Browse publications by year: 2022

  1. Rashid M, Yousaf Z, Din A, Munawar M, Aftab A, Riaz N, et al.
    Front Plant Sci, 2022;13:889604.
    PMID: 35707614 DOI: 10.3389/fpls.2022.889604
    Leafy vegetable crops are considered as a natural source of mineral nutrients that could decrease the risk factor of many growth issues in children and adults. Spinach is globally considered as the most desirable leafy crop, due to its taste and nutrient richness along with greater nitrate contents and better nitrogen use efficiency. To evaluate the mineral nutrient efficiency of this crop, thirty genetically diverse spinach accessions were analyzed through nutritional and functional marker strategies. The accession 163,310 from Pakistan was found to be rich in minerals (sodium, calcium, potassium, zinc, and manganese) and nitrates. However, the oxalate contents were lesser in the accessions that had greater quantity of nutrients. These represented a negative correlation between mineral availability and oxalate accumulation in the leaves. To study the relationship of oxalates and minerals in the accessions, a functional marker analysis was performed, based on the genes involved in oxalate metabolism and disease resistance in spinach. High level of genetic polymorphism was observed among the accessions represented with 115 polymorphic bands out of 130 bands. Heat map clustering represented the accessions from Asian countries (Pakistan, India, China, and Iran) as the most adaptable accessions to the local environment. The correlation between nutritional and genetic analysis also revealed the nutrient richness of these accessions along with good oxalate metabolism and disease resistance. Hence, these accessions could be considered as useful genotypes in future breeding programs.
  2. Selvavinayagam ST, Yong YK, Tan HY, Zhang Y, Subramanian G, Rajeshkumar M, et al.
    Front Med (Lausanne), 2022;9:887974.
    PMID: 35770011 DOI: 10.3389/fmed.2022.887974
    BACKGROUND: The magnitude of protection conferred following recovery from COVID-19 or by vaccine administration, and the duration of protective immunity developed, remains ambiguous.

    METHODS: We investigated the factors associated with anti-SARS-CoV-2 S1 IgG decay in 519 individuals who recovered from COVID-19 illness or received COVID-19 vaccination with two commercial vaccines, viz., an adenoviral vector-based (AZD1222) and a whole-virion-based inactivated (BBV152) vaccine in Chennai, India from March to December 2021. Blood samples collected during regular follow-up post-infection/-vaccination were examined for anti-SARS-CoV-2 S1 IgG by a commercial automated chemiluminescent immunoassay (CLIA).

    RESULTS: Age and underlying comorbidities were the two variables that were independently associated with the development of a breakthrough infection. Individuals who were >60 years of age with underlying comorbid conditions (viz., hypertension, diabetes mellitus and cardiovascular disease) had a ~15 times and ~10 times greater odds for developing a breakthrough infection and hospitalization, respectively. The time elapsed since the first booster dose was associated with attrition in anti-SARS-CoV-2 IgG, where each month passed was associated with an ebb in the anti-SARS-CoV-2 IgG antibody levels by a coefficient of -6 units.

    CONCLUSIONS: Our findings advocate that the elderly with underlying comorbidities be administered with appropriate number of booster doses with AZD1222 and BBV152 against COVID-19.

  3. Baral S, Rao A, Rwema JOT, Lyons C, Cevik M, Kågesten AE, et al.
    PLoS One, 2022;17(8):e0273389.
    PMID: 36037216 DOI: 10.1371/journal.pone.0273389
    BACKGROUND: COVID-19 has rapidly emerged as a global public health threat with infections recorded in nearly every country. Responses to COVID-19 have varied in intensity and breadth, but generally have included domestic and international travel limitations, closure of non-essential businesses, and repurposing of health services. While these interventions have focused on testing, treatment, and mitigation of COVID-19, there have been reports of interruptions to diagnostic, prevention, and treatment services for other public health threats.

    OBJECTIVES: We conducted a scoping review to characterize the early impact of COVID-19 on HIV, tuberculosis, malaria, sexual and reproductive health, and malnutrition.

    METHODS: A scoping literature review was completed using searches of PubMed and preprint servers (medRxiv/bioRxiv) from November 1st, 2019 to October 31st, 2020, using Medical Subject Headings (MeSH) terms related to SARS-CoV-2 or COVID-19 and HIV, tuberculosis, malaria, sexual and reproductive health, and malnutrition. Empiric studies reporting original data collection or mathematical models were included, and available data synthesized by region. Studies were excluded if they were not written in English.

    RESULTS: A total of 1604 published papers and 205 preprints were retrieved in the search. Overall, 8.0% (129/1604) of published studies and 10.2% (21/205) of preprints met the inclusion criteria and were included in this review: 7.3% (68/931) on HIV, 7.1% (24/339) on tuberculosis, 11.6% (26/224) on malaria, 7.8% (19/183) on sexual and reproductive health, and 9.8% (13/132) on malnutrition. Thematic results were similar across competing health risks, with substantial indirect effects of the COVID-19 pandemic and response on diagnostic, prevention, and treatment services for HIV, tuberculosis, malaria, sexual and reproductive health, and malnutrition.

    DISCUSSION: COVID-19 emerged in the context of existing public health threats that result in millions of deaths every year. Thus, effectively responding to COVID-19 while minimizing the negative impacts of COVID-19 necessitates innovation and integration of existing programs that are often siloed across health systems. Inequities have been a consistent driver of existing health threats; COVID-19 has worsened disparities, reinforcing the need for programs that address structural risks. The data reviewed here suggest that effective strengthening of health systems should include investment and planning focused on ensuring the continuity of care for both rapidly emergent and existing public health threats.

    MeSH terms: Humans; Tuberculosis*; Malnutrition*; Pandemics/prevention & control
  4. Lim HT, Kok BH, Lim CP, Abdul Majeed AB, Leow CY, Leow CH
    Biomed Eng Adv, 2022 Dec;4:100054.
    PMID: 36158162 DOI: 10.1016/j.bea.2022.100054
    With severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as an emergent human virus since December 2019, the world population is susceptible to coronavirus disease 2019 (COVID-19). SARS-CoV-2 has higher transmissibility than the previous coronaviruses, associated by the ribonucleic acid (RNA) virus nature with high mutation rate, caused SARS-CoV-2 variants to arise while circulating worldwide. Neutralizing antibodies are identified as immediate and direct-acting therapeutic against COVID-19. Single-domain antibodies (sdAbs), as small biomolecules with non-complex structure and intrinsic stability, can acquire antigen-binding capabilities comparable to conventional antibodies, which serve as an attractive neutralizing solution. SARS-CoV-2 spike protein attaches to human angiotensin-converting enzyme 2 (ACE2) receptor on lung epithelial cells to initiate viral infection, serves as potential therapeutic target. sdAbs have shown broad neutralization towards SARS-CoV-2 with various mutations, effectively stop and prevent infection while efficiently block mutational escape. In addition, sdAbs can be developed into multivalent antibodies or inhaled biotherapeutics against COVID-19.
  5. Zakaria N, Zakaria NH, Bin Abdul Rassip MNA, Lee KY
    BMJ Open, 2022 Oct 10;12(10):e064687.
    PMID: 36216421 DOI: 10.1136/bmjopen-2022-064687
    OBJECTIVE: This national-level study aimed to determine the prevalence and risk factors of burnout, as well as the coping strategies among nurses in the Ministry of Health (MOH) Malaysia.

    DESIGN: Using a complex sampling design, a two-stage stratified cluster sampling was performed to recruit MOH nurses between August and November 2019.

    SETTING AND PARTICIPANTS: A total of 2428 nurses from 32 hospitals and 28 district health offices answered the questionnaires based on Maslach Burnout Inventory for Human Services and Brief COPE. Complex sampling analysis was applied.

    OUTCOME MEASURES: The outcome of interest was the prevalence of burnout and its three domains of emotional exhaustion (EE), depersonalisation (DP) and low personal accomplishment. ORs using 95% CIs were calculated. Significant factors at the univariate level were entered into the multivariate logistic regression to identify independent predictors of burnout.

    RESULTS: One in four (24.4%) nurses experienced burnout. Younger, single, and childless nurses had a higher prevalence of burnout. Shift working nurses were 1.6 times more likely to develop burnout. Those who performed >6 night shifts per month were 1.5 times more predisposed to burnout (95% CI 1.01 to 2.36; p<0.05). While encountering traumatic events at work led to 4.2 times (95% CI 2.31, 7.63; p<0.05) higher risk of burnout, those who received post-traumatic psychological support were better protected. The use of dysfunctional coping strategies was detrimental as it was positively correlated with EE and DP.

    CONCLUSION: Addressing modifiable stressors of burnout at individual and institutional levels identified in this study can be potentially beneficial in reducing burnout and its undesirable effects among nurses. Interventions that promote positive coping strategies should be implemented. Organisational-driven efforts must target the improvement of work schedules for nurses and the establishment of a structured debriefing service for post-trauma counselling.

    MeSH terms: Adaptation, Psychological; Cross-Sectional Studies; Humans; Malaysia/epidemiology; Surveys and Questionnaires
  6. Che Rahim MJ, Abdull Wahab SF, Fauzi MH, Nadarajan C, Ab Hamid SA
    Ultrasound, 2022 Nov;30(4):292-298.
    PMID: 36969538 DOI: 10.1177/1742271X211051767
    BACKGROUND: Contrast-enhanced ultrasonography (CEUS) using saline was studied to detect supradiaphragmatic central venous catheter malposition. Commonly used echocardiographic views are apical 4-chamber (A4c) and subcostal views. However, this standard method is not feasible in certain situations. We explored the feasibility of the right ventricle inflow parasternal long axis (RVI-PLAX) echocardiographic view and dextrose 50% (D50%) contrast solution for detecting supradiaphragmatic central venous catheter malposition.

    METHOD: This pilot study screened 60 patients who underwent ultrasound-guided supradiaphragmatic central venous catheter insertion. We compared the investigators' guidewire's J-tip detection, D50% rapid atrial swirl sign (RASS) findings on the RVI-PLAX view and the central venous catheter tip on chest radiograph. We also compared the mean capillary blood sugar level before and after the 5 ml D50% flush.

    RESULTS: No guidewire J-tips were detected from the RVI-PLAX view. The first and second investigators' diagnosis of central venous catheter malposition detected on RVI-PLAX CEUS achieved an almost perfect agreement (κ = 1.0 (95% confidence interval (CI): 0.90 to 1.0), p 

  7. Khan MN, Kabir MA, Shariff AA, Rahman MM
    PLOS Glob Public Health, 2022;2(2):e0000091.
    PMID: 36962249 DOI: 10.1371/journal.pgph.0000091
    Caesarean section (CS) use is rising rapidly in Bangladesh, though lack of CS use remains common among disadvantage women. This increases risks of long-term obstetric complications as well as maternal and child deaths among disadvantage women. We aimed to determine the interaction effects of women's disadvantage characteristics on CS use in Bangladesh. For this we have analysed a total of 27,093 women's data extracted from five rounds of Bangladesh Demographic and Health Survey conducted during 2004 and 2017/18. The outcome variable was CS use, coded as use (1) and non-use (0). The major exposure variables were individual level, household level, and community level characteristics. Multilevel logistic regression model was used to determine association of CS use with socio-demographic characteristics and the interactions of three variables: working status, wealth quintile, and place of residence. We found a 751% increase of CS use over the last 13 years-from 3.88% in 2004 to 33% in 2017/18. Nearly, 80% of the total CS operation occurred in the private health facilities followed by the government health facilities (15%). Women living in rural areas with no engagement in formal income generating activities showed a 11% (OR, 0.89, 95% CI, 0.71-0.99) lower use of CS in 2004. This association was further strengthened over time, and a 51% (OR, 0.49, 0.03-0.65) lower in CS use was reported in 2017/18. Similarly, around 12%-83% lower likelihoods of CS use were found among rural poor and poorer women. These indicate Bangladesh is facing a double burden of CS use, that is a group of women with improved socio-economic condition are using this life saving procedure without medical necessity while their counterpart of disadvantage characteristics could not access the service. Improved monitoring from the government along with support to use CS services for the disadvantage groups on necessity are important.
  8. Duong M, Rangarajan S, Zaman M, Nasir NM, Seron P, Yeates K, et al.
    PLOS Glob Public Health, 2022;2(2):e0000141.
    PMID: 36962310 DOI: 10.1371/journal.pgph.0000141
    INTRODUCTION: Portable spirometers are commonly used in longitudinal epidemiological studies to measure and track the forced expiratory volume in first second (FEV1) and forced vital capacity (FVC). During the course of the study, it may be necessary to replace spirometers with a different model. This raise questions regarding the comparability of measurements from different devices. We examined the correlation, mean differences and agreement between two different spirometers, across diverse populations and different participant characteristics.

    METHODS: From June 2015 to Jan 2018, a total of 4,603 adults were enrolled from 628 communities in 18 countries and 7 regions of the world. Each participant performed concurrent measurements from the MicroGP and EasyOne spirometer. Measurements were compared by the intra-class correlation coefficient (ICC) and Bland-Altman method.

    RESULTS: Approximately 65% of the participants achieved clinically acceptable quality measurements. Overall correlations between paired FEV1 (ICC 0.88 [95% CI 0.87, 0.88]) and FVC (ICC 0.84 [0.83, 0.85]) were high. Mean differences between paired FEV1 (-0.038 L [-0.053, -0.023]) and FVC (0.033 L [0.012, 0.054]) were small. The 95% limits of agreement were wide but unbiased (FEV1 984, -1060; FVC 1460, -1394). Similar findings were observed across regions. The source of variation between spirometers was mainly at the participant level. Older age, higher body mass index, tobacco smoking and known COPD/asthma did not adversely impact on the inter-device variability. Furthermore, there were small and acceptable mean differences between paired FEV1 and FVC z-scores using the Global Lung Initiative normative values, suggesting minimal impact on lung function interpretation.

    CONCLUSIONS: In this multicenter, diverse community-based cohort study, measurements from two portable spirometers provided good correlation, small and unbiased differences between measurements. These data support their interchangeable use across diverse populations to provide accurate trends in serial lung function measurements in epidemiological studies.

  9. Akel KB, Noppert GA, Rajamoorthy Y, Lu Y, Singh A, Harapan H, et al.
    PLOS Glob Public Health, 2022;2(7):e0000734.
    PMID: 36962371 DOI: 10.1371/journal.pgph.0000734
    The COVID-19 pandemic presents an opportunity to assess the relationship between personal experiences and vaccine decision-making. The aim of this study was to examine the associations between experiences with COVID-19 and COVID-19 vaccination status. We administered 28 repeated cross-sectional, online surveys between June 2020 and June 2021 in the US and Asia. The main exposure was media showing COVID-19 cases, and we distinguished those with no such experience, those seeing a not severe case of disease, and those seeing a severe case of disease. Logistic regression models estimated the association between experience and acceptance of a hypothetical COVID-19 vaccine (pre-rollout) or actual vaccination (post-rollout). We explored perceived susceptibility as a potential mediator. Intent to vaccinate was lowest in the US and Taiwan, and highest in India, Indonesia, and China. Across all countries, seeing a severe case of COVID-19 in the media was associated with 1.72 times higher odds of vaccination intent in 2020 (95% CI: 1.46, 2.02) and 2.13 times higher odds of vaccination in 2021 (95% CI: 1.70, 2.67), compared to those not seeing a case or a less severe case. Perceived susceptibility was estimated to mediate 25% of the relationship with hypothetical vaccination (95% CI: 18%, 31%, P<0.0001), and 16% of the relationship with actual vaccination 16% (95% CI: 12%, 19%, P<0.0001). Seriousness of experiences could relate to intention to vaccinate against COVID-19. Media exposures are a modifiable experience, and this study highlights how this experience can relate to risk perceptions and eventual vaccination, across a variety of countries where the course of the pandemic differed.
  10. Brackstone K, Marzo RR, Bahari R, Head MG, Patalinghug ME, Su TT
    PLOS Glob Public Health, 2022;2(10):e0000742.
    PMID: 36962550 DOI: 10.1371/journal.pgph.0000742
    With the emergence of the highly transmissible Omicron variant, large-scale vaccination coverage is crucial to the national and global pandemic response, especially in populous Southeast Asian countries such as the Philippines and Malaysia where new information is often received digitally. The main aims of this research were to determine levels of hesitancy and confidence in COVID-19 vaccines among general adults in the Philippines and Malaysia, and to identify individual, behavioural, or environmental predictors significantly associated with these outcomes. Data from an internet-based cross-sectional survey of 2558 participants from the Philippines (N = 1002) and Malaysia (N = 1556) were analysed. Results showed that Filipino (56.6%) participants exhibited higher COVID-19 hesitancy than Malaysians (22.9%; p < 0.001). However, there were no significant differences in ratings of confidence between Filipino (45.9%) and Malaysian (49.2%) participants (p = 0.105). Predictors associated with vaccine hesitancy among Filipino participants included women (OR, 1.50, 95% CI, 1.03-1.83; p = 0.030) and rural dwellers (OR, 1.44, 95% CI, 1.07-1.94; p = 0.016). Among Malaysian participants, vaccine hesitancy was associated with women (OR, 1.50, 95% CI, 1.14-1.99; p = 0.004), social media use (OR, 11.76, 95% CI, 5.71-24.19; p < 0.001), and online information-seeking behaviours (OR, 2.48, 95% CI, 1.72-3.58; p < 0.001). Predictors associated with vaccine confidence among Filipino participants included subjective social status (OR, 1.13, 95% CI, 1.54-1.22; p < 0.001), whereas vaccine confidence among Malaysian participants was associated with higher education (OR, 1.30, 95% CI, 1.03-1.66; p < 0.028) and negatively associated with rural dwellers (OR, 0.64, 95% CI, 0.47-0.87; p = 0.005) and online information-seeking behaviours (OR, 0.42, 95% CI, 0.31-0.57; p < 0.001). Efforts should focus on creating effective interventions to decrease vaccination hesitancy, increase confidence, and bolster the uptake of COVID-19 vaccination, particularly in light of the Dengvaxia crisis in the Philippines.
  11. Tun S, Balasingam V, Singh DS
    PLOS Glob Public Health, 2022;2(8):e0000469.
    PMID: 36962722 DOI: 10.1371/journal.pgph.0000469
    The Drug Dependency Treatment and Research Unit (DDTRU) in Myanmar established opioid substitution with methadone in 2006. Reducing HIV transmission could be affected by eliminating the unsafe needle sharing among injecting drug uses and treatment with opioid substitution. The quality of life (QOL) among the clients retained in the methadone program is important for their personal development and is an indication of the treatment efficacy. This study evaluated factors associated with the QOL of methadone patients to ensure efficient service delivery. It also identified how patients' characteristics had differed QOL scores of respondents. This cross-sectional study was conducted in five cities with stratified random sampling. The study assessed the QOL of methadone patients in Myanmar. The study recruited 210 respondents to answer structured questionnaires for their quality of life: WHOQOL-BREF questionnaires and urine sample collection for methadone and illicit drug use. Survey responses on the QOL were transformed into 100-scale ratings, and higher QOL scores reflect better QOL. The average score of total QOL was 60.82%; precisely 60.09% in the physical domain, 63.11% in the psychological domain, 59.87% in the social relation domain, 60.41% in the environmental domain respectively. Respondents who reported illicit drug use had lower QOL scores. Statistically significant association of the QOL category of the methadone patients was identified with frequent methadone treatment episodes, the infection status of HIV, current treatment on antiretroviral therapy (ART), tuberculosis (TB) treatment history, sexually transmitted infections (STI) history in their lifetime, current work status as peer, Addiction Severity Index (ASI) for drug use, satisfaction with current marital status, satisfaction with current leisure status, history of psychological abuse within 30 days, heroin injection within 30 days, frequency of injection, and reported use of barbiturates (p<0.05). Addressing these factors will improve the treatment service intervention and the quality of life among methadone patients.
  12. Rahim S, Sharif MM, Amin MR, Rahman MT, Karim MM
    PLOS Glob Public Health, 2022;2(12):e0000834.
    PMID: 36962767 DOI: 10.1371/journal.pgph.0000834
    Diagnosis of visceral leishmaniasis (VL) through the detection of its causative agents namely Leishmania donovani and L. infantum is traditionally based on immunochromatographic tests, microscopy of bone marrow, spleen aspirates, liver or lymph node and differential diagnosis. While the first process has low specificity, the later one carries the risk of fatal hemorrhage. Over the last decade, multiple Polymerase Chain Reaction (PCR) based diagnosis has been developed using blood and urine sample with a varying degree of sensitivity and specificity, an issue worth improving for precision diagnosis. Earlier, we reported a PCR-based diagnosis of L. donovani in peripheral blood using a novel set of PCR primers with absolute specificity. Using the same set of primers and PCR conditions, here we describe diagnosis of L. donovani from urine, for a non-invasive, rapid and safe diagnosis. Diagnosis of VL was carried out using urine samples collected from clinically diagnosed VL patients (n = 23) of Bangladesh in Real Time PCR. Test results were validated by comparing blood samples from the same set of patients. Sensitivity and specificity of this diagnosis was analyzed using retrospective bone marrow samples, collected earlier from confirmed VL patients (n = 19). The method showed 100% sensitivity in detecting L. donovani in urine and corresponding blood and retrospective bone marrow samples, as well as 100% specificity in control groups. A Real Time PCR-based molecular detection system using urine sample is hereafter presented what could be a, non-invasive approach for VL detection with precision and perfection.
  13. Martinez S, Sullivan A, Hagan E, Goley J, Epstein JH, Olival KJ, et al.
    Glob Health Sci Pract, 2022 Dec 21;10(6).
    PMID: 36951282 DOI: 10.9745/GHSP-D-22-00106
    As part of a public health behavior change and communication strategy related to the identification of a novel ebolavirus in bats in Sierra Leone in 2016, a consortium of experts launched an effort to create a widely accessible resource for community awareness and education on reducing disease risk. The resulting picture book, Living Safely With Bats, includes technical content developed by a consortium of experts in public health, animal health, conservation, bats, and disease ecology from 30 countries. The book has now been adapted, translated, and used in more than 20 countries in Africa and Asia. We review the processes used to integrate feedback from local stakeholders and multidisciplinary experts. We also provide recommendations for One Health and other practitioners who choose to pursue the development and evaluation of this or similar zoonotic disease risk mitigation tools.
    MeSH terms: Africa; Animals; Chiroptera*; Humans; Sierra Leone; Ebolavirus*
  14. Muller S, Tilakaratne WM
    Head Neck Pathol, 2022 Mar;16(1):54-62.
    PMID: 35312982 DOI: 10.1007/s12105-021-01402-9
    The fifth chapter of the upcoming fifth edition of the 2022 World Health Organization Classification of Tumours of the Head and Neck titled Tumours of the oral cavity and mobile tongue, has had some modifications from the 2017 fourth edition. A new section "Non-neoplastic Lesions", introduces two new entries: necrotizing sialometaplasia and melanoacanthoma. The combined Oral potentially malignant disorders and Oral epithelial dysplasia section in the 2015 WHO has now been separated and submucous fibrosis and HPV-associated dysplasia are also discussed in separate sections. Carcinoma cuniculatum and verrucous carcinoma are described in dedicated sections, reflecting that the oral cavity is the most common location in the head and neck for both these entities which have distinct clinical and histologic features from conventional squamous cell carcinoma. This review summarizes the changes in Chapter 5 with special reference to new additions, deletions, and sections that reflect current clinical, histological, and molecular advances.
    MeSH terms: Humans; Mouth Neoplasms/classification*; Mouth Neoplasms/pathology; Oral Submucous Fibrosis/classification; Oral Submucous Fibrosis/pathology; Sialometaplasia, Necrotizing/classification; Sialometaplasia, Necrotizing/pathology; Tongue/pathology; Tongue Neoplasms/classification; World Health Organization; Carcinoma, Verrucous/classification; Carcinoma, Verrucous/pathology; Acanthoma/classification; Acanthoma/pathology
  15. Devereaux PJ, Marcucci M, Painter TW, Conen D, Lomivorotov V, Sessler DI, et al.
    N Engl J Med, 2022 May 26;386(21):1986-1997.
    PMID: 35363452 DOI: 10.1056/NEJMoa2201171
    BACKGROUND: Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding.

    METHODS: We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025.

    RESULTS: A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, -2.6 percentage points; 95% CI, -3.8 to -1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, -1.1 to 1.7; one-sided P = 0.04 for noninferiority).

    CONCLUSIONS: Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.).

    MeSH terms: Canada; Hemorrhage/etiology; Hemorrhage/prevention & control; Humans; Surgical Procedures, Operative; Thrombosis/chemically induced; Thrombosis/drug therapy
  16. Ramli FF, Cowen PJ, Godlewska BR
    Pharmaceuticals (Basel), 2022 Apr 16;15(4).
    PMID: 35455482 DOI: 10.3390/ph15040485
    Ebselen is an organoselenium compound developed as an antioxidant and subsequently shown to be a glutathione peroxidase (GPx) mimetic. Ebselen shows some efficacy in post-stroke neuroprotection and is currently in trial for the treatment and prevention of hearing loss, Meniere's Disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro screening studies show that ebselen is also an effective inhibitor of the enzyme inositol monophosphatase (IMPase), which is a key target of the mood-stabilising drug lithium. Further, in animal experimental studies, ebselen produces effects on the serotonin system very similar to those of lithium and also decreases behavioural impulsivity. The antidepressant effects of lithium in treatment-resistant depression (TRD) have been attributed to its ability to facilitate presynaptic serotonin activity; this suggests that ebselen might also have a therapeutic role in this condition. Human studies utilising magnetic resonance spectroscopy support the notion that ebselen, at therapeutic doses, inhibits IMPase in the human brain. Moreover, neuropsychological studies support an antidepressant profile for ebselen based on positive effects on emotional processing and reward seeking. Ebselen also lowers a human laboratory measure of impulsivity, a property that has been associated with lithium's anti-suicidal effects in patients with mood disorders. Current clinical studies are directed towards assessment of the neuropsychological effects of ebselen in TRD patients. It will also be important to ascertain whether ebselen is able to lower impulsivity and suicidal behaviour in clinical populations. The objective of this review is to summarise the developmental history, pre-clinical and clinical psychopharmacological properties of ebselen in psychiatric disorders and its potential application as a treatment for TRD.
  17. Oresegun DR, Thorpe P, Benavente ED, Campino S, Muh F, Moon RW, et al.
    Front Genet, 2022;13:855052.
    PMID: 35677565 DOI: 10.3389/fgene.2022.855052
    Plasmodium knowlesi, a malaria parasite of Old World macaque monkeys, is used extensively to model Plasmodium biology. Recently, P. knowlesi was found in the human population of Southeast Asia, particularly Malaysia. P. knowlesi causes uncomplicated to severe and fatal malaria in the human host with features in common with the more prevalent and virulent malaria caused by Plasmodium falciparum. As such, P. knowlesi presents a unique opportunity to develop experimental translational model systems for malaria pathophysiology informed by clinical data from same-species human infections. Experimental lines of P. knowlesi represent well-characterized genetically stable parasites, and to maximize their utility as a backdrop for understanding malaria pathophysiology, genetically diverse contemporary clinical isolates, essentially wild-type, require comparable characterization. The Oxford Nanopore PCR-free long-read sequencing platform was used to sequence and de novo assemble P. knowlesi genomes from frozen clinical samples. The sequencing platform and assembly pipelines were designed to facilitate capturing data and describing, for the first time, P. knowlesi schizont-infected cell agglutination (SICA) var and Knowlesi-Interspersed Repeats (kir) multiple gene families in parasites acquired from nature. The SICAvar gene family members code for antigenically variant proteins analogous to the virulence-associated P. falciparum erythrocyte membrane protein (PfEMP1) multiple var gene family. Evidence presented here suggests that the SICAvar family members have arisen through a process of gene duplication, selection pressure, and variation. Highly evolving genes including PfEMP1family members tend to be restricted to relatively unstable sub-telomeric regions that drive change with core genes protected in genetically stable intrachromosomal locations. The comparable SICAvar and kir gene family members are counter-intuitively located across chromosomes. Here, we demonstrate that, in contrast to conserved core genes, SICAvar and kir genes occupy otherwise gene-sparse chromosomal locations that accommodate rapid evolution and change. The novel methods presented here offer the malaria research community not only new tools to generate comprehensive genome sequence data from small clinical samples but also new insight into the complexity of clinically important real-world parasites.
  18. Papot E, Jacoby S, Arlinda D, Avihingsanon A, Azwa I, Borok M, et al.
    HIV Res Clin Pract, 2022 Jul 19;23(1):37-46.
    PMID: 35938597
    A rapidly changing landscape of antiretrovirals and their procurement at scale has permitted the evaluation of new optimised second-line antiretroviral therapy (ART) in low- and middle-income countries. D2EFT is an open-label randomised controlled non-inferiority phase IIIB/IV trial in people living with HIV-1 (PWH) whose first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART is failing. At inception, it compared a standard of care of boosted darunavir with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) to the novel NRTI-sparing regimen of boosted darunavir with dolutegravir. Implemented in 2017, participating sites were across Africa, Asia and Latin America. Around the time of implementation, the World Health Organization updated its treatment guidelines and recommended scaling up tenofovir disoproxil fumarate-lamivudine-dolutegravir (TLD). This situation pushed D2EFT investigators to consider the impact of the roll-out of TLD on the D2EFT research question. The protocol team agreed it was important to study TLD in second-line when an NNRTI regimen was failing, and focused on options to expedite the work by studying the question within the existing trial and network. All key issues (statistical, programmatic and financial) were reviewed to assess the benefits and risks of adding a third arm to the ongoing study, as opposed to developing a new randomised clinical trial with the same control arm and within the same network. The development of a new trial was deemed to be longer than adding a third arm, and to create a challenging situation with two competing clinical trials at the same sites which would slow down recruitment and impair both trials. On the other hand, adding a third arm would be demanding in terms of operationalisation, increased sample size and statistical biases to control. The optimal strategy was deemed to be the addition of a third arm, arriving retrospectively at a simplified multi-arm multi-stage clinical trial design to achieve statistical validity. The D2EFT study maintains additional value in a quickly evolving second-line ART strategy allowed by the progress in global access to ART.
    MeSH terms: Darunavir/therapeutic use; Drug Therapy, Combination; Humans; Retrospective Studies; Reverse Transcriptase Inhibitors/therapeutic use; Viral Load
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