Of 77 children (39 males [51%]; median age 2.8 years) with PALF, the overall survival was 55% (n = 42); 52% (n = 40) survived with supportive management, 2.6% (n = 2) after LT. As compared to children who survived without LT, children who had LT/died had lower hemoglobin, aspartate transferase, γ-glutamyl transpeptidase (GGT), and higher serum bilirubin, alkaline phosphatase, ammonia, and serum sodium (p < 0.05). On multivariate analysis, significant independent predictor for death or LT were peak bilirubin > 452 µmol/L and peak GGT < 96 IU/L. The C-index of LIU and aLIU score were 0.79 and 0.68, respectively, indicating that LIU score was a good model in predicting outcome of PALF. CONCLUSIONS: Overall survival of PALF remained poor. High peak bilirubin and low GGT predict poor outcome of PALF. LIU score is a good model in predicting outcome of PALF and maybe useful in selecting children for emergency LT.

Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population.

Background and Aims: Thiopurines, which are immunosuppressive drugs for maintaining remission for inflammatory bowel disease, are known to cause myelotoxicity in patients with Nudix Hydroxylase 15 (NUDT15) genetic variants in some Asian countries with monoethnic populations. We aimed to investigate the association of NUDT15 variants with leukopenia in a multiethnic population in Southeast Asia. Methods: Patients with a confirmed diagnosis of inflammatory bowel disease were recruited. We collected demographic and clinical characteristics and whole blood counts before and after initiating thiopurines. Thiopurine S-methyltransferase (TPMT) and NUDT15 genotypes were analyzed with the single nucleotide polymorphisms (SNPs) genotyping assay. Leukopenia was defined as a white blood cell (WBC) count < 3,000/µl. Results: In this study, 19 (18.6%) of the 102 patients who had adequate thiopurine therapy experienced leukopenia, 11 patients (57.9%) had NUDT15 c.415C > T variants, 2 patients (10.5%) had NUDT15 c.52G > A variants while one (5.3%) had a TPMT variation. Individually, NUDT15 c.415C > T had a sensitivity and specificity of 57.9% and 94.0% (odds ratio [OR] = 21.45, 95% CI 5.94-77.41, p < 0.001), respectively, for predicting thiopurine-induced leukopenia, while NUDT15 c.52G > A was only observed in patients with leukopenia. As compared with patients with wild-type NUDT15, both NUDT15 variations had a combined sensitivity and specificity of 68.4% and 94%, respectively (OR = 33.80, 95% CI 8.99-127.05, p < 0.001), for predicting thiopurine-induced leukopenia as well as a shorter onset to leukopenia (median onset [months] 2.0 vs. 5.5; p = 0.045). Sub-group analysis showed that both NUDT15 variations were strongly associated with leukopenia among the Chinese and Indians but not among the Malays. Conclusion: Nudix Hydroxylase 15 variants strongly predicted thiopurine-induced leukopenia across a multiethnic Southeast Asian population, particularly among the Chinese and Indians.

Prevalence of respiratory viruses among paediatric patients in acute respiratory illnesses in Malaysia.

OBJECTIVES: Acute respiratory infections (ARIs) are one of the leading causes of childhood morbidity and mortality worldwide. However, there is limited surveillance data on the epidemiological burden of respiratory pathogens in tropical countries like Malaysia. This study aims to estimate the prevalence of respiratory pathogens causing ARIs among children aged <18 years old in Malaysia and their epidemiological characteristics. METHODS: Nasopharyngeal swab specimens received at 12 laboratories located in different states of Malaysia from 2015-2019 were studied. Detection of 18 respiratory pathogens were performed using multiplex PCR. RESULTS: Data from a total of 23,306 paediatric patients who presented with ARI over a five-year period was studied. Of these, 18538 (79.5%) were tested positive. The most prevalent respiratory pathogens detected in this study were enterovirus/ rhinovirus (6837/ 23000; 29.7%), influenza virus (5176/ 23000; 22.5%) and respiratory syncytial virus (RSV) (3652/ 23000; 15.9%). Throughout the study period, RSV demonstrated the most pronounce seasonality; peak infection occurred during July to September. Whereas the influenza virus was detected year-round in Malaysia. No seasonal variation was noted in other respiratory pathogens. The risk of RSV hospitalisation was found to be significantly higher in children aged less than two years old, whereas hospitalisation rates for the influenza virus peaked at children aged between 3-6 years old. CONCLUSION: This study provides insight into the epidemiology and the seasonality of the causative pathogens of ARI among the paediatric population in Malaysia. Knowledge of seasonal respiratory pathogens epidemiological dynamics will facilitate the identification of a target window for vaccination.

Safety, tolerability and efficacy of LEGA-Kid® mechanical percussion device versus conventional chest physiotherapy in children: a randomised, single-blind controlled study.

INTRODUCTION: Chest physiotherapy (CPT) may benefit children aged below five years who suffer from lower respiratory tract infection (LRTI). However, its effects depend on the technique used. This study aimed to determine whether mechanical CPT using the LEGA-Kid® mechanical percussion device is superior to manual CPT in children with LRTI. METHODS: Children aged five months to five years who were admitted and referred for CPT from January to April 2017 were randomised to either manual CPT or mechanical CPT with LEGA-Kid. Outcomes measured before intervention and two hours after intervention were respiratory rate (RR), oxygen saturation and modified Respiratory Distress Assessment Instrument (mRDAI) score. RESULTS: All 30 enrolled patients showed significant reduction in post-intervention RR and mRDAI scores. There was an 8% reduction in RR for the manual CPT group (p = 0.002) and a 16.5% reduction in the mechanical CPT group (p = 0.0001), with a significantly greater reduction in the latter (p = 0.024). mRDAI scores decreased by 2.96 in the manual group (p = 0.0001) and 3.62 in the mechanical group (p = 0.002), with no significant difference between the groups. There was no significant improvement in oxygen saturation, and no adverse events were observed after CPT. CONCLUSION: Children receiving both manual and mechanical CPT showed improvements in respiratory distress symptoms, with no adverse effects. A combined strategy of nebulised hypertonic saline followed by CPT for LRTI removes airway secretions and results in improvements in moderately severe respiratory distress. The LEGA-Kid mechanical CPT method is superior to manual CPT in reducing the RR.

Genetic variants involved in innate immunity modulate the risk of inflammatory bowel diseases in an understudied Malaysian population.

BACKGROUND AND AIM: Inflammatory bowel diseases (IBD) are chronic gastrointestinal inflammatory conditions comprising two major subtypes: Crohn's disease (CD) and ulcerative colitis (UC). The incidence of IBD is increasing in Asian countries including Malaysia. The aim of this study was to determine whether 32 single nucleotide polymorphisms (SNPs) strongly associated with IBD from genome-wide association studies, performed mainly in Caucasian populations, are associated with IBD in a Malaysian population, correlating these findings with local and systemic inflammation. METHODS: Selected SNPs were investigated in a Malaysian cohort comprising 36 IBD patients and 75 controls using customized matrix-assisted laser desorption ionization time-of-flight genotyping. Local mRNA and/or systemic protein levels of IL-10, IL-12, IL-22, IL-23, and TNF-α were measured in these same subjects. RESULTS: ATG16L2 rs11235667 and LINC00824 rs6651252 was significantly associated with increased CD risk while IL12B rs56167332 was a significant protective factor. Three SNPs (SBNO2 rs2024092, CARD9 rs10781499, and rs17085007 between GPR12-USP12) were significantly associated with increased UC risk while NKX2-3 rs4409764 was a significant protective factor. After adjusting for age, gender, and ethnicity, SBNO2 rs2024092, ATG16L2 rs11235667, CARD9 rs10781499, and LINC00824 rs6651252 remained associated with IBD. Interestingly, the risk alleles of IL10 rs3024505, CARD9 rs1078149, and IL12 rs6556412 were associated with higher levels of IL-10, IL-22, and IL-23 in these same subjects, respectively. CONCLUSIONS: This study identified eight SNPs associated with IBD and/or its subtypes in the Malaysia population, significantly advancing our understanding of the genetic contribution to IBD in this understudied population. Three of these SNPs modulated relevant cytokine levels and thus, may directly contribute to IBD pathogenesis.

Characteristics and outcome of primary sclerosing cholangitis associated with inflammatory bowel disease in Asian children.

BACKGROUND: Current knowledge on the clinical features and natural history of childhood primary sclerosing cholangitis - inflammatory bowel disease in Asia is limited. We described the presenting features and natural history of primary sclerosing cholangitis-inflammatory bowel disease seen in a cohort of Southeast Asian children. METHODS: We conducted a retrospective review of childhood primary sclerosing cholangitis-inflammatory bowel disease from three tertiary centers in Singapore and Malaysia. RESULTS: Of 24 patients (boys, 58%; median age at diagnosis: 6.3 years) with primary sclerosing cholangitis-inflammatory bowel disease (ulcerative colitis, n = 21; Crohn's disease, n = 1; undifferentiated, n = 2), 63% (n = 15) were diagnosed during follow-up for colitis, and 21% (n = 5) presented with acute or chronic hepatitis, 17% (n = 4) presented simultaneously. Disease phenotype of liver involvement showed 79% had sclerosing cholangitis-autoimmune hepatitis overlap, 54% large duct disease, and 46% small duct disease. All patients received immunosuppression therapy. At final review after a median [±S.D.] duration follow-up of 4.7 [±3.8] years, 12.5% patients had normal liver enzymes, 75% persistent disease, and 12.5% liver failure. The proportion of patients with liver cirrhosis increased from 13% at diagnosis to 29%; 21% had portal hypertension, and 17% had liver dysfunction. One patient required liver transplant. Transplant-free survival was 95%. For colitis, 95% had pancolitis, 27% rectal sparing, and 11% backwash ileitis at initial presentation. At final review, 67% patients had quiescent bowel disease with immunosuppression. One patient who had UC with pancolitis which was diagnosed at 3 years old developed colorectal cancer at 22 years of age. All patients survived. CONCLUSIONS: Liver disease in primary sclerosing cholangitis-inflammatory bowel disease in Asian children has variable severity. With immunosuppression, two-thirds of patients have quiescent bowel disease but the majority have persistent cholangitis and progressive liver disease.

Parental concern of feeding difficulty predicts poor growth status in their child.

BACKGROUND: Parents often express concerns about feeding difficulties in their child. We hypothesized that these parental concerns were associated with adverse growth status in early childhood. We aimed to determine the prevalence of such concerns and whether these concerns were associated with adverse growth status in early childhood. METHODS: We performed a cross-sectional study among healthy children aged 12-36 months attending three well-baby clinics in three urban areas in Malaysia and Singapore between December 2016 and February 2017. Parents were interviewed for concerns about their child's feeding and presence of behavioral and organic red flags for feeding difficulties. We defined growth faltering as weight-for-age < 3rd centile and short stature as height-for-age < 3rd centile according to World Health Organization Growth Standards. RESULTS: Of the 303 children studied (boys = 160, 52.8%; mean [± SD] chronological age at interview 21.3 [± 4.0] months), 13% (n = 38/292) had growth faltering and 19.5% (n = 50/256) had short stature. Overall, 36.3% (n = 110) of parents expressed concerns about their child's feeding behavior. Sixty-eight percent (n = 206) of parents reported presence of at least one behavioral and 18.5% (n = 56) had at least one organic red flag for feeding difficulties, respectively. 9.9% (n = 30) had both behavioral and organic red flags for feeding difficulties. Growth faltering was significantly associated with parental concern about feeding (odds ratio [OR] 3.049, p < 0.001), food refusal (OR 4.047, p < 0.001) and presence of at least one organic red flag (OR 2.625, p = 0.012). CONCLUSION: We found that parental concerns about their child's feeding to be common. Presence of parental concern, food refusal in the child and presence of organic red flags for feeding difficulties are associated growth faltering in early childhood.

Vitamin D non-sufficiency is prevalent in children with chronic liver disease in a tropical country.

BACKGROUND: To determine vitamin D status in children with chronic liver disease (CLD) in a tropical country. METHODS: Cross-sectional study in Malaysian children with CLD. Factors affecting serum vitamin D level (definition: deficient < 30 nmol/L; insufficient 30-50 nmol/L; sufficient ≥ 50 nmol/L) was analyzed. RESULTS: Of the 59 children studied (males 32, 54%; median age 6.8 ± 5.3 years), the three most common causes were biliary atresia (n = 25), autoimmune hepatitis (n = 16) and sclerosing cholangitis (n = 6). The overall mean daily vitamin D intake was 715 ± 562 units/day. Thirteen (22%) patients had at least one clinical signs of rickets. Seventeen (29%) had serum bilirubin level ≥ 34 µmol/L. Eight (14%) children were deficient in vitamin D, eight (14%) were vitamin D-insufficient and 43 (73%) were sufficient. As compared with children with serum bilirubin <34 µmol/L, those with serum bilirubin ≥34 µmol/L were more likely to have rickets (24% vs. 65%; P < 0.002) and a lower serum vitamin D level (86.0 ± 54.9 nmol/L vs. 65.4 ± 48.2 nmol/L; P = 0.05) despite being given a significantly higher vitamin D dose (608 ± 571 vs. 970 ± 543 units/day; P = 0.008). The proportion of children with either deficient or insufficient vitamin D status was significantly higher in children with bilirubin level ≥34 µmol/L than in children <34 µmol/L (47% vs. 19%; P = 0.028). CONCLUSION: Vitamin D deficiency and insufficiency is common in children with CLD in a tropical country. Regular monitoring of vitamin D status and screening for metabolic bone disease in all children with CLD is recommended. Higher dose of oral supplement or parenteral route should be considered, especially in those with bilirubin ≥34 µmol/L.

Quality indicators in pediatric colonoscopy in a low-volume center: Implications for training.

AIM: To study implications of measuring quality indicators on training and trainees' performance in pediatric colonoscopy in a low-volume training center. METHODS: We reviewed retrospectively the performance of pediatric colonoscopies in a training center in Malaysia over 5 years (January 2010-December 2015), benchmarked against five quality indicators: appropriateness of indications, bowel preparations, cecum and ileal examination rates, and complications. The European Society of Gastrointestinal Endoscopy guideline for pediatric endoscopy and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition training guidelines were used as benchmarks. RESULTS: Median (± SD) age of 121 children [males = 74 (61.2%)] who had 177 colonoscopies was 7.0 (± 4.6) years. On average, 30 colonoscopies were performed each year (range: 19-58). Except for investigations of abdominal pain (21/177, 17%), indications for colonoscopies were appropriate in the remaining 83%. Bowel preparation was good in 87%. One patient (0.6%) with severe Crohn's disease had bowel perforation. Cecum examination and ileal intubation rate was 95% and 68.1%. Ileal intubation rate was significantly higher in diagnosing or assessing inflammatory bowel disease (IBD) than non-IBD (72.9% vs 50.0% P = 0.016). Performance of four trainees was consistent throughout the study period. Average cecum and ileal examination rate among trainees were 97% and 77%. CONCLUSION: Benchmarking against established guidelines helps units with a low-volume of colonoscopies to identify area for further improvement.

Chronic liver disease is universal in children with biliary atresia living with native liver.

AIM: To examine the medical status of children with biliary atresia (BA) surviving with native livers. METHODS: In this cross-sectional review, data collected included complications of chronic liver disease (CLD) (cholangitis in the preceding 12 mo, portal hypertension, variceal bleeding, fractures, hepatopulmonary syndrome, portopulmonary hypertension) and laboratory indices (white cell and platelet counts, total bilirubin, albumin, international normalized ratio, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase). Ideal medical outcome was defined as absence of clinical evidence of CLD or abnormal laboratory indices. RESULTS: Fifty-two children [females = 32, 62%; median age 7.4 years, n = 35 (67%) older than 5 years] with BA (median age at surgery 60 d, range of 30 to 148 d) survived with native liver. Common complications of CLD noted were portal hypertension (40%, n = 21; 2 younger than 5 years), cholangitis (36%) and bleeding varices (25%, n = 13; 1 younger than 5 years). Fifteen (29%) had no clinical complications of CLD and three (6%) had normal laboratory indices. Ideal medical outcome was only seen in 1 patient (2%). CONCLUSION: Clinical or laboratory evidence of CLD are present in 98% of children with BA living with native livers after hepatoportoenterostomy. Portal hypertension and variceal bleeding may be seen in children younger than 5 years of age, underscoring the importance of medical surveillance for complications of BA starting at a young age.

On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system.

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

Prevalence and antibiotic susceptibility of bacteria from acute and chronic wounds in Malaysian subjects.

INTRODUCTION: Chronic wounds represent a major health burden worldwide. It has been hypothesized that the polymicrobial nature of wounds plays an important role in their healing process. Thus, a review of pathogen frequency and susceptibility patterns in wounds is necessary to provide appropriate guidelines for antimicrobial usage. METHODOLOGY: In this study, microbiota and antimicrobial resistance in both acute and chronic wound patients treated at the University of Malaya Medical Centre, Malaysia, were compared. Wound swabs from 84 patients with acute wounds and 84 patients with chronic wounds were collected. The specimens were cultured using standard microbiological techniques. Isolates were then tested for antibiotic sensitivity with the broth microdilution method. RESULTS: Of 210 pathogenic bacteria isolates, Staphylococcus aureus (49; 23.3%) and Pseudomonas aeruginosa (31; 14.8%) were the most prevalent bacteria found in wounds. Staphylococcus aureus was found significantly more often in patients with chronic wounds (41; 48.8%) than in patients with acute wounds (8; 9.5%), while Staphylococcus epidermidis was found predominantly in acute wounds (15; 17.9%). At the time of study, patients with chronic wounds (58.3%) had received more antibiotic treatments in the past previous 12 months compared with patients with acute wounds (16.7%). In the antibiotic susceptibility test, Staphylococcus spp. revealed highest resistance towards penicillin and ampicillin. Isolates showed no decrease in susceptibility against a number of newly developed antibiotics (linezolid, daptomycin, and tigecycline). CONCLUSIONS: Our finding showed that bacteria diversity and antimicrobial-resistant strains are more frequently found in chronic wounds than in acute wounds.

Separation and enrichment of enantiopure from racemic compounds using magnetic levitation.

Crystallization of a solution with high enantiomeric excess can generate a mixture of crystals of the desired enantiomer and the racemic compound. Using a mixture of S-/RS-ibuprofen crystals as a model, we demonstrated that magnetic levitation (MagLev) is a useful technique for analysis, separation and enantioenrichment of chiral/racemic products.

Crystallization in lactose refining-a review.

In the dairy industry, crystallization is an important separation process used in the refining of lactose from whey solutions. In the refining operation, lactose crystals are separated from the whey solution through nucleation, growth, and/or aggregation. The rate of crystallization is determined by the combined effect of crystallizer design, processing parameters, and impurities on the kinetics of the process. This review summarizes studies on lactose crystallization, including the mechanism, theory of crystallization, and the impact of various factors affecting the crystallization kinetics. In addition, an overview of the industrial crystallization operation highlights the problems faced by the lactose manufacturer. The approaches that are beneficial to the lactose manufacturer for process optimization or improvement are summarized in this review. Over the years, much knowledge has been acquired through extensive research. However, the industrial crystallization process is still far from optimized. Therefore, future effort should focus on transferring the new knowledge and technology to the dairy industry.