BCR-ABL kinase domain mutations in tyrosine kinase inhibitors-naïve and -exposed Southeast Asian chronic myeloid leukemia patients

BCR-ABL kinase domain (KD) mutation is the main mechanism associated with resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML) patients. This study targeted a large cohort of CML (n = 171) comprising 80 naïve CML cases without prior TKI exposure as well as 91 cases undergoing 1st generation (imatinib) and/or 2nd generation (nilotinib/dasatinib) TKI therapy. KD mutations were analyzed by denaturing high performance liquid chromatography followed by direct sequencing. Twenty-one types of mutations were found in 37 patients including 13 known mutations and 8 previously unidentified mutations. Thirty cases had a single mutation while 7 cases had multiple mutations. Twenty-three percent of patients receiving first-line imatinib, 69% of imatinib-resistant patients receiving 2nd generation TKI, and 75% of advanced phase patients treated with front-line 2nd generation TKI had KD mutations. Interestingly, 9% of TKI-naïve CML cases were also discovered to carry the KD mutations including 5 novel variants. Patients who received hydroxyurea had a 2-fold increase in KD mutations as compared to newly diagnosed patients but they still had a lower mutation frequency than TKI-exposed cases. Mutations in the naïve cases were mainly localized in the C-helix domain and SH3 contact site whereas in exposed cases predominantly in the drug contact site, P-loop, and catalytic domain. T315I resistant mutation was identified only in TKI-exposed cases. In conclusion, several known and novel BCR-ABL KD mutations were discovered in the TKI-naïve and -exposed Southeast Asian CML patients, supporting the concept that naturally occurring KD mutations were present in leukemic cells prior to drug exposure. T315I resistant mutation was completely undetectable in this naïve Southeast Asian cohort; its incidence, however, increases with drug exposure.     

Plasma fractionation in Asia–Pacific: challenges and perspectives

Patients in every country should have access to quality blood products. National health authorities play a critical role in ensuring that patients’ needs are met with safe and cost-effective products. Fractionated plasma products, as other blood products, are essential therapeutics used in the prevention, management, and treatment of life-threatening conditions resulting from trauma, metabolic congenital deficiencies, immunological disorders or infections. A few high development index (HDI) countries in the region have sufficient access to a broad portfolio of plasma products (coagulation factors, immunoglobulin, albumin) through domestic (e.g. Australia, Japan, Korea) or contract (e.g. Singapore, New Zealand) plasma fractionation programmes. China is gradually establishing a modern plasma fractionation industry. Other countries face plasma product shortages leading to inappropriate clinical use of plasma for transfusion and of non-virally inactivated cryoprecipitate, and ultimately to inappropriate treatment of patients. The volume of plasma fractionated in the region is too low to meet the needs. The volume (about 6 million l) represents 20% of the total volume fractionated worldwide for 60% of the world population. There is a rationale to encourage plasma contract fractionation programmes or operation of domestic facilities (when justified) to use local resources. However, many challenges are being faced as national plasma fractionation programmes require a mature blood collection infrastructure. Unfortunately, several LDI countries lack a mature national blood programme and a legislative framework on national policies and legislation on blood donations. They lack a safe blood donor base and a well-organized, nationally coordinated blood transfusion services; their blood collection system is scattered among different entities, resulting in non-uniform screening and testing procedures. Financial and human resources are lacking. Still, a few countries (e.g. Hong Kong, Malaysia, Singapore, Taiwan) have strengthened the national blood programmes, national blood policies have been implemented and the management of the blood transfusion service improved, allowing to implement contract plasma fractionation programme with established fractionators. Others are considering initiating (Indonesia and Malaysia) or enhancing (Thailand) domestic fractionation. Plasma fractionation programmes require good awareness and understanding by national regulatory authorities on quality criteria of plasma products. Local plasma product market and potential trends should be evaluated to determine plasma needs and the capacity to implement collection of plasma by apheresis from volunteer dedicated donors to supplement recovered plasma as a source material for fractionation. Appropriate choice of a contract fractionation partner should be made and contract terms discussed carefully. The fractionation technology and product portfolio should be evaluated to make sure that intended products can meet domestic needs (e.g. range, potency and formulation). A reimbursement policy (in particular for IVIG) for a range of proven indications should be established, as approved in the marketing authorization dossier. Confidence of clinicians and patients in the quality and safety of domestic vs. imported products should be built. With the economical development of the region and the ageing population trends, the needs for plasma products are expected to increase, justifying efforts to fractionate domestic plasma (e.g. initially through contract fractionation) and increase guarantee of supply in quality plasma products.     

Loss-of-function HSD17B13 variants,non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

Background/Aims17β-hydroxysteroid dehydrogenase 13 (HSD17B13) variants were recently reported to have significantly lower odds of non-alcoholic fatty liver disease (NAFLD). This is a two-part study that aimed to evaluate the association of HSD17B13 variants with NAFLD and its histological severity, and to identify the association of the variants with clinical outcomes in a cohort of biopsy-proven NAFLD patients.MethodsConsecutive biopsy-proven NAFLD patients and controls without fatty liver were recruited for this study between 2009 and 2014. Genotyping for HSD17B13 variants was performed using rhAmp assays. A total of 165 patients with NAFLD were monitored up until August 2019. Clinical outcomes were recorded.ResultsHSD17B13 rs72613567 TA allele and rs6834314 G allele were associated with lower odds of non-alcoholic steatohepatitis (NASH) in the overall cohort and among ethnic Chinese, but not among ethnic Malays or Indians (P<0.05). During a mean follow-up of 89 months, 32 patients (19.4%) experienced at least one clinical outcome (cardiovascular events, n=22; liver-related complications, n=6; extra-hepatic malignancy, n=5; and mortality, n=6). The rs72613567 homozygous TA allele and the rs6834314 homozygous G allele were independently associated with a lower incidence of liver-related complications (hazard ratio [HR], 0.004; 95% confidence interval [CI], 0.00–0.64; P=0.033 and HR, 0.01; 95% CI, 0.00–0.97; P=0.048, respectively) and were associated with lower grade of hepatocyte ballooning among the ethnic Chinese.ConclusionHSD17B13 rs72613567 and rs6834314 variants were inversely associated with NAFLD and NASH, and were associated with lower incidence of adverse liver outcomes in a cohort of multi-ethnic Asian patients with NAFLD.     

The role of antimalarial treatment in the elimination of malaria

With declining transmission of malaria in several regions of the world and renewed interest in the elimination of malaria, strategies for malaria control using antimalarial drugs are being revisited. Drug-based strategies to reduce transmission of malaria need to target the asymptomatic carriers of infection. Drugs that are effective against gametocytes are few in number, but it may be possible to reduce gametocyte production by killing the asexual stages, for which more drugs are available. Drugs for use in large-scale programmes must be safe and tolerable. Strategies include improving access to treatment for malaria with an efficacious drug, intermittent-treatment programmes, and mass drug administration, with and without screening for malaria. Recent proposals have targeted high-risk groups for interventions. None of the strategies has been rigorously tested with appropriate control groups for comparison. Because of the lack of field evidence, modelling has been used. Models have shown, first, that for long-lasting effects, drug administration programmes should be linked with vector control, and second, that if elimination is the aim, programmes are likely to be more successful when applied to smaller populations of a few thousand or less. In order to sustain the gains following the scaling up of vector control and use of artemisinin combination therapies (ACTs), strategies that use antimalarials effectively need to be devised and evidence generated for the most cost-efficient way forward.     

Febrile illness in Asia: gaps in epidemiology,diagnosis and management for informing health policy

BackgroundIncreasing evidence is becoming available on the aetiology and management of fevers in Asia; the importance of these fevers has increased with the decline in the incidence of malaria.AimsTo conduct a narrative review of the epidemiology and management of fevers in South and South-East Asia and to highlight gaps in our knowledge that impair evidence-based health policy decisions.SourcesA narrative review of papers published since 2012 on developments in fever epidemiology, diagnosis and treatment in South and South-East Asia. The papers that the authors felt were pivotal, from their personal perspectives, are discussed.ContentWe identified 100 studies. Among the 30 studies (30%)—including both children and adults—that investigated three or more pathogens, the most frequently reported fever aetiology was dengue (reported by 15, 50%), followed by leptospirosis (eight, 27%), scrub typhus (seven, 23%) and Salmonella serovar Typhi (six, 20%). Among four studies investigating three or more pathogens in children, dengue and Staphylococcus aureus were the most frequent, followed by non-typhoidal Salmonella spp, Streptococcus pneumoniae, Salmonella serovar Typhi, and Orientia tsutsugamushi. Increased awareness is needed that rickettsial pathogens are common but do not respond to cephalosporins, and that alternative therapies, such as tetracyclines, are required.ImplicationsMany key gaps remain, and consensus guidelines for study design are needed to aid comparative understanding of the epidemiology of fevers. More investment in developing accurate and affordable diagnostic tests for rural Asia and independent evaluation of those already on the market are needed. Treatment algorithms, including simple biomarker assays, appropriate for empirical therapy of fevers in different areas of rural Asia should be a major aim of fever research. Enhanced antimicrobial resistance (AMR) surveillance and openly accessible databases of geography-specific AMR data would inform policy on empirical and specific therapy. More investment in innovative strategies facilitating infectious disease surveillance in remote rural communities would be an important component of poverty reduction and improving public health.     

Positive selection of protective variants for type 2 diabetes from the Neolithic onward: a case study in Central Asia

The high prevalence of type 2 diabetes and its uneven distribution among human populations is both a major public health concern and a puzzle in evolutionary biology. Why is this deleterious disease so common, while the associated genetic variants should be removed by natural selection? The ‘thrifty genotype'' hypothesis proposed that the causal genetic variants were advantageous and selected for during the majority of human evolution. It remains, however, unclear whether genetic data support this scenario. In this study, we characterized patterns of selection at 10 variants associated with type 2 diabetes, contrasting one herder and one farmer population from Central Asia. We aimed at identifying which alleles (risk or protective) are under selection, dating the timing of selective events, and investigating the effect of lifestyle on selective patterns. We did not find any evidence of selection on risk variants, as predicted by the thrifty genotype hypothesis. Instead, we identified clear signatures of selection on protective variants, in both populations, dating from the beginning of the Neolithic, which suggests that this major transition was accompanied by a selective advantage for non-thrifty variants. Combining our results with worldwide data further suggests that East Asia was particularly prone to such recent selection of protective haplotypes. As much effort has been devoted so far to searching for thrifty variants, we argue that more attention should be paid to the evolution of non-thrifty variants.     

Carriage of Streptococcus pneumoniae in children under five years of age prior to pneumococcal vaccine introduction in Southeast Asia: A systematic review and meta-analysis (2001–2019)

A number of pneumococcal carriage studies in children have been conducted in recent years. However, summary data of carriage prevalence and serotype distribution from South East Asia Region (SEAR) are limited. This may lead to the misconception that Streptococcus pneumoniae vaccine-types are uncommon in the region. Systematic reviews of pneumococcal carriage and the distribution of serotypes are critically important for evidence-based decision-making. We aimed to summarize published data on the serotype prevalence of S. pneumoniae carried in the nasopharynx of children under 5 years of age in SEAR. We performed a systematic review and meta-analysis for relevant studies on S. pneumoniae carriage conducted prior to PCV program implementation from online journal databases published between January 2001 to December 2019. The pooled prevalence of S. pneumoniae in healthy children under 5 years of age in SEAR was 36.0% (95% CI 34.2%–37.8%), and ranged from 68.0% (95% CI: 61.9%–74.0%) in Cambodia to 7.6% (95% CI: 5.7%–9.6%) in Malaysia. Serotypes 6A/B, 23F and 19F were the most common serotypes in children <5 years, accounting for 12.9% (95% CI: 9.4%–16.3%), 9.3% (95% CI: 5.9%–12.8%) and 10.1% (95% CI: 6.6%–13.5%) of isolates, respectively. Vaccine policy makers should take these results into account when making decisions on pneumococcal conjugate vaccine programs implementation. Given the paucity of data, collection of more extensive and updated information of S. pneumoniae serotype epidemiology in children under five years in SEAR is also very important for future studies.     

Prevalence and genotype distribution of cervical human papillomavirus infection in Macao

Population‐specific epidemiological data on human papillomavirus (HPV) infection are essential for formulating strategies to prevent cervical cancer. The age‐specific prevalence of HPV infection was determined among 1,600 women enrolled for cervical screening in Macao. A U‐shaped age‐specific prevalence curve with a first peak (prevalence rate, 10%) at 20–25 years and a second peak (13%) at 51–55 years was observed. Co‐infections with multiple types were detected in 32.5% of HPV‐positive subjects and without significant variation among different age groups (P = 0.318). The majority (84.6%) of the positive samples harbored high‐ or probable high‐risk HPV types, and these types also exhibited a similar U‐shaped age‐specific prevalence curve. In contrast, low and unknown‐risk HPV types remained at a low prevalence (1.5–2.5%) throughout the age groups between 20 and 50 years, and with a small peak (4.5%) at 51–55 years. HPV 52 was the most common type found in 26.8% of positive samples, followed by HPV 16 (15.5%), HPV 68 (11.4%), HPV 18 and HPV 58 (8.9% each), HPV 54 (8.1%), HPV 53 (7.3%), HPV 39 (6.5%), HPV 33 and HPV 66 (5.7% each). In conclusion, because of the early peak of infection, vaccination and educational campaigns in Macao should start early and target at teenagers. The presence of a second peak containing mainly high‐risk HPV types in older women indicates the need to evaluate the cover of the cervical screening programme for older women. Further study to determine the contribution of HPV 52 in high‐grade cervical neoplasia and invasive cancers in Macao is warranted. J. Med. Virol. 82:1724–1729, 2010. © 2010 Wiley‐Liss, Inc.     

Trends in general and abdominal obesity among Korean adults: findings from 1998, 2001, 2005, and 2007 Korea National Health and Nutrition Examination Surveys

We examined trends in obesity among Korean adults, using body mass index (BMI) and waist circumference (WC) as reported in national surveys. Data (10,043 men and 12,758 non-pregnant women) were derived from four waves of the Korea National Health and Nutrition Examination Survey conducted in 1998, 2001, 2005, and 2007. Between 1998 and 2007, the distribution of BMI and WC showed shifts toward the right among men. Mean values of BMI and WC and the corresponding overweight (includes obesity) and obesity prevalences showed increasing trends in men but not in women. Women aged 60+ showed significant increases in obesity measures, including mean BMI and WC, and the associated prevalences. Among women aged 20-39, the prevalence of underweight increased significantly between 1998 and 2007, and BMI showed a decreasing tendency. These time trends in young women were the reverse of the trends in young men. In conclusion, policy efforts to abate overweight and obesity trends need to be exercised among men and older women. In addition, more national studies regarding potential increases in underweight among young women are warranted.