Systemic therapy and radiotherapy related complications and subsequent hospitalisation rates: a systematic review.

BACKGROUND: Hospitalisation  resulting from complications of systemic therapy and radiotherapy places a substantial burden on the patient, society, and healthcare system. To formulate preventive strategies and enhance patient care, it is crucial to understand the connection between complications and the need for subsequent hospitalisation. This review aimed to assess the existing literature on complications related to systemic and radiotherapy treatments for cancer, and their impact on hospitalisation rates. METHODS: Data was obtained via electronic searches of the PubMed, Scopus, Embase and Google Scholar online databases to select relevant peer-reviewed papers for studies published between January 1, 2000, and August 30, 2023. We searched for a combination of keywords in electronic databases and used a standard form to extract data from each article. The initial specific interest was to categorise the articles based on the aspects explored, especially complications due to systemic and radiotherapy and their impact on hospitalisation. The second interest was to examine the methodological quality of studies to accommodate the inherent heterogeneity. The study protocol was registered with PROSPERO (CRD42023462532). FINDINGS: Of 3289 potential articles 25 were selected for inclusion with ~ 34 million patients. Among the selected articles 21 were cohort studies, three were randomised control trials (RCTs) and one study was cross-sectional design. Out of the 25 studies, 6 studies reported ≥ 10 complications, while 7 studies reported complications ranging from 6 to 10. Three studies reported on a single complication, 5 studies reported at least two complications but fewer than six, and 3 studies reported higher numbers of complications (≥ 15) compared with other selected studies. Among the reported complications, neutropenia, cardiac complications, vomiting, fever, and kidney/renal injury were the top-most. The severity of post-therapy complications varied depending on the type of therapy. Studies indicated that patients treated with combination therapy had a higher number of post-therapy complications across the selected studies. Twenty studies (80%) reported the overall rate of hospitalisation among patients. Seven studies revealed a hospitalisation rate of over 50% among cancer patients who had at least one complication. Furthermore, two studies reported a high hospitalisation rate (> 90%) attributed to therapy-repeated complications. CONCLUSION: The burden of post-therapy complications is emerging across treatment modalities. Combination therapy is particularly associated with a higher number of post-therapy complications. Ongoing research and treatment strategies are imperative for mitigating the complications of cancer therapies and treatment procedures. Concurrently, healthcare reforms and enhancement are essential to address the elevated hospitalisation rates resulting from treatment-related complications in cancer patients.

Assessing health-related quality of life among cancer survivors during systemic and radiation therapy in Bangladesh: a cancer-specific exploration.

BACKGROUND: Evaluating the effects of cancer diagnosis and treatment on a patient's overall well-being is crucial and health-related quality of life (HRQoL) is a reliable metric for assessing this impact. Little is known about HRQoL among cancer survivors across various stages and treatments. The study examined individual and clinical factors influencing HRQoL among cancer survivors. METHODS: A cross-sectional study was conducted in two specialised cancer care hospitals in Dhaka, Bangladesh. Cancer-diagnosed adults receiving treatment at selected hospitals from January to May 2022 were enrolled. The 5-level EuroQol-5 Dimensions version (EQ-5D-5L) instrument was used to collect HRQoL data. HRQoL scores were derived using UK value sets. The investigation used a multivariable Tobit regression model to determine the association between independent variables and HRQoL scores. RESULTS: A total of 607 adult patients were enrolled, with 55% being females and 66% aged 36 to 64 years. Reported health problems in five EQ-5D domains include mobility (11%), self-care (11%), usual daily activities (19%), pain/discomfort (21%), and anxiety/depression (46%). Patients with throat, brain, lung, blood, and liver cancer had lower utility scores. Advanced-stage cancer survivors had lower utility scores (ß = -49 units, 95% codfidence interval [CI]: -0.75 to -0.22) compared to early-stage survivors. Physically inactive survivors had lower utility scores by 0.41 units (95% CI: -0.51 to -0.30) compared to their counterparts. Private hospital patients had higher utility scores, whereas patients belonged to poor socioeconomic groups scored worse than wealthier ones. CONCLUSIONS: This study highlights the impact of clinical and individual characteristics on HRQoL among cancer survivors. These findings advocate for an enhanced Bangladeshi cancer patient care model through timely interventions or programs, early detection or diagnosis, tailored treatments, and the promotion of physical activity to bolster HRQoL outcomes.

Introgression of the bread wheat D genome encoded Lr34/Yr18/Sr57/Pm38/Ltn1 adult plant resistance gene into Triticum turgidum (durum wheat).

KEY MESSAGE: Lack of function of a D-genome adult plant resistance gene upon introgression into durum wheat. The wheat Lr34/Yr18/Sr57/Pm38/Ltn1 adult plant resistance gene (Lr34), located on chromosome arm 7DS, provides broad spectrum, partial, adult plant resistance to leaf rust, stripe rust, stem rust and powdery mildew. It has been used extensively in hexaploid bread wheat (AABBDD) and conferred durable resistance for many decades. These same diseases also occur on cultivated tetraploid durum wheat and emmer wheat but transfer of D genome sequences to those subspecies is restricted due to very limited intergenomic recombination. Herein we have introgressed the Lr34 gene into chromosome 7A of durum wheat. Durum chromosome substitution line Langdon 7D(7A) was crossed to Cappelli ph1c, a mutant derivative of durum cultivar Cappelli homozygous for a deletion of the chromosome pairing locus Ph1. Screening of BC1F2 plants and their progeny by KASP and PCR markers, 90 K SNP genotyping and cytology identified 7A chromosomes containing small chromosome 7D fragments encoding Lr34. However, in contrast to previous transgenesis experiments in durum wheat, resistance to wheat stripe rust was not observed in either Cappelli/Langdon 7D(7A) or Bansi durum plants carrying this Lr34 encoding segment due to low levels of Lr34 gene expression.

Impact of COVID-19 pandemic on tourism geographies of Bangladesh: study on Sylhet region.

This qualitative study examines the impact of the COVID-19 pandemic on tourism geographies of Sylhet region in Bangladesh developing analytical linkages between pandemic and tourism geography. On the basis of in-depth interviews, the study explores micro effects on diverse actors involved in the tourism process of Sylhet division. As one of the emerging tourism hubs, why Sylhet region demands special treatment from local, national and international authorities and policymakers to mitigate the adverse effects of the ongoing coronavirus pandemic, has been investigated in this paper. However, the central argument of the study is that the COVID-19 pandemic has severely affected the demand and supply chains, local businesses, transportations, hotels and restaurants, tea industry, corporations, and local professional lives due to the imposed restrictions on human mobility, causing a sharp decline in socio-economic activities of Sylhet's tourism geographies.

High-risk HPV infection-associated hypermethylated genes in oropharyngeal squamous cell carcinomas.

BACKGROUND: HPV-positive oropharyngeal squamous cell carcinomas (OPSCCs) are sensitive to chemo-radiation therapy and have favorable survival outcomes compared with HPV-negative cancers. These tumors are usually not related to tobacco and alcohol exposure. Therefore, diagnosing HPV-positive OPSCCs for the appropriate disease management is crucial, and no suitable markers are available for detecting early malignancies in HPV-infected tissues. In this study, we attempt to find HPV-specific epigenetic biomarkers for OPSCCs. METHODS: A total of 127 surgical samples were analyzed for HPV positivity and promoter methylation of a panel of genes. HPV detection was performed by PCR detection of HPV E6 and E7 viral oncoproteins. In addition, promoter methylation of a total of 8 genes (DAPK, FHIT, RASSF1A, TIMP3, AGTR1, CSGALNACT2, GULP1 and VGF) was analyzed by quantitative-methylation specific PCR (QMSP), and their associations with HPV positivity or RB/p16 expressions were evaluated. RESULTS: AGTR1 and FHIT were frequently methylated in HPV-positive OPSCC samples with a good area under the curve (AUC over 0.70). In addition, these genes' promoter methylation was significantly associated with p16 positive and RB negative cases, which were the characteristics of OPSCC cases with favorable survival outcomes. Either AGTR1 or FHIT methylated cases were significantly associated with HPV-positive cancers with 92.0% sensitivity (P < 0.001). Also, they had significantly better overall survival (P = 0.047) than both unmethylated cases. CONCLUSIONS: A combination of AGTR1 and FHIT methylation demonstrated a suitable detection marker of OPSCCs derived from the HPV-infected field, familiar with p16-positive and RB-negative phenotypes.

Structural basis for Na(+) transport mechanism by a light-driven Na(+) pump.

Krokinobacter eikastus rhodopsin 2 (KR2) is the first light-driven Na(+) pump discovered, and is viewed as a potential next-generation optogenetics tool. Since the positively charged Schiff base proton, located within the ion-conducting pathway of all light-driven ion pumps, was thought to prohibit the transport of a non-proton cation, the discovery of KR2 raised the question of how it achieves Na(+) transport. Here we present crystal structures of KR2 under neutral and acidic conditions, which represent the resting and M-like intermediate states, respectively. Structural and spectroscopic analyses revealed the gating mechanism, whereby the flipping of Asp116 sequesters the Schiff base proton from the conducting pathway to facilitate Na(+) transport. Together with the structure-based engineering of the first light-driven K(+) pumps, electrophysiological assays in mammalian neurons and behavioural assays in a nematode, our studies reveal the molecular basis for light-driven non-proton cation pumps and thus provide a framework that may advance the development of next-generation optogenetics.

An Improved Vulnerability Exploitation Prediction Model with Novel Cost Function and Custom Trained Word Vector Embedding.

Successful cyber-attacks are caused by the exploitation of some vulnerabilities in the software and/or hardware that exist in systems deployed in premises or the cloud. Although hundreds of vulnerabilities are discovered every year, only a small fraction of them actually become exploited, thereby there exists a severe class imbalance between the number of exploited and non-exploited vulnerabilities. The open source national vulnerability database, the largest repository to index and maintain all known vulnerabilities, assigns a unique identifier to each vulnerability. Each registered vulnerability also gets a severity score based on the impact it might inflict upon if compromised. Recent research works showed that the cvss score is not the only factor to select a vulnerability for exploitation, and other attributes in the national vulnerability database can be effectively utilized as predictive feature to predict the most exploitable vulnerabilities. Since cybersecurity management is highly resource savvy, organizations such as cloud systems will benefit when the most likely exploitable vulnerabilities that exist in their system software or hardware can be predicted with as much accuracy and reliability as possible, to best utilize the available resources to fix those first. Various existing research works have developed vulnerability exploitation prediction models by addressing the existing class imbalance based on algorithmic and artificial data resampling techniques but still suffer greatly from the overfitting problem to the major class rendering them practically unreliable. In this research, we have designed a novel cost function feature to address the existing class imbalance. We also have utilized the available large text corpus in the extracted dataset to develop a custom-trained word vector that can better capture the context of the local text data for utilization as an embedded layer in neural networks. Our developed vulnerability exploitation prediction models powered by a novel cost function and custom-trained word vector have achieved very high overall performance metrics for accuracy, precision, recall, F1-Score and AUC score with values of 0.92, 0.89, 0.98, 0.94 and 0.97, respectively, thereby outperforming any existing models while successfully overcoming the existing overfitting problem for class imbalance.

Cost-effectiveness of inhaled oxytocin for prevention of postpartum haemorrhage: a modelling study applied to two high burden settings.

BACKGROUND: Access to oxytocin for prevention of postpartum haemorrhage (PPH) in resource-poor settings is limited by the requirement for a consistent cold chain and for a skilled attendant to administer the injection. To overcome these barriers, heat-stable, non-injectable formulations of oxytocin are under development, including oxytocin for inhalation. This study modelled the cost-effectiveness of an inhaled oxytocin product (IHO) in Bangladesh and Ethiopia. METHODS: A decision analytic model was developed to assess the cost-effectiveness of IHO for the prevention of PPH compared to the standard of care in Bangladesh and Ethiopia. In Bangladesh, introduction of IHO was modelled in all public facilities and home deliveries with or without a skilled attendant. In Ethiopia, IHO was modelled in all public facilities and home deliveries with health extension workers. Costs (costs of introduction, PPH prevention and PPH treatment) and effects (PPH cases averted, deaths averted) were modelled over a 12-month program. Life years gained were modelled over a lifetime horizon (discounted at 3%). Cost of maintaining the cold chain or effects of compromised oxytocin quality (in the absence of a cold chain) were not modelled. RESULTS: In Bangladesh, IHO was estimated to avert 18,644 cases of PPH, 76 maternal deaths and 1954 maternal life years lost. This also yielded a cost-saving, with the majority of gains occurring among home deliveries where IHO would replace misoprostol. In Ethiopia, IHO averted 3111 PPH cases, 30 maternal deaths and 767 maternal life years lost. The full IHO introduction program bears an incremental cost-effectiveness ratio (ICER) of between 2 and 3 times the per-capita Gross Domestic Product (GDP) ($1880 USD per maternal life year lost) and thus is unlikely to be considered cost-effective in Ethiopia. However, the ICER of routine IHO administration considering recurring cost alone falls under 25% of per-capita GDP ($175 USD per maternal life-year saved). CONCLUSIONS: IHO has the potential to expand access to uterotonics and reduce PPH-associated morbidity and mortality in high burden settings. This can facilitate reduced spending on PPH management, making the product highly cost-effective in settings where coverage of institutional delivery is lagging.

Systematic review and meta-analysis of the prevalence of smokeless tobacco consumption among adults in Bangladesh, India and Myanmar.

OBJECTIVE: To estimate the pooled prevalence of smokeless tobacco consumption (STC) by gender and location in Bangladesh, India and Myanmar and to identify periodic changes in STC prevalence using data extracted from published studies. METHODS: We searched for a combination of keywords in electronic databases and used a standard form to extract data from each article. We undertook a meta-analysis to estimate pooled prevalence and confidence intervals within these countries. To compare periodic changes in STC prevalence, we grouped studies into five-year periods (2000-2004, 2005-2009, 2010-2014 and 2015-2019). RESULTS: The pooled estimates of STC prevalence were 25% (95% CI: 22-28%), 22% (95% CI: 15-28%) and 21% (95% CI: 14-28%) for Bangladesh, India and Myanmar, respectively. In pooled estimates across these countries, we found higher STC prevalence for men (30%; 95% CI: 24-35%) than women (16%; 95% CI: 10-23%) and for rural dwellings (24%; 95% CI: 18-31%) than urban dwellings (17%; 95% CI: 10-24%). We found significant decrease in STC in Bangladesh and India in the period 2010-2014 and 2015-2019, respectively. In Myanmar, STC prevalence increased significantly and substantially in 2010-2014, to levels higher than in Bangladesh and India. CONCLUSIONS: The prevalence of STC in Bangladesh, India and Myanmar is highest in rural areas and among men. Public health prevention strategies are needed to maintain decrease in STC in Bangladesh and India, and to reverse the increased use in Myanmar.

OBJECTIF: Estimer la prévalence poolée de la consommation de tabac sans fumée (CTSF) par sexe et lieu au Bangladesh, en Inde et au Myanmar et identifier les changements périodiques de la prévalence des CTSF à l'aide de données extraites d'études publiées. MÉTHODES: Nous avons recherché une combinaison de mots-clés dans les bases de données électroniques et utilisé un formulaire standard pour extraire les données de chaque article. Nous avons entrepris une méta-analyse pour estimer la prévalence poolée et les intervalles de confiance dans ces pays. Pour comparer les changements périodiques de la prévalence des CTSF, nous avons regroupé les études en périodes de cinq ans (2000-2004, 2005-2009, 2010-2014, 2015-2019). RÉSULTATS: Les estimations poolées de la prévalence des CTSF étaient de 25% (IC95%: 22-28%), 22% (IC95%: 15-28%) et 21% (IC95%: 14-28%) pour le Bangladesh, l'Inde et le Myanmar, respectivement. Dans les estimations poolées de ces pays, nous avons constaté une prévalence des CTSF plus élevée pour les hommes (30%; IC95%: 24-35%) que pour les femmes (16%; IC95%: 10-23%) et pour les habitations rurales (24%; IC95%: 18-31%) que les habitations urbaines (17%; IC95%: 10-24%). Nous avons constaté une diminution significative des CTSF au Bangladesh et en Inde au cours de la période 2010-2014 et 2015-2019 respectivement. Au Myanmar, la prévalence des CTSF a augmenté de manière significative et substantielle en 2010-2014, à des niveaux plus élevés qu'au Bangladesh et en Inde. CONCLUSIONS: La prévalence des CTSF au Bangladesh, en Inde et au Myanmar est la plus élevée dans les zones rurales et chez les hommes. Des stratégies de prévention de la santé publique sont nécessaires pour maintenir la diminution des CTSF au Bangladesh et en Inde et pour inverser l'augmentation de la consommation au Myanmar.

Health care cost of overweight-related diseases in Bangladesh.

OBJECTIVE: To estimate the economic burden of overweight in Bangladesh. DESIGN: We used data from Household Income and Expenditure Survey, 2010. A prevalence-based approach was used to calculate the population attributable fraction (PAF) for diseases attributable to overweight. Cost of illness methodology was used to calculate annual out of pocket (OOP) expenditure for each disease using nationally representative survey data. The cost attributable to overweight for each disease was estimated by multiplying the PAF by annual OOP expenditure. The total cost of overweight was estimated by adding PAF-weighted costs of treating the diseases. SETTING: Nationwide, covering the whole of Bangladesh. PARTICIPANTS: Individuals whose BMI ≥ 25 kg/m2. RESULTS: The total cost attributable to overweight in Bangladesh in 2010 was estimated at US$147·38 million. This represented about 0·13 % of Bangladesh's Gross Domestic Product and 3·69 % of total health care expenditure in 2010. The sensitivity analysis revealed that the total cost could be as high as US$334 million or as low as US$71 million. CONCLUSIONS: A substantial amount of health care resource is devoted to the treatment of overweight-related diseases in Bangladesh. Effective national strategies for overweight prevention programme should be established and implemented.

Analysis of five deep-sequenced trio-genomes of the Peninsular Malaysia Orang Asli and North Borneo populations.

BACKGROUND: Recent advances in genomic technologies have facilitated genome-wide investigation of human genetic variations. However, most efforts have focused on the major populations, yet trio genomes of indigenous populations from Southeast Asia have been under-investigated. RESULTS: We analyzed the whole-genome deep sequencing data (~ 30×) of five native trios from Peninsular Malaysia and North Borneo, and characterized the genomic variants, including single nucleotide variants (SNVs), small insertions and deletions (indels) and copy number variants (CNVs). We discovered approximately 6.9 million SNVs, 1.2 million indels, and 9000 CNVs in the 15 samples, of which 2.7% SNVs, 2.3% indels and 22% CNVs were novel, implying the insufficient coverage of population diversity in existing databases. We identified a higher proportion of novel variants in the Orang Asli (OA) samples, i.e., the indigenous people from Peninsular Malaysia, than that of the North Bornean (NB) samples, likely due to more complex demographic history and long-time isolation of the OA groups. We used the pedigree information to identify de novo variants and estimated the autosomal mutation rates to be 0.81 × 10- 8 - 1.33 × 10- 8, 1.0 × 10- 9 - 2.9 × 10- 9, and ~ 0.001 per site per generation for SNVs, indels, and CNVs, respectively. The trio-genomes also allowed for haplotype phasing with high accuracy, which serves as references to the future genomic studies of OA and NB populations. In addition, high-frequency inherited CNVs specific to OA or NB were identified. One example is a 50-kb duplication in DEFA1B detected only in the Negrito trios, implying plausible effects on host defense against the exposure of diverse microbial in tropical rainforest environment of these hunter-gatherers. The CNVs shared between OA and NB groups were much fewer than those specific to each group. Nevertheless, we identified a 142-kb duplication in AMY1A in all the 15 samples, and this gene is associated with the high-starch diet. Moreover, novel insertions shared with archaic hominids were identified in our samples. CONCLUSION: Our study presents a full catalogue of the genome variants of the native Malaysian populations, which is a complement of the genome diversity in Southeast Asians. It implies specific population history of the native inhabitants, and demonstrated the necessity of more genome sequencing efforts on the multi-ethnic native groups of Malaysia and Southeast Asia.

A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy.

YAP1 is one of the most important effectors of the Hippo pathway and has crosstalk with other cancer promoting pathways. YAP1 contributes to cancer development in various ways that include promoting malignant phenotypes, expansion of cancer stem cells and drug resistance of cancer cells. Because pharmacologic or genetic inhibition of YAP1 suppresses tumor progression and increases the drug sensitivity, targeting YAP1 may open a fertile avenue for a novel therapeutic approach in relevant cancers. Recent enormous studies have established the efficacy of immunotherapy, and several immune checkpoint blockades are in clinical use or in the phase of development to treat various cancer types. Immunosuppression in the tumor microenvironment (TME) induced by cancer cells, immune cells and associated stromal cells promotes tumor progression and causes drug resistance. Accumulated evidences of scientific efforts from the last few years suggest that YAP1 influences macrophages, myeloid-derived suppressor cells and regulatory T-cells to facilitate immunosuppressive TME. Although the underlying mechanisms is not clearly discerned, it is evident that YAP1 activating pathways in different cellular components induce immunosuppressive TME. In this review, we summarize the evidences involved in the dual roles of YAP1 in cancer development and immunosuppression in the TME. We also discuss the possibility of YAP1 as a novel therapeutic target.

Arsenic promotes the COX2/PGE2-SOX2 axis to increase the malignant stemness properties of urothelial cells.

Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion and chemoresistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB.

CD24 regulates cancer stem cell (CSC)-like traits and a panel of CSC-related molecules serves as a non-invasive urinary biomarker for the detection of bladder cancer.

BACKGROUND: CD24 is a cornerstone of tumour progression in urothelial carcinoma of the bladder (UCB). However, its contribution to cancer stem cell (CSC)-like traits and the clinical utility of CD24 as a urinary biomarker for cancer detection have not been determined. METHODS: The functional relevance of CD24 was evaluated using in vitro and in vivo approaches. The clinical utility of CSC-related molecules was assessed in urine samples by quantitative RT-PCR. RESULTS: The knockdown of CD24 attenuated cancer stemness properties. The high-CD24-expressing cells, isolated from patient-derived UCB xenograft tumours, exhibited their enhanced stemness properties. CD24 was overexpressed not only in primary tumours but also in urine from UCB subjects. By assessment of 15 candidate CSC-related molecules in urine samples of a training cohort, a panel of three molecules (CD24, CD49f, and NANOG) was selected. The combination of these three molecules yielded a sensitivity and specificity of 81.7% and 74.3%, respectively, in an independent cohort. A combined set of 84 cases and 207 controls provided a sensitivity and specificity of 82% and 76%, respectively. CONCLUSION: CD24 has a crucial role in maintaining the urothelial cancer stem-like traits and a panel of CSC-related molecules has potential as a urinary biomarker for non-invasive UCB detection.

Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia.

Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50-33 thousand years ago (kya), followed by East Asian (~ 40-15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.

In vitro invasion inhibition assay using antibodies against Plasmodium knowlesi Duffy binding protein alpha and apical membrane antigen protein 1 in human erythrocyte-adapted P. knowlesi A1-H.1 strain.

BACKGROUND: The rapid process of malaria erythrocyte invasion involves ligand-receptor interactions. Inducing antibodies against specific ligands or receptors that abrogate the invasion process is a key challenge for blood stage vaccine development. However, few candidates were reported and remain to be validated for the discovery of new vaccine candidates in Plasmodium knowlesi. METHODS: In order to investigate the efficacy of pre-clinical vaccine candidates in P. knowlesi-infected human cases, this study describes an in vitro invasion inhibition assay, using a P. knowlesi strain adapted to in vitro growth in human erythrocytes, PkA1-H.1. Recombinant proteins of P. knowlesi Duffy binding protein alpha (PkDBPα) and apical membrane antigen 1 (PkAMA1) were produced in Escherichia coli system and rabbit antibodies were generated from immune animals. RESULTS: PkDBPα and PkAMA1 recombinant proteins were expressed as insoluble and produced as a functional refolded form for this study. Antibodies against PkDBPα and PkAMA1 specifically recognized recombinant proteins and native parasite proteins in schizont-stage parasites on the merozoite organelles. Single and combination of anti-PkDBPα and anti-PkAMA1 antibodies elicited strong growth inhibitory effects on the parasite in concentration-dependent manner. Meanwhile, IgG prevalence of PkDBPα and PkAMA1 were observed in 13.0 and 46.7% in human clinical patients, respectively. CONCLUSION: These data provide support for the validation of in vitro growth inhibition assay using antibodies of DBPα and AMA1 in human-adapted P. knowlesi parasite PkA1-H.1 strain.

Diversity pattern of Duffy binding protein sequence among Duffy-negatives and Duffy-positives in Sudan.

BACKGROUND: Vivax malaria is a leading public health concern worldwide. Due to the high prevalence of Duffy-negative blood group population, Plasmodium vivax in Africa historically is less attributable and remains a neglected disease. The interaction between Duffy binding protein and its cognate receptor, Duffy antigen receptor for chemokine plays a key role in the invasion of red blood cells and serves as a novel vaccine candidate against P. vivax. However, the polymorphic nature of P. vivax Duffy binding protein (DBP), particularly N-terminal cysteine-rich region (PvDBPII), represents a major obstacle for the successful design of a DBP-based vaccine to enable global protection. In this study, the level of pvdbpII sequence variations, Duffy blood group genotypes, number of haplotypes circulating, and the natural selection at pvdbpII in Sudan isolates were analysed and the implication in terms of DBP-based vaccine design was discussed. METHODS: Forty-two P. vivax-infected blood samples were collected from patients from different areas of Sudan during 2014-2016. For Duffy blood group genotyping, the fragment that indicates GATA-1 transcription factor binding site of the FY gene (- 33T > C) was amplified by PCR and sequenced by direct sequencing. The region II flanking pvdbpII was PCR amplified and sequenced by direct sequencing. The genetic diversity and natural selection of pvdbpII were done using DnaSP ver 5.0 and MEGA ver 5.0 programs. Based on predominant, non-synonymous, single nucleotide polymorphisms (SNPs), prevalence of Sudanese haplotypes was assessed in global isolates. RESULTS: Twenty SNPs (14 non-synonymous and 6 synonymous) were identified in pvdbpII among the 42 Sudan P. vivax isolates. Sequence analysis revealed that 11 different PvDBP haplotypes exist in Sudan P. vivax isolates and the region has evolved under positive selection. Among the identified PvDBP haplotypes five PvDBP haplotypes were shared among Duffy-negative as well as Duffy-positive individuals. The high selective pressure was mainly found on the known B cell epitopes (H3) of pvdbpII. Comparison of Sudanese haplotypes, based on 10 predominant non-synonymous SNPs with 10 malaria-endemic countries, demonstrated that Sudanese haplotypes were prevalent in most endemic countries. CONCLUSION: This is the first pvdbp genetic diversity study from an African country. Sudanese isolates display high haplotype diversity and the gene is under selective pressure. Haplotype analysis indicated that Sudanese haplotypes are a representative sample of the global population. However, studies with a large number of samples are needed. These findings would be valuable for the development of PvDBP-based malaria vaccine.

Clinical and molecular surveillance of artemisinin resistant falciparum malaria in Myanmar (2009-2013).

BACKGROUND: Emergence of artemisinin-resistant malaria in Southeast Asian countries threatens the global control of malaria. Although K13 kelch propeller has been assessed for artemisinin resistance molecular marker, most of the mutations need to be validated. In this study, artemisinin resistance was assessed by clinical and molecular analysis, including k13 and recently reported markers, pfarps10, pffd and pfmdr2. METHODS: A prospective cohort study in 1160 uncomplicated falciparum patients was conducted after treatment with artemisinin-based combination therapy (ACT), in 6 sentinel sites in Myanmar from 2009 to 2013. Therapeutic efficacy of ACT was assessed by longitudinal follow ups. Molecular markers analysis was done on all available day 0 samples. RESULTS: True recrudescence treatment failures cases and day 3 parasite positivity were detected at only the southern Myanmar sites. Day 3 positive and k13 mutants with higher prevalence of underlying genetic foci predisposing to become k13 mutant were detected only in southern Myanmar since 2009 and comparatively fewer mutations of pfarps10, pffd, and pfmdr2 were observed in western Myanmar. K13 mutations, V127M of pfarps10, D193Y of pffd, and T448I of pfmdr2 were significantly associated with day 3 positivity (OR: 6.48, 3.88, 2.88, and 2.52, respectively). CONCLUSIONS: Apart from k13, pfarps10, pffd and pfmdr2 are also useful for molecular surveillance of artemisinin resistance especially where k13 mutation has not been reported. Appropriate action to eliminate the resistant parasites and surveillance on artemisinin resistance should be strengthened in Myanmar. Trial registration This study was registered with ClinicalTrials.gov, identifier NCT02792816.

Double burden of underweight and overweight among Bangladeshi adults differs between men and women: evidence from a nationally representative survey.

OBJECTIVE: To estimate the prevalence of underweight and overweight among Bangladeshi adults and to determine if the double burden of underweight and overweight differs by gender and other socio-economic characteristics of individuals. DESIGN: We used data from the Bangladesh Demographic and Health Survey 2011. Multinominal logistic regression was used to examine associations between the different nutritional statuses of individuals and related determinants. Interaction effect was checked between gender and various socio-economic factors. SETTING: Nationwide, covering the whole of Bangladesh. SUBJECTS: Individuals aged >18 years (women, n 16 052; men, n 5090). RESULTS: Underweight was observed among 28·3 % of men and 24·4 % of women, whereas overweight was observed among 8·4 % of men and 16·9 % of women. The odds of being overweight were significantly lower among urban men (OR=0·46; 95 % CI 0·37, 0·57) compared with urban women, whereas the odds of being underweight were significantly higher among urban men (OR=1·33; 95 % CI 1·07, 1·64) compared with urban women. The odds of being overweight were lower among higher educated men (OR=0·48; 95 % CI 0·39, 0·58) and men of rich households (OR=0·45; 95 % CI 0·37, 0·54) compared with higher educated women and women of rich households, respectively. CONCLUSIONS: There are important gender differences in the prevalence of underweight and overweight among the adult population in Bangladesh. Women with higher education, in rich and urban households have higher chances of being overweight and lower chances of being underweight compared with their male counterparts.

Economic burden of underweight and overweight among adults in the Asia-Pacific region: a systematic review.

OBJECTIVE: To assess the economic burden of underweight and overweight among adults in the Asia-Pacific region. METHOD: Systematic review of articles published until March 2015. RESULTS: Seventeen suitable articles were found, of which 13 assess the economic burden of overweight/obesity and estimate that it accounts for 1.5-9.9% of a country's total healthcare expenditure. Four articles on the economic burden of underweight estimate it at 2.5-3.8% of the country's total GDP. Using hospital data, and compared to normal weight individuals, four articles estimated extra healthcare costs for overweight individuals of 7-9.8% and more, and extra healthcare costs for obese individuals of 17-22.3% and higher. CONCLUSION: Despite methodological diversity across the studies, there is a consensus that both underweight and overweight impose a substantial financial burden on healthcare systems in the Asia-Pacific region.