Novel therapeutic targets for preserving a healthy endothelium: Strategies for reducing the risk of vascular and cardiovascular disease

The endothelium lies in a strategic anatomical position between the circulating blood and the vascular smooth-muscle cells. It is a source of vasodilators such as nitric oxide, prostacyclin, and hyperpolarizing factor as well as heparin-like substances and other molecules with antiproliferative properties. These effects of endothelial cells may explain why platelets and monocytes usually do not adhere at the blood vessel wall. However, under pathological conditions, endothelial dysfunction occurs and significantly contributes to the increase of platelet- -vessel wall interaction, vasoconstriction, pro-inflammation, and proliferation. Under these conditions, endothelium-dependent vasodilation is reduced, and endothelium-dependent constrictor responses are augmented. Upon vessel wall injury, the platelets rapidly adhere to the exposed sub-endothelial matrix, which is mediated by several cellular receptors present on platelets or endothelial cells and various adhesive proteins. Subsequent platelet activation results in the recruitment of additional platelets and the generation of platelet aggregates, so forming a stable platelet plug. Therapeutic strategies aimed at improving or preserving endothelial function therefore may be promising in terms of preventing and treating coronary artery disease. Diagnostic modalities for assessing endothelial function should allow for the early detection of vascular endothelial dysfunction before the manifestation of serious adverse vascular disorders. (Cardiol J 2011; 18, 4: 352–363

Molecular characterization of pathogenic Leptospira sp. in small mammals captured from the human leptospirosis suspected areas of Selangor state, Malaysia

Leptospirosis is caused by the spirochetal bacterium Leptospira of which rodents are considered the most important reservoir. This study aims to determine and characterize virulent Leptospira species among rodents and small mammals found in human settlements and recreational spots within the Hulu Langat and Gombak districts of Selangor, Malaysia; regions that frequently report probable human leptospirosis cases. Molecular analysis revealed an overall Leptospira detection rate of 14.3% among the 266 small mammals captured, and the human settlements were found to have the highest number of isolates (15.1%), followed by recreational sites (14.5%). The molecular characterization conducted based on the lipL32, secY genes and MLST revealed that the strains belonged to four different species, including; Leptospira interrogans (29; 76.3%; ST50, ST238, ST243), L. kirschneri (5; 13.15%; ST110), L. borgpetersenii (3; 8%; ST143) and L. weilii (1; 2.63%; ST242). The study revealed genotypes of circulating strains among small mammals in Malaysia, which include Leptospira locus ST110 L. kirschneri, ST 50 L. interrogans, ST143 L. borgpetersenii and ST242 L. weilii. Among the small mammals studied, 17/105 (16.2%) Rattus norvegicus, 7/59 (11.9%) of Rattus rattus, 5/24 (20.8%) of Maxomys whiteheadi, 4/18 (22.2%) of Sundamys muelleri, 2/22 (9%), Tupaia gliss, 2/16 (12.5%) Rattus tiomanicus and 1/4 (25%) of Suncus murinus carried pathogenic leptospires. The data from the present study may imply that, in addition to rodents, other small mammals also serve as maintenance hosts for Leptospira. Hence, much remains unknown about Leptospira maintenance hosts, and there is need for further investigation to ascertain the prevailing serovars of pathogenic Leptospira in Malaysia. This will assist in the development of efficient diagnostic assays with improved microscopic agglutination test (MAT) panels, and in the implementation of suitable prevention and control measures

Diagnostic accuracy of rapid diagnostic tests for the early detection of leptospirosis

Background: Leptospirosis is often misdiagnosed with several other tropical febrile illnesses in Malaysia due to similarities in clinical manifestations. Although treatment regimens could be started based on clinical judgments, early diagnosis has become paramount as a guide to chemotherapeutic interventions. Confirmed laboratory diagnosis through MAT or PCR is time consuming and usually available only in reference laboratories and not practical in healthcare settings. Rapid and easy to perform diagnostic tests are widely used in these settings as the point of care diagnosis. The present study was undertaken to compare the diagnostic performance of two IgM based immunodiagnostic assay kits for acute leptospirosis. Methods: A total of 50 serum samples were collected from patients clinically suspected for acute leptospirosis on admission in the Hospital Serdang, from June 2016 to June 2017. All the samples were subjected to MAT, lipL32 PCR and the two rapid tests (Leptocheck-WB and ImmuneMed Leptospira IgM Duo Rapid test). Results: Out of the 50 clinically suspected patients sampled, 19 were confirmed positive for leptospirosis. Six (12%) were confirmed by MAT and 13 (26%) by PCR. Similarly, of the 50 clinically suspected cases, 17 (34%) showed positivity for Leptocheck-WB and 7 (14%) for ImmuneMed Leptospira IgM Duo Rapid test. The overall sensitivity and specificity was 47.37% and 80.65% for Leptocheck-WB, and 21.05% and 90.32% for ImmuneMed Leptospira IgM Duo Rapid test. In another set of previously confirmed MAT positive samples (1:400-1:3600) obtained from a reference laboratory, Leptocheck-WB showed higher sensitivity (90.72%) than ImmuneMed Leptospira IgM Duo Rapid test (40.21%), and comparable specificity for ImmuneMed Leptospira IgM Duo Rapid test (88.89%) and Leptocheck-WB (82.86%). Conclusion: The sensitivity was higher for Leptocheck-WB and had a comparable specificity with ImmuneMed Leptospira IgM Duo Rapid test. Therefore, based on the present study, Leptocheck-WB is found to be a more sensitive rapid immunodiagnostic test for acute leptospirosis screening in hospital settings

An outbreak of leptospirosis among reserve military recruits, Hulu Perdik, Malaysia

Here, we investigated an outbreak of leptospirosis among reserve military recruits that occurred following a survival exercise in the Hulu Perdik forest within the Hulu Langat district, Kuala Lumpur, Malaysia. Blood samples from the 12 patients that presented symptoms for febrile illness on clinical examination were subjected to laboratory investigation, comprising Lepto IgM rapid test, IgM ELISA, and microscopic agglutination test (MAT). All these patients were interviewed for possible risk factors for leptospirosis. Rodent trapping and environmental sampling for possible isolation of leptospires in the outbreak site was performed. The isolated leptospires were genetically characterized and investigated for the potential epidemiological link with human leptospirosis. Among the 12 patients, two (2/12; 16.6%) were confirmed positive for leptospirosis by microscopic agglutination test (MAT with titers 400-800; serovar autumnalis and hardjobovis). Two Leptospira species from rodents (L. interrogans and L. borgpetersenii) and two from the environment (L. kmetyi and L. wolffii) were identified. The possible epidemiological link between human serovars and animal Leptospira species indicates rodents as the potential reservoir while the environment (soil and water) serves as a transmission route. This investigation highlights the robust presence of pathogenic leptospires on Malaysian environment and rodents which may present the risk of infection, especially among high-risk individuals. Hence, occupational risk individuals are cautioned to observe appropriate preventive measures including prophylaxis and seek immediate medical attention for any illness following similar activities

Vitamin D as an Adjunctive Therapy in Asthma. Part 1: A Review of Potential Mechanisms

Vitamin D deficiency (VDD) is highly prevalent worldwide. The classical role for vitamin D is to regulate calcium absorption form the gastrointestinal tract and influence bone health. Recently vitamin D receptors and vitamin D metabolic enzymes have been discovered in numerous sites systemically supporting diverse extra-skeletal roles of vitamin D, for example in asthmatic disease. Further, VDD and asthma share several common risk factors including high latitude, winter season, industrialization, poor diet, obesity, and dark skin pigmentation. Vitamin D has been demonstrated to possess potent immunomodulatory effects, including effects on T cells and B cells as well as increasing production of antimicrobial peptides (e.g. cathelicidin). This immunomodulation may lead to asthma specific clinical benefits in terms of decreased bacterial/viral infections, altered airway smooth muscle-remodeling and efunction as well as modulation of response to standard anti-asthma therapy (e.g. glucocorticoids and immunotherapy). Thus, vitamin D and its deficiency have a number of biological effects that are potentially important in altering the course of disease pathogenesis and severity in asthma. The purpose of this first of a two-part review is to review potential mechanisms whereby altering vitamin D status may influence asthmatic disease

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Perbandingan antara rehabilitasi pulmonari di rumah dengan di hospital bagi pesakit COPD dalam memperbaiki status fungsi paru-paru

Kajian ini bertujuan untuk mengenalpasti keberkesanan program rehabilitasi pulmonari di hospital berbanding dengan program rehabilitasi pulmonari di rumah dalam mempe rbai k i k eadaan pe sak i t be rpenyak i t peny empi tan pulmonari kronik (COPD) Hospital Universiti Kebangsaan Malaysia. Seramai 35 orang pesakit berumur antara 17 hingga 78 tahun telah dirawak sama ada untuk rehabilitasi pulmonari di hospital (48.6%, n = 20) atau di rumah (43%, n = 15) oleh Ahli Fisioterapi. Untuk program rehabilitasi di hospital, pesakit dijadualkan hadir ke hospital dua kali seminggu selama lapan minggu. Untuk program rehabilitasi di rumah, pesakit dijadualkan hadir ke Jabatan Fisioterapi sebanyak dua kali untuk mempelajari senaman yang perlu dilakukan sebelum mereka dibenarkan melakukan senaman sendiri di rumah. Sebuah diari diberikan kepada setiap pesakit untuk merekodkan senaman yang dilakukan. Panggilan telefon dibuat sekali setiap dua minggu untuk tujuan pemantauan. Penilaian fungsi paru-paru, ujian enam minit berjalan kaki (6MWT) dan skor Borg dilakukan sebelum dan sesudah lapan minggu rehabilitasi dijalankan. Keputusan menunjukkan tiada perubahan bererti dalam fungsi paru-paru untuk kedua-dua kumpulan sebelum dan selepas rehabilitasi.Terdapat perbezaan bererti (p < 0.05) dalam 6MWT sebelum dan selepas rehabilitasi bagi pesakit yang mengikuti program rehabilitasi pulmonari di hospital. Sebaliknya, perbezaan adalah tidak bererti (p > 0.05) bagi pesakit yang mengikuti rehabilitasi pulmonari di rumah. Keputusan juga menunjukkan bahawa tidak terdapat korelasi bererti antara fungsi paruparu dengan 6MWT walaupun terdapat peningkatan dalam jarak perjalanan di peringkat garis pangkal atau minggu ke lapan. Sebagai kesimpulan, program rehabilitasi pulmonari di hospital didapati lebih berkesan daripada program rehabilitasi pulmonari di rumah dalam meningkatkan kelasakan senaman yang mana akan dapat membantu megurangkan dispnea di kalangan pesakit COPD

Player's Affective States as Meta AI Design on Augmented Reality Games

Games are considered one of the most popular entertainment forms worldwide. The interaction in the game environment makes the players addicted to playing the game. One technique to build an addicting game is utilizing the player's emotions using Meta Artificial Intelligence (AI). The player's emotions can be utilized by adjusting the game difficulty. Most of the game offers static and steady difficulty development throughout the game. This research proposes a Meta AI game design using the player's affective states. We argue that a dynamic difficulty development throughout the game will increase the player's game experiences. The player's facial expressions are utilized to extract the player's affective state information. To recognize the player's facial expressions, a Facial Expressions Recognition (FER) model was trained using VGG-16 architecture and The Indonesian Mixed Emotion Dataset (IMED) dataset in addition to a self-collected dataset. The emotions recognition model (from player's facial expressions) achieved the best validation accuracy of 99.98%. The model was implemented in the proposed Meta AI game design. The Meta AI game design proposed in this game was implemented in several game scenarios to be compared and evaluated. The proposed Meta AI game design was evaluated by 31 respondents using Game Experiences Questionnaire (GEQ). Overall, the results show that the game with Meta AI and Augmented Reality implemented significantly improved the Game Experiences Questionnaire (GEQ) score and the player's overall satisfaction compared to the other game scenarios