B-cell lymphoma research in Malaysia - A narrative review.

Lymphomas are a diverse group of malignant proliferations that arise as discrete tissue masses. The most widely accepted taxonomy for lymphoma is the World Health Organization classification of tumours of haematopoietic and lymphoid tissues, the 5th edition of which was released in June 2022. Most (85% to 90%) lymphoid neoplasms are of B cell origin. Mature B-cell neoplasms are a heterogeneous group of malignancies with similar disease courses and treatment paradigms. This review focuses on the various mature B-cell lymphomas in Malaysia, including Hodgkin lymphoma. A literature search was performed in various bibliographic databases. A total of 64 papers were included in this review. We found 15 papers on Hodgkin lymphoma, 14 on follicular lymphoma, 12 on Burkitt lymphoma, 5 on mucosa-associated lymphoid tissue (MALT) lymphoma, 4 on plasmablastic lymphoma, 3 on mantle cell lymphoma, 1 each on primary mediastinal large B-cell lymphoma, B-lymphoblastic lymphoma, and 3 on other unspecified B-cell lymphomas. The site, age, distribution, prognostic markers, and the various subclassification of B cell lymphomas were studied from these papers. Prognostic genetic markers in B-cell lymphomas include C-MYC, BCL2 and BCL6 as they are the most prevalent mutations in this condition. Anecdotal outcomes range from rapid fatality to unexplained spontaneous remission. This review adds to the existing literature on lymphoma in Malaysia by compiling the evidence that may lead to further research on the diagnosis and treatment of lymphoma in Malaysia and worldwide.

Associations between ambient temperature and pregnancy outcomes from three south Asian sites of the Global Network Maternal Newborn Health Registry: A retrospective cohort study.

OBJECTIVE: Growing evidence suggests that environmental heat stress negatively influences fetal growth and pregnancy outcomes. However, few studies have examined the impact of heat stress on pregnancy outcomes in low-resource settings. We combined data from a large multi-country maternal-child health registry and meteorological data to assess the impacts of heat stress. DESIGN: Retrospective cohort study. SETTING: Three sites based in south Asia as part of the Global Network for Women's and Children's Health research in India (Belagavi and Nagpur) and Pakistan (Thatta). POPULATION OR SAMPLE: Data from women enrolled between 2014 and 2020 in the Global Network's Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnancies, were used. METHODS: A total of 126 273 pregnant women were included in this analysis. Daily maximal air temperatures (Tmax ) were acquired from local meteorological records. Associations between averages of daily maximal temperatures for each trimester and main outcomes were analysed using a modified Poisson regression approach. MAIN OUTCOMES MEASURES: Incidence of stillbirth, preterm birth, low birthweight (<2500 g) or evidence of pregnancy hypertension or pre-eclampsia. RESULTS: In the overall cohort, risk of preterm birth was positively associated with greater temperature in the second trimester (relative risk [RR] 1.05, 95% CI 1.02-1.07, p = 0.0002). Among individual sites, the risk of preterm birth was greatest in Nagpur (RR 1.07, 95% CI 1.03-1.11, p = 0.0005) and associated with second-trimester temperature. The overall risk of low birthweight was associated with ambient temperature in second trimester (RR 1.02, 95% CI 1.01-1.04, p = 0.01). The risk for LBW was associated with first-trimester heat in Thatta and with second-trimester heat in Nagpur. Finally, the overall risk of gestational hypertensive disease was associated with greater temperature in the third trimester among all sites (RR 1.07, 95% CI 1.02-1.12, p = 0.005) and was particularly significant for Nagpur (RR 1.13, 95% CI 1.05-1.23, p = 0.002). These findings highlight the increased risk of detrimental obstetric and neonatal outcomes with greater temperature. CONCLUSION: In a multi-country, community-based study, greater risk of adverse outcomes was observed with increasing temperature. The study highlights the need for deeper understanding of covarying factors and intervention strategies, especially in regions where high temperatures are common.

Neurodevelopment, vision and auditory outcomes at age 2 years in offspring of participants in the 'Women First' maternal preconception nutrition randomised controlled trial.

BACKGROUND: Maternal nutrition in preconception and early pregnancy influences fetal growth. Evidence for effects of prenatal maternal nutrition on early child development (ECD) in low-income and middle-income countries is limited. OBJECTIVES: To examine impact of maternal nutrition supplementation initiated prior to or during pregnancy on ECD, and to examine potential association of postnatal growth with ECD domains. DESIGN: Secondary analysis regarding the offspring of participants of a maternal multicountry, individually randomised trial. SETTING: Rural Democratic Republic of the Congo, Guatemala, India and Pakistan. PARTICIPANTS: 667 offspring of Women First trial participants, aged 24 months. INTERVENTION: Maternal lipid-based nutrient supplement initiated preconceptionally (arm 1, n=217), 12 weeks gestation (arm 2, n=230) or not (arm 3, n=220); intervention stopped at delivery. MAIN OUTCOME MEASURES: The INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) cognitive, language, gross motor, fine motor, positive and negative behaviour scores; visual acuity and contrast sensitivity scores and auditory evoked response potentials (ERP). Anthropometric z-scores, family care indicators (FCI) and sociodemographic variables were examined as covariates. RESULTS: No significant differences were detected among the intervention arms for any INTER-NDA scores across domains, vision scores or ERP potentials. After adjusting for covariates, length-for-age z-score at 24 months (LAZ24), socio-economic status, maternal education and FCI significantly predicted vision and INTER-NDA scores (R2=0.11-0.38, p<0.01). CONCLUSIONS: Prenatal maternal nutrition supplementation was not associated with any neurodevelopmental outcomes at age 2 years. Maternal education, family environment and LAZ24 predicted ECD. Interventions addressing multiple components of the nurturing care model may offer greatest impact on children's developmental potential. TRIAL REGISTRATION NUMBER: NCT01883193.

Diffuse large B-cell lymphoma research in Malaysia: A review.

Lymphomas are prevalent worldwide and a common malignancy reported in Malaysia. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of B-cell lymphomas accounting for 54% to 65% of all B-cell lymphomas and 39% to 57% of all malignant lymphomas. However, DLBCL comprises a heterogeneous group of diseases with different clinical presentations, biology and response to treatment. Recent advances in understanding the genetic landscape and molecular features of DLBCL have identified high-risk subsets with poor outcomes to chemo-immunotherapy that are actively being studied in various clinical trials. C-MYC is a proto-oncogene located in chromosome 8q24. 10 to 15 % of patients with newly diagnosed DLBCL have an underlying rearrangement of the MYC oncogene, resulting in dysregulated cellular survival and proliferation. Approximately half of these cases also carry a rearrangement of the anti-apoptotic proto-oncogene BCL2 and/or its transcription repressor BCL6. Over 20 case reports of DLBCL cases with notable features in Malaysia have found in the literature, in addition to a few extensive case series and included in this review. R-CHOP remains the mainstay of therapy and can help achieve control of long-term disease in nearly 90% of patients presenting with limited-stage and in up to 60% of those presenting with advanced stages. This review captures all 52 studies that reported DLBCL in Malaysia and summarises the essential aspects, including prevalence, subtype, prognostic markers clinical features in presentation and limited outcomes of cases when available.

Maternal nutritional status modifies heat-associated growth restriction in women with chronic malnutrition.

Rapid changes in the global climate are deepening existing health disparities from resource scarcity and malnutrition. Rising ambient temperatures represent an imminent risk to pregnant women and infants. Both maternal malnutrition and heat stress during pregnancy contribute to poor fetal growth, the leading cause of diminished child development in low-resource settings. However, studies explicitly examining interactions between these two important environmental factors are lacking. We leveraged maternal and neonatal anthropometry data from a randomized controlled trial focused on improving preconception maternal nutrition (Women First Preconception Nutrition trial) conducted in Thatta, Pakistan, where both nutritional deficits and heat stress are prevalent. Multiple linear regression of ambient temperature and neonatal anthropometry at birth (n = 459) showed a negative association between daily maximal temperatures in the first trimester and Z-scores of birth length and head circumference. Placental mRNA-sequencing and protein analysis showed transcriptomic changes in protein translation, ribosomal proteins, and mTORC1 signaling components in term placenta exposed to excessive heat in the first trimester. Targeted metabolomic analysis indicated ambient temperature associated alterations in maternal circulation with decreases in choline concentrations. Notably, negative impacts of heat on birth length were in part mitigated in women randomized to comprehensive maternal nutritional supplementation before pregnancy suggesting potential interactions between heat stress and nutritional status of the mother. Collectively, the findings bridge critical gaps in our current understanding of how maternal nutrition may provide resilience against adverse effects of heat stress in pregnancy.

Full blood count values in adolescents and its comparison by gender and ethnicity in Seremban district, Malaysia.

BACKGROUND: Adolescence is when an individual undergoes development and growth. Many studies suggest variations in the number and size of blood cells during this period in various individuals. The full blood count (FBC) is often the starting point of medical investigations, which help diagnose a wide range of illnesses, infections, and diseases. This study aimed to report the mean FBC values and compare them by gender and ethnicity, using blood results from the thalassemia screening programme in Seremban District, Malaysia. MATERIALS AND METHODS: This cross-sectional study used secondary data from the thalassemia screening programme on Form 4 students aged 15-16 years from January 2018 to October 2018 by the Seremban District Health Office, Malaysia. These students participated in the thalassemia screening programme in which their blood samples were taken for FBC analysis. The data were extracted for this study. RESULTS: There were statistically significant gender-based differences for total white blood cell (WBC) count, neutrophils, lymphocytes, mixed WBC, and platelets. It was also observed that ethnic-specific differences were statistically significant for RBC count, platelets, platelet distribution width and mean platelet volume. CONCLUSION: This study was able to report the mean FBC values among Malaysian adolescents with respect to their gender and ethnicity, of which there is a lack of published data.

Improved first trimester maternal iodine status with preconception supplementation: The Women First Trial.

Maternal iodine (I) status is critical in embryonic and foetal development. We examined the effect of preconception iodine supplementation on maternal iodine status and on birth outcomes. Non-pregnant women in Guatemala, India and Pakistan (n ~ 100 per arm per site) were randomized ≥ 3 months prior to conception to one of three intervention arms: a multimicronutrient-fortified lipid-based nutrient supplement containing 250-µg I per day started immediately after randomization (Arm 1), the same supplement started at ~12 weeks gestation (Arm 2) and no intervention supplement (Arm 3). Urinary I (µg/L) to creatinine (mg/dl) ratios (I/Cr) were determined at 12 weeks for Arm 1 versus Arm 2 (before supplement started) and 34 weeks for all arms. Generalized linear models were used to assess the relationship of I/Cr with arm and with newborn anthropometry. At 12 weeks gestation, adjusted mean I/Cr (µg/g) for all sites combined was significantly higher for Arm 1 versus Arm 2: (203 [95% CI: 189, 217] vs. 163 [95% CI: 152, 175], p < 0.0001). Overall adjusted prevalence of I/Cr < 150 µg/g was also lower in Arm 1 versus Arm 2: 32% (95% CI: 26%, 38%) versus 43% (95% CI: 37%, 49%) (p = 0.0052). At 34 weeks, adjusted mean I/Cr for Arm 1 (235, 95% CI: 220, 252) and Arm 2 (254, 95% CI: 238, 272) did not differ significantly but were significantly higher than Arm 3 (200, 95% CI: 184, 218) (p < 0.0001). Nominally significant positive associations were observed between I/Cr at 12 weeks and birth length and head circumference z-scores (p = 0.028 and p = 0.005, respectively). These findings support the importance of first trimester iodine status and suggest need for preconception supplementation beyond salt iodization alone.

Preconceptional Lipid-Based Nutrient Supplementation in 2 Low-Resource Countries Results in Distinctly Different IGF-1/mTOR Placental Responses.

BACKGROUND: Preconceptional maternal small-quantity lipid-based nutrient supplementation (SQLNS) improved intrauterine linear growth in low-resource countries as demonstrated by the Women First Preconception Maternal Nutrition Trial (WF). Fetal growth is dependent on nutrient availability and regulated by insulin-like growth factor 1 (IGF-1) through changes in placental transfer capacity, mediated by the mechanistic target of rapamycin (mTOR) pathway. OBJECTIVES: Our objective was to evaluate the role of placental mTOR and IGF-1 signaling on fetal growth in women from 2 low-resource countries with high rates of stunting after they received preconceptional SQLNS. METHODS: We studied 48 women from preconception through delivery who were from Guatemala and Pakistan and received SQLNS or not, as part of the WF study. Placental samples were obtained at delivery (control, n = 24; SQLNS, n = 24). Placental protein or mRNA expression of eukaryotic translation initiation factor binding protein-1 (4E-BP1), ribosomal protein S6 (rpS6), AMP-activated protein kinase α (AMPKA), IGF-1, insulin-like growth factor receptor (IGF-1R), and pregnancy associated plasma protein (PAPP)-A, and DNA methylation of the IGF1 promoter were determined. Maternal serum IGF-1, insulin-like growth factor binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, PAPP-A, PAPP-A2, and zinc were measured. RESULTS: Mean ± SEM maternal prepregnancy BMI differed between participants in Guatemala (26.5 ± 1.3) and Pakistan (19.8 ± 0.7) (P < 0.001). In Pakistani participants, SQLNS increased the placental rpS6(T37/46):rpS6 ratio (1.5-fold) and decreased the AMPKA(T172):AMPKA ratio. Placental IGF1 mRNA expression was positively correlated with birth length and birth weight z-scores. Placental PAPP-A (30-fold) and maternal serum zinc (1.2-fold) increased with SQLNS. In Guatemalan participants SQLNS did not influence placental mTOR signaling. Placental IGF-1R protein expression was positively associated with birth length and birth weight z-scores. SQLNS increased placental PAPP-A (40-fold) and maternal serum IGFBP-4 (1.6-fold). CONCLUSIONS: In Pakistani pregnant women with poor nutritional status, preconceptional SQLNS activated placental mTOR and IGF-1 signaling and was associated with improved fetal growth. In contrast, in Guatemalan women SQLNS did not activate placental nutrient-sensing pathways. In populations experiencing childhood stunting, preconceptional SQLNS improves placental function and fetal growth only in the context of poor maternal nutrition. This trial was registered at clinicaltrials.gov as NCT01883193.

A link between long non-coding RNA (lncRNA) and thalassaemia: A review.

The long non-coding RNAs (lncRNAs) are the most prevalent and functionally diverse member of the non-coding RNA (ncRNA). The lncRNA has previously been considered to be a form of transcriptional "noise" but recent studies have found that the lncRNA to be associated with various disease conditions. It has also been found to play important roles in various physiological processes such as haemopoiesis, where lncRNA is reported to act as a fine-tuner of this very important process. To date, the effects of dysregulated lncRNA in thalassaemia has not been fully explored. This review article focuses on the possible roles of dysregulated lncRNAs in the pathogenesis of thalassaemia.

Longitudinal Changes of One-Carbon Metabolites and Amino Acid Concentrations during Pregnancy in the Women First Maternal Nutrition Trial.

BACKGROUND: Maternal dietary restriction and supplementation of one-carbon (1C) metabolites can impact offspring growth and DNA methylation. However, longitudinal research of 1C metabolite and amino acid (AA) concentrations over the reproductive cycle of human pregnancy is limited. OBJECTIVE: To investigate longitudinal 1C metabolite and AA concentrations prior to and during pregnancy and the effects of a small-quantity lipid-based nutrition supplement (LNS) containing >20 micronutrients and prepregnancy BMI (ppBMI). METHODS: This study was an ancillary study of the Women First Trial (NCT01883193, clinicaltrials.gov) focused on a subset of Guatemalan women (n = 134), 49% of whom entered pregnancy with a BMI ≥25 kg/m2. Ninety-five women received LNS during pregnancy (+LNS group), while the remainder did not (-LNS group). A subset of women from the Pakistan study site (n = 179) were used as a replication cohort, 124 of whom received LNS. Maternal blood was longitudinally collected on dried blood spot (DBS) cards at preconception, and at 12 and 34 wk gestation. A targeted metabolomics assay was performed on DBS samples at each time point using LC-MS/MS. Longitudinal analyses were performed using linear mixed modeling to investigate the influence of time, LNS, and ppBMI. RESULTS: Concentrations of 23 of 27 metabolites, including betaine, choline, and serine, changed from preconception across gestation after application of a Bonferroni multiple testing correction (P < 0.00185). Sixteen of those metabolites showed similar changes in the replication cohort. Asymmetric and symmetric dimethylarginine were decreased by LNS in the participants from Guatemala. Only tyrosine was statistically associated with ppBMI at both study sites. CONCLUSIONS: Time influenced most 1C metabolite and AA concentrations with a high degree of similarity between the 2 diverse study populations. These patterns were not significantly altered by LNS consumption or ppBMI. Future investigations will focus on 1C metabolite changes associated with infant outcomes, including DNA methylation. This trial was registered at clinicaltrials.gov as NCT01883193.

Maternal Characteristics Affect Fetal Growth Response in the Women First Preconception Nutrition Trial.

The objective of this secondary analysis was to identify maternal characteristics that modified the effect of maternal supplements on newborn size. Participants included 1465 maternal-newborn dyads in Guatemala, India, and Pakistan. Supplementation commenced before conception (Arm 1) or late 1st trimester (Arm 2); Arm 3 received usual care. Characteristics included body mass index (BMI), stature, anemia, age, education, socio-economic status (SES), parity, and newborn sex. Newborn outcomes were z-scores for length (LAZ), weight (WAZ), and weight to length ratio-for-age (WLRAZ). Mixed-effect regression models included treatment arm, effect modifier, and arm * effect modifier interaction as predictors, controlling for site, characteristics, and sex. Parity (para-0 vs. para ≥1), anemia (anemia/no anemia), and sex were significant effect modifiers. Effect size (95% CI) for Arm 1 vs. 3 was larger for para-0 vs. ≥1 for all outcomes (LAZ 0.56 (0.28, 0.84, p < 0.001); WAZ 0.45 (0.20, 0.07, p < 0.001); WLRAZ 0.52 (0.17, 0.88, p < 0.01) but only length for Arm 2 vs. 3. Corresponding effects for para ≥1 were >0.02. Arm 3 z-scores were all very low for para-0, but not para ≥1. Para-0 and anemia effect sizes for Arm 1 were > Arm 2 for WAZ and WLRAZ, but not LAZ. Arm 1 and 2 had higher WAZ for newborn boys vs. girls. Maternal nulliparity and anemia were associated with impaired fetal growth that was substantially improved by nutrition intervention, especially when commenced prior to conception.

A multicountry randomized controlled trial of comprehensive maternal nutrition supplementation initiated before conception: the Women First trial.

Background: Reported benefits of maternal nutrition supplements commenced during pregnancy in low-resource populations have typically been quite limited. Objectives: This study tested the effects on newborn size, especially length, of commencing nutrition supplements for women in low-resource populations ≥3 mo before conception (Arm 1), compared with the same supplement commenced late in the first trimester of pregnancy (Arm 2) or not at all (control Arm 3). Methods: Women First was a 3-arm individualized randomized controlled trial (RCT). The intervention was a lipid-based micronutrient supplement; a protein-energy supplement was also provided if maternal body mass index (kg/m2) was <20 or gestational weight gain was less than recommendations. Study sites were in rural locations of the Democratic Republic of the Congo (DRC), Guatemala, India, and Pakistan. The primary outcome was length-for-age z score (LAZ), with all anthropometry obtained <48 h post delivery. Because gestational ages were unavailable in DRC, outcomes were determined for all 4 sites from WHO newborn standards (non-gestational-age-adjusted, NGAA) as well as INTERGROWTH-21st fetal standards (3 sites, gestational age-adjusted, GAA). Results: A total of 7387 nonpregnant women were randomly assigned, yielding 2451 births with NGAA primary outcomes and 1465 with GAA outcomes. Mean LAZ and other outcomes did not differ between Arm 1 and Arm 2 using either NGAA or GAA. Mean LAZ (NGAA) for Arm 1 was greater than for Arm 3 (effect size: +0.19; 95% CI: 0.08, 0.30, P = 0.0008). For GAA outcomes, rates of stunting and small-for-gestational-age were lower in Arm 1 than in Arm 3 (RR: 0.69; 95% CI: 0.49, 0.98, P = 0.0361 and RR: 0.78; 95% CI: 0.70, 0.88, P < 0.001, respectively). Rates of preterm birth did not differ among arms. Conclusions: In low-resource populations, benefits on fetal growth-related birth outcomes were derived from nutrition supplements commenced before conception or late in the first trimester. This trial was registered at clinicaltrials.gov as NCT01883193.

Repeat 24-hour recalls and locally developed food composition databases: a feasible method to estimate dietary adequacy in a multi-site preconception maternal nutrition RCT.

Background: Our aim was to utilize a feasible quantitative methodology to estimate the dietary adequacy of >900 first-trimester pregnant women in poor rural areas of the Democratic Republic of the Congo, Guatemala, India and Pakistan. This paper outlines the dietary methods used. Methods: Local nutritionists were trained at the sites by the lead study nutritionist and received ongoing mentoring throughout the study. Training topics focused on the standardized conduct of repeat multiple-pass 24-hr dietary recalls, including interview techniques, estimation of portion sizes, and construction of a unique site-specific food composition database (FCDB). Each FCDB was based on 13 food groups and included values for moisture, energy, 20 nutrients (i.e. macro- and micronutrients), and phytate (an anti-nutrient). Nutrient values for individual foods or beverages were taken from recently developed FAO-supported regional food composition tables or the USDA national nutrient database. Appropriate adjustments for differences in moisture and application of nutrient retention and yield factors after cooking were applied, as needed. Generic recipes for mixed dishes consumed by the study population were compiled at each site, followed by calculation of a median recipe per 100 g. Each recipe's nutrient values were included in the FCDB. Final site FCDB checks were planned according to FAO/INFOODS guidelines. Discussion: This dietary strategy provides the opportunity to assess estimated mean group usual energy and nutrient intakes and estimated prevalence of the population 'at risk' of inadequate intakes in first-trimester pregnant women living in four low- and middle-income countries. While challenges and limitations exist, this methodology demonstrates the practical application of a quantitative dietary strategy for a large international multi-site nutrition trial, providing within- and between-site comparisons. Moreover, it provides an excellent opportunity for local capacity building and each site FCDB can be easily modified for additional research activities conducted in other populations living in the same area.

Gibberellins Producing Endophytic Fungus Porostereum spadiceum AGH786 Rescues Growth of Salt Affected Soybean.

In the pursuit of sustainable agriculture through environment and human health friendly practices, we evaluated the potential of a novel gibberellins (GAs) producing basidiomycetous endophytic fungus Porostereum spadiceum AGH786, for alleviating salt stress and promoting health benefits of soybean. Soybean seedlings exposed to different levels of NaCl stress (70 and 140 mM) under greenhouse conditions, were inoculated with the AGH786 strain. Levels of phytohormones including GAs, JA and ABA, and isoflavones were compared in control and the inoculated seedlings to understand the mechanism through which the stress is alleviated. Gibberellins producing endophytic fungi have been vital for promoting plant growth under normal and stress conditions. We report P. spadiceum AGH786 as the ever first GAs producing basidiomycetous fungus capable of producing six types of GAs. In comparison to the so for most efficient GAs producing Gibberella fujikuroi, AGH786 produced significantly higher amount of the bioactive GA3. Salt-stressed phenotype of soybean seedlings was characterized by low content of GAs and high amount of ABA and JA with reduced shoot length, biomass, leaf area, chlorophyll contents, and rate of photosynthesis. Mitigation of salt stress by AGH786 was always accompanied by high GAs, and low ABA and JA, suggesting that this endophytic fungus reduces the effect of salinity by modulating endogenous phytohormones of the seedlings. Additionally, this strain also enhanced the endogenous level of two isoflavones including daidzen and genistein in soybean seedlings under normal as well as salt stress conditions as compared to their respective controls. P. spadiceum AGH786 boosted the NaCl stress tolerance and growth in soybean, by modulating seedlings endogenous phytohormones and isoflavones suggesting a valuable contribution of this potent fungal biofertilizer in sustainable agriculture in salt affected soils.