Thalassemia in Asia 2021 Thalassemia in Brunei Darussalam.

Acknowledging and understanding the extent of thalassemia and hemoglobinopathy issues in a country is crucial for the benefit of implementing a national preventive and control program to reduce its prevalence. In order to obtain reliable prevalence data, the gene frequencies of the thalassemias and other hemoglobinopathies should be investigated. Molecular studies on thalassemia have yet to be done for Brunei's population. It was estimated that carriers of thalassemia or hemoglobinopathies in Brunei is approximately 5.0% or less of the overall population. There are about 200 current cases of thalassemia and other hemoglobinopathies including adults and children reported across all four districts of Brunei. Blood parameter analysis, microscopy, hemoglobin (Hb) electrophoresis and high performance liquid chromatography (HPLC) are the most common methods of investigation in aiding diagnosis in the hospital laboratory. Genotyping analysis conducted in an overseas laboratory has been employed to confirm some diagnosis. Compiled data from 2009-2017 at the Hematology Laboratory of the Raja Isteri Pengiran Anak Saleha Hospital, Jalan Putera Al-Muhtadee Billah, Bandar Seri Begawan, Brunei Darussalam, showed that the most reported diagnoses are α-thalassemia (α-thal) trait, ß-thalassemia (ß-thal) trait, heterozygous Hb E (HBB: c.79G>A)/ß-thal, ß-thal major (ß-TM) and ß-thal intermedia (ß-TI). The data reported indicate the importance of establishing a thalassemia registry with relevant data on patients and patient outcomes as a tool for monitoring and improving patient care.

The burden and risks factors for intracerebral hemorrhage in a Southeast Asian population.

OBJECTIVE: The characteristics of intracerebral hemorrhage in Southeast Asian countries are insufficiently represented in the literature despite a large proportion of new stroke cases and deaths. This study aims to report the epidemiological and clinical presentation of intracerebral hemorrhage in Brunei Darussalam and investigate its incidence according to sex and age, as well as in relation to clinical presentation, radiological findings, and prognostic factors. METHODS: This retrospective study of intracerebral hemorrhage admissions was conducted from 1 January 2016-31 December 2019. Crude incidence rates were calculated by age and sex. Patient characteristics/demographics, mortality and functional outcomes were analyzed. Multivariate Cox regression models were used for investigating predictors of mortality. RESULTS: The study cohort consisted of 255 patients (median age, 52 years); most were men (64.3% [164/255]) and had hypertension (76.9% [196/255]). The annual incidence rate was 14.6 per 100,000 (95% confidence interval, 12.9-16.5), and incidence rates were higher in men than in women for all age groups. A 7-day and 30-day mortality rate of 22.7% and 31.4%, respectively, was reported. Increased 30-day mortality was associated with patients on dialysis, diabetes mellitus, Glasgow Coma Scale score ≤ 8, bilateral dilated pupils, higher international normalized ratio, hematoma in the cerebellum or brainstem, hematoma volume, and presence of intraventricular hematoma. CONCLUSIONS: This study provided insight into several aspects of the burden of intracerebral hemorrhage in Brunei Darussalam where an increasing incidence trend in men was observed. Intracerebral hemorrhage is associated with significant mortality and severe disability, and hypertension remains a significant risk factor.

Proposed Data-Driven Approach for Occupational Risk Management of Aircrew Fatigue.

BACKGROUND: Fatigue is pervasive, under-reported, and potentially deadly where flight operations are concerned. The aviation industry appears to lack a standardized, practical, and easily replicable protocol for fatigue risk assessment which can be consistently applied across operators. AIM: Our paper sought to present a framework, supported by real-world data with subjective and objective parameters, to monitor aircrew fatigue and performance, and to determine the safe crew configuration for commercial airline operations. METHODS: Our protocol identified risk factors for fatigue-induced performance degradation as triggers for fatigue risk and performance assessment. Using both subjective and objective measurements of sleep, fatigue, and performance in the form of instruments such as the Karolinska Sleepiness Scale, Samn-Perelli Crew Status Check, Psychomotor Vigilance Task, sleep logs, and a wearable actigraph for sleep log correlation and sleep duration and quality charting, a workflow flagging fatigue-prone flight operations for risk mitigation was developed and trialed. RESULTS: In an operational study aimed at occupational assessment of fatigue and performance in airline pilots on a three-men crew versus a four-men crew for a long-haul flight, we affirmed the technical feasibility of our proposed framework and approach, the validity of the battery of assessment instruments, and the meaningful interpretation of fatigue and work performance indicators to enable the formulation of safe work recommendations. CONCLUSION: A standardized occupational assessment protocol like ours is useful to achieve consistency and objectivity in the occupational assessment of fatigue and work performance.

Conducting multiple mini-interviews in the midst of COVID-19 pandemic.

Multiple mini-interview (MMI) is a 'multiple sample-based' approach comprising multiple focused encounters intended to access and assess a range of attributes in order to gain more objectively multiple impressions of an applicant's interpersonal skills, thoughtfulness and general demeanour. It is designed to focus on four domains that are not considered to be comprehensive, but are considered to be vital for a successful career in the health sciences: critical thinking, ethical decision making, communication and knowledge of the healthcare system. Traditionally, the MMI is conducted face-to-face, but with COVID-19 pandemic and the implementation of social distancing measures, no onsite or campus teaching, banning of mass gatherings and cancellation of face-to-face interviews, Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah Institute of Health Sciences at Universiti Brunei Darussalam explored the feasibility of conducting MMI through virtual means. This report provides an account of our experience in conducting internet-MMI for the selection of new applicants into the August 2020 cohort of the Medicine programme. We also aimed to determine whether the scores derived from internet-MMI were reliable and equivalent to the scores derived from traditional MMI.

Colorectal Cancer in Brunei Darussalam: An Overview and Rationale for National Screening Programme.

Colorectal cancer (CRC) is the third most common cancer worldwide after lung and breast cancers, and ranks second in terms of cancer mortality globally. Brunei Darussalam reports high incidence of CRC in the Southeast Asian region and has no formal national screening programme for CRC. Screening for CRC in Brunei Darussalam is offered in an opportunistic fashion for individuals with average or above average risks for CRC, that is, the individual has a positive family history of CRC or neoplasms and is more than 50 years old. Opportunistic screening is widely practiced but this is not standardised. The Ministry of Health in Brunei Darussalam is currently in the process of implementing a CRC screening programme as part of a larger national health screening based on the increasing incidence of non-communicable diseases (NCDs). This review article assesses the situation of CRC in Brunei Darussalam from the 1980s to present day, including incidence of CRC in different age groups, ethnicities and genders; relevant non-modifiable and modifiable risk factors of CRC in Brunei Darussalam setting; and common CRC screening techniques used in Brunei Darussalam as well as other Asia-Pacific countries. The review also discusses the merits of a national CRC screening programme. With the increasing incidence of CRC worldwide and in Brunei Darussalam, national screening for CRC in Brunei Darussalam is an important strategy to lower morbidity and mortality rates. A review of the progress and outcome of the national screening programme will be available a few years after rollout.

Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS.

Neurotrophin receptors corresponding to vertebrate Trk, p75(NTR) or Sortilin have not been identified in Drosophila, thus it is unknown how neurotrophism may be implemented in insects. Two Drosophila neurotrophins, DNT1 and DNT2, have nervous system functions, but their receptors are unknown. The Toll receptor superfamily has ancient evolutionary origins and a universal function in innate immunity. Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. Toll-6 and Toll-7 are expressed in the CNS throughout development and regulate locomotion, motor axon targeting and neuronal survival. DNT1 (also known as NT1 and spz2) and DNT2 (also known as NT2 and spz5) interact genetically with Toll-6 and Toll-7, and DNT1 and DNT2 bind to Toll-6 and Toll-7 promiscuously and are distributed in vivo in domains complementary to or overlapping with those of Toll-6 and Toll-7. We conclude that in fruit flies, Tolls are not only involved in development and immunity but also in neurotrophism, revealing an unforeseen relationship between the neurotrophin and Toll protein families.

Roles of PDK-1 and PKN in regulating cell migration and cortical actin formation of PTEN-knockout cells.

Mutations in the tumor suppressor protein PTEN (phosphatase and tensin homologue deleted on chromosome 10) enhance cell migration, yet the underlying molecular mechanisms remain largely uncharacterized. Loss of PTEN in mouse embryonic fibroblasts (MEFs) correlates with striking cortical actin accumulation. However, how loss of PTEN leads to cortical actin formation and whether the presence of cortical actin contributes to the increased cell migration are unclear. Here we show that overexpression of dominant-negative forms of (DN) PTEN, RhoA or its kinase-dead (KD) effector, PKN, inhibited cortical actin formation, indicating that cortical actin of Pten(-/-) MEFs is mediated by the PTEN/Rho/PKN pathway. However, neither DN RhoA nor KD PKN inhibited the enhanced migration of Pten(-/-) cells, in contrast to the inhibitory effect of DN Rac. In agreement with the previous observation that DN Akt inhibits migration of Pten(-/-) cells, we demonstrate here that overexpression of KD PDK-1, the Akt kinase, reduces Pten(-/-) cell migration. Furthermore, overexpression of DN forms of Akt, Rac, or PDK-1, all of which inhibit migration of Pten(-/-) cells, had no effect on cortical actin accumulation. Our findings suggest that PDK-1/Akt signaling pathway plays a major role in regulating cell migration induced by PTEN deficiency.

Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1.

Bone morphogenetic proteins (BMPs) regulate multiple cellular processes, including cell differentiation and migration. Their signals are transduced by the kinase receptors BMPR-I and BMPR-II, leading to Smad transcription factor activation via BMPR-I. LIM kinase (LIMK) 1 is a key regulator of actin dynamics as it phosphorylates and inactivates cofilin, an actin depolymerizing factor. During a search for LIMK1-interacting proteins, we isolated clones encompassing the tail region of BMPR-II. Although the BMPR-II tail is not involved in BMP signaling via Smad proteins, mutations truncating this domain are present in patients with primary pulmonary hypertension (PPH). Further analysis revealed that the interaction between LIMK1 and BMPR-II inhibited LIMK1's ability to phosphorylate cofilin, which could then be alleviated by addition of BMP4. A BMPR-II mutant containing the smallest COOH-terminal truncation described in PPH failed to bind or inhibit LIMK1. This study identifies the first function of the BMPR-II tail domain and suggests that the deregulation of actin dynamics may contribute to the etiology of PPH.

Cloning and characterization of a testis and brain-specific isoform of mouse 3'-phosphoinositide-dependent protein kinase-1, mPDK-1 beta.

3'-Phosphoinositide-dependent protein kinase-1 (PDK-1) phosphorylates and activates members of the protein kinase AGC family and plays a key role in receptor tyrosine kinase signaling. Here we report the cloning and characterization of a splice variant of mouse PDK-1, mPDK-1 beta. The cDNA encoding mPDK-1 beta contains two alternative start codons and translation from these start codons generates proteins that are, respectively, 27 or 51 amino acid residues shorter at the amino-terminus than the previously identified PDK-1 isolated from mouse liver (now renamed mPDK-1 alpha) [J. Biol. Chem. 274 (1999) 8117]. Analysis of mouse tissues shows that mPDK-1 beta is highly expressed in the testis and various functional regions of the brain. Expression of this isoform is increased in the brain of aged mice. Both mPDK-1 alpha and mPDK-1 beta are autophosphorylated at both serine and threonine residues in vitro and showed similar levels of tyrosine phosphorylation when co-expressed with either constitutively active Src or Fyn tyrosine kinases in cells. However, the mPDK-1 isoforms showed significant differences in their response to pervanadate- or insulin plus vanadate-stimulated tyrosine phosphorylation. Taken together, our findings suggest that the two PDK-1 isoforms may be differentially regulated in cells. The specific expression of mPDK-1 beta in mouse testis and brains of aged mice also suggests potential involvement of this kinase in regulating animal spermatogenesis and aging.