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This case-series aims to report three cases of endogenous endophthalmitis due to invasive Klebsiella pneumoniae syndrome. Case 1 A 34-year-old lady who was admitted for pneumonia developed painful blurring of vision and redness in the right eye (RE) for one week. An examination of the RE revealed visual acuity (VA) of light perception (PL) with positive relative afferent pupillary defect (RAPD), proptosis, and restriction of extraocular movement with hypopyon. The patient was treated for RE panophthalmitis with a lung abscess and was started on systemic and topical antibiotics. The vitreous tap culture grew Klebsiella pneumoniae. Despite treatment, the patient's condition deteriorated, and evisceration was undertaken. Case 2 A 38-year-old lady presented with a sudden painful RE associated with blurred vision and redness for two days, and fever for one week. RE VA was hand movement with a positive RAPD and anterior chamber cells of 2+. A B-scan revealed a dome-shaped subretinal mass with exudative retinal detachment. The patient was treated for RE panophthalmitis complicated by a basal ganglia abscess. The urine and vitreous tap cultures grew Klebsiella pneumoniae. She responded to high-dose intravenous and intravitreal antibiotics. Unfortunately, her RE became phthisical. Case 3 A 70-year-old lady presented with painless blurring of vision over the RE. The blood and urine cultures grew Klebsiella pneumoniae. RE VA was PL, and she was treated for endogenous endophthalmitis. The vitreous culture grew Klebsiella pneumoniae. Unfortunately, the RE became phthisical. In conclusion, endophthalmitis due to Klebsiella pneumoniae is invasive and carries a poor prognosis if prompt treatment is not rendered.

Background Heart failure (HF) trials have stringent inclusion and exclusion criteria, but limited data exist regarding generalizability of trials. We compared patient characteristics and outcomes between patients with HF and reduced ejection fraction (HFrEF) in trials and observational registries. Methods and Results Individual patient data for 16 922 patients from five randomized clinical trials and 46 914 patients from two HF registries were included. The registry patients were categorized into trial-eligible and non-eligible groups using the most commonly used inclusion and exclusion criteria. A total of 26 104 (56%) registry patients fulfilled the eligibility criteria. Unadjusted all-cause mortality rates at 1 year were lowest in the trial population (7%), followed by trial-eligible patients (12%) and trial-non-eligible registry patients (26%). After adjustment for age and sex, all-cause mortality rates were similar between trial participants and trial-eligible registry patients [standardized mortality ratio (SMR) 0.97; 95% confidence interval (CI) 0.92–1.03] but cardiovascular mortality was higher in trial participants (SMR 1.19; 1.12–1.27). After full case-mix adjustment, the SMR for cardiovascular mortality remained higher in the trials at 1.28 (1.20–1.37) compared to RCT-eligible registry patients. Conclusion In contemporary HF registries, over half of HFrEF patients would have been eligible for trial enrolment. Crude clinical event rates were lower in the trials, but, after adjustment for case-mix, trial participants had similar rates of survival as registries. Despite this, they had about 30% higher cardiovascular mortality rates. Age and sex were the main drivers of differences in clinical outcomes between HF trials and observational HF registries.

Introduction: Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with a high mortality rate, though outcomes of the different lung compliance phenotypes are unclear. We aimed to measure lung compliance and examine other factors associated with mortality in COVID-19 patients with ARDS. Methods: Adult patients with COVID-19 ARDS who required invasive mechanical ventilation at 8 hospitals in Singapore were prospectively enrolled. Factors associated with both mortality and differences between high (

Since the introduction of polymer banknotes, they have become a new tool for corneal foreign body (CFB) self-removal. Being easily available, lightweight, and sturdy, polymer papers have become a popular and innovative method to dislodge CFB. Although ophthalmology services are easily accessible in Malaysia, ignorance, lack of health awareness, and the desire to avoid medical costs are among the reasons why patients remove CFB themselves. The sequalae span from only a faint scar with relatively good vision to total blindness. Our case series highlights three cases of CFB self-removal using polymer banknotes and their sequalae. To echo what has been known previously, self-awareness and occupational hazard education remain the most important and effective way to prevent vision loss.

Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, the function of BRN2 during the metastatic process of melanoma remains largely unknown. We therefore investigated the effect of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole-genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2-expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2-expressing cells under non-adherent conditions to death by anoikis. Alternative inhibitors of c-MET showed similar results. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2-expressing cells resistant to therapy and cell death by anoikis.

Background Information on the extent of high-risk prescribing for nonsteroidal anti-inflammatory drugs (NSAIDs) across developing countries is scarce. Objectives This study examines the prescribing pattern for NSAIDs in primary care, assesses the extent of high-risk NSAIDs prescribing and identifies associated factors. Setting 129 public and 416 private primary care clinics in Malaysia. Methods Data were derived from the National Medical Care Survey 2014, a cross-sectional survey on primary care morbidity patterns and clinical activities in Malaysia. Types of NSAIDs, indications for NSAIDs use and proportion of high-risk NSAIDs prescribing were assessed. Factors associated with high-risk NSAIDs prescribing were identified with a multivariable logistic regression. Weighted results, adjusted for sampling design and non-response were presented. Main outcome measures Prescribing pattern of NSAIDs, proportion of high-risk NSAIDs prescribing and its associated factors. Results Among the 55,489 patients who received NSAIDs, diclofenac was the most frequently prescribed NSAID (40.5%, 95% CI 40.1-40.9%), followed by mefenamic acid (29.2%, 95% CI 28.8-29.6%). The commonest indications for NSAIDs use were musculoskeletal condition and respiratory tract infection, both at 17.8% (95% CI 17.4-18.1%). A total of 22.9% (95% CI 22.6-23.3%) patients received high-risk NSAID prescriptions. Of these, 47.8% (95% CI 46.9-48.7%) did not receive adequate gastroprotection despite being at risk, 24.8% (95% CI 24.0-25.5%) were prescribed NSAIDs despite having cardiovascular comorbidities and 22.4% (95% CI 21.7-23.2%) were prescribed high-dose NSAIDs. The odds of receiving high-risk NSAID prescriptions increased with the number of drugs prescribed (OR 1.23, 95% CI 1.06-1.43) and the number of diagnoses in one visit (OR 2.21, 95% CI 1.71-2.86). The odds of being prescribed high-risk NSAID prescriptions were lower in patients with secondary (OR 0.52, 95% CI 0.35-0.77) and tertiary education (OR 0.39, 95% CI 0.22-0.68) compared to patients without formal education. Patients' citizenship, indication for NSAID prescriptions and whether a medical certificate was issued were also significantly associated with the likelihood of receiving high-risk NSAID prescriptions. Conclusions A quarter of NSAIDs prescribed in Malaysian primary care setting is categorised as high-risk prescribing. Targeted strategies are necessary to improve patient safety.

Purpose: To investigate the prevalence of fundus and macular optical coherence tomography (OCT) findings, and the spectrum of dengue-related fundus presentation in a Malaysian tertiary hospital. The associations between platelet count and haematocrit level with fundus and macular OCT findings were also investigated. Design: Cross-sectional study. Methods: The study was conducted at Hospital Raja Permaisuri Bainun, Ipoh, from June to August 2015. Patients who consented to participate underwent a comprehensive ocular examination. Examination included a best-corrected distance (6 m) and near visual acuities, standard black-on-white Amsler chart testing, pupillary light reflex, fundus examination, followed by dilated fundus photographs and OCT of the macula. Results: A total of 134 patients were included in the study. The prevalence of positive fundus finding and macular OCT finding was 35% (95% confidence interval [CI]: 27%, 43%) and 13% (95% CI: 8%, 19%), respectively; 62 eyes of 47 patients had positive fundus findings, whereas 30 eyes of 18 patients had positive macular OCT findings. Scotoma (p < 0.001), near vision disturbance (p = 0.04), and abnormal Amsler findings (p < 0.001) were significantly associated with presence of macular OCT findings compared to absence of macular OCT findings. In the total of 268 eyes, the two most common fundus findings were vessel tortuosity (53 [20%]) and yellow subretinal dot (28 [10%]). Out of 30 eyes, diffuse retinal thickening was the most frequent OCT finding (22 [73%]), followed by 4 (13%) with foveolitis, 3 (10%) with cystoid macular oedema and 1 (3%) with submacular fluid. Platelet count and haematocrit were not associated with abnormal fundus or macular OCT manifestation in patients suffering from dengue fever. Conclusion: Our study revealed that the prevalence of clinical fundus and macular OCT findings among dengue inpatients was higher when compared to other countries, especially during dengue outbreaks. Furthermore, the spectrum of fundus and macular OCT findings in our population can be varied.

Background and objective Guidelines for chronic obstructive pulmonary disease (COPD) advocate regular influenza vaccination, which has been shown to reduce exacerbations. However, influenza vaccination rates remain low. This quality improvement project was initiated to help improve influenza vaccination rates in a tertiary hospital. Methods All patients with COPD in the airway program (TAP) in the National University Hospital at the end of 2013 were recruited. The interventions were implemented in 2014; thus, population was stratified into the pre-intervention group and post-intervention group. Those who died in 2014 were excluded. They were (1) patient education posters in the clinics on the need for regular influenza vaccination, (2) direct interventions by physicians, and (3) intervention by the nurses when vaccinations were neglected. Physicians were made aware of previous vaccination rates, vaccination card reminders were placed in the clinics, and a new electronic healthcare record system (EHR) was implemented. The patients were followed up till the end of 2015 or until death. When an influenza vaccination was administered, the patients were asked which of the interventions led to the vaccination. A questionnaire was delivered to the physicians to determine the interventions that led to any change in vaccination prescription practices. Results The pre-intervention influenza vaccination rate was low at 47.7%. The post-intervention influenza vaccination rate improved to 80.7% with the multi-pronged approach. Physicians initiated the majority of vaccinations (87.9%), while nurses helped intervene in a further 12.1%. Physicians' vaccination prescription practices changed as a result of self-awareness of low vaccination rates, vaccination card reminders, and the new EHR. Patient education made minimal impact. Conclusion This project demonstrates that with regular audits to track progress and several easy-to-implement interventions, improving influenza vaccination rates is an achievable goal.

The prevalence of house dust mites (HDM)-sensitization is high in allergic asthma (AA), especially in tropical/subtropical countries in Asia and South America. As HDM-sensitization can contribute to the subsequent development of HDM-driven asthma, poor asthma control and exacerbations, allergen immunotherapy (AIT) might reduce the growing global burden of allergic asthma. AIT builds immunotolerance via upregulation of T-regulatory (reg) cells, leading to increase secretion of IL-10 and TGF-β which suppress the Th2 response to allergens. IL-10 also induces the class-switch to plasma cells that produce IgG4 that competes with Ig E’s binding on mast cell. Encouragingly, 2 recent multicentre trials showed that HDM AIT could lead to improvements in clinically relevant health outcomes: reduction in asthma exacerbations and inhaled corticosteroid usage. The uptake of AIT remains low due to difficulties with long-term adherence and lack of robust cost-effectiveness studies. There is limited standardization of techniques to compare the efficacy between different AIT administration routes and formulation. In clinical practice, it is challenging to differentiate “asthma with HDM sensitization” from “HDM-driven asthma”. Additionally, Blomia tropicalis (Blo.t) play an important allergenic role especially in tropics, in addition to the Dermatophagoides species but is not found in many AIT formulations. It is uncertain if Blo.t sensitised patients will respond equally to these HDM AIT. We will summarise (a) global differences in HDM sensitization, (b) disease-modifying mechanisms behind HDM AIT (c) differences between the subcutaneous and sublingual route (d) therapeutic strategies in HDM-driven asthma to maximise cost-effectiveness.

A carotid-cavernous fistula (CCF) is an arteriovenous fistula with an abnormal connection between the carotid artery and cavernous sinus that can be sight and life-threatening. The conjunctival injection is often the most prominent feature, and patients are commonly misdiagnosed for other ocular conditions leading to a delay in diagnosis and treatment. All three patients in this case series presented with persistent red eyes. They were all treated for conjunctivitis and only referred for further workup when other progressing ocular symptoms occurred. The diagnosis of CCF was confirmed with digital subtraction angiography and with successful endovascular embolization, their ocular symptoms resolved with preserved optic nerve function. A high index of suspicion in patients presenting with an atypical red eye is very crucial for timely diagnosis of CCF.

Endogenous Klebsiella pneumoniae panophthalmitis commonly affects those with compromised immunity. The occurrence of this infection in healthy individuals is rare. We describe the case of a healthy adult who presented with endogenous Klebsiella pneumoniae panophthalmitis from an asymptomatic liver abscess. A 64-year-old, previously healthy gentleman presented with rapidly progressive left eye periorbital swelling and blurring of vision. He had a low-grade fever three days prior to the development of ocular symptoms, but otherwise no other systemic complaints. Visual acuity was light perception in the left eye, and ocular motility was restricted in all directions of gaze. Ocular examination revealed proptosis, severe conjunctival chemosis, hazy cornea, and fibrin deposition in the anterior chamber. The posterior segment could not be visualized. Ultrasound of the hepatobiliary system revealed an abscess in the right lobe of his liver. His blood cultures grew Klebsiella pneumoniae. Despite being treated with high-dose intravenous antibiotics, his eye condition deteriorated. Evisceration was performed when he developed scleral melting and globe perforation. We highlight the importance of a high index of suspicion of endogenous Klebsiella panophthalmitis as it can be easily missed in healthy adults. Early diagnosis and prompt management are needed to prevent morbidity and mortality from this devastating infection.

Infection with malaria parasites continues to be a major global public health issue. While current control measures have enabled a significant decrease in morbidity and mortality over the last 20 years, additional tools will be required if we are to progress toward malaria parasite eradication. Malaria vaccine research has focused on the development of subunit vaccines; however, more recently, interest in whole-parasite vaccines has reignited. Whole-parasite vaccines enable the presentation of a broad repertoire of antigens to the immune system, which limits the impact of antigenic polymorphism and genetic restriction of the immune response. We previously reported that whole-parasite vaccines can be prepared using chemically attenuated parasites within intact red blood cells or using killed parasites in liposomes, although liposomes were less immunogenic than attenuated parasites. If they could be frozen or freeze-dried and be made more immunogenic, liposomal vaccines would be ideal for vaccine deployment in areas where malaria is endemic. Here, we develop and evaluate a Plasmodium yoelii liposomal vaccine with enhanced immunogenicity and efficacy due to incorporation of TLR4 agonist, 3D(6-acyl) PHAD, and mannose to target the liposome to antigen-presenting cells. Following vaccination, mice were protected, and strong cellular immune responses were induced, characterized by parasite-specific splenocyte proliferation and a mixed Th1/Th2/Th17 cytokine response. Parasite-specific antibodies were induced, predominantly of the IgG1 subclass. CD4+ T cells and gamma interferon were critical components of the protective immune response. This study represents an important development toward evaluation of this whole-parasite blood-stage vaccine in a phase I clinical trial.

Background: he number of patients on warfarin therapy is rising steadily. Although warfarin is beneficial, it carries a high risk of bleeding, especially if the international normalized ratio (INR) values exceed 3.0. Currently, no warfarin initiation regimens have been developed for the Asian population, especially for Malaysians. Objective: This article describes the efficacy and safety of a new initiation regimen for warfarin among warfarin-naive patients. Method: Data were retrospectively collected from the ambulatory and inpatient settings. Results: A total of 165 patients who each had a target INR of 2.0 to 3.0 were included in the study. The mean age was 57.2 years and 94 patients were male. A total of 108 patients used Regimen 1 (5 mg/5 mg/3mg) and the rest of the patients used Regimen 2 (5 mg/3 mg/3 mg). Most patients used warfarin either for atrial fibrillation (52.1%) or for venous thromboembolism (29.7%). Overall, 88 of the patients had INR values above 50% from the baseline on Day 4. Additionally, 13 patients had INR values of >3.2, which required withholding and lower dose of warfarin. The predicted weekly maintenance warfarin dose (23 ± 0.5 mg/week) was found to have correlated closely with the actual maintenance dose (22.8 ± 0.5 mg/week; r2 = 0.75). Nearly two thirds (70.3%) of the patients achieved the target INR on Day 11. Conclusion: The warfarin initiation regimens in this study was simple, safe, and suitable to be used in both ambulatory and inpatient settings for managing warfarin therapy.

Purpose To describe the epidemiology of open globe injuries and its prognostic factors from the perspectives of a tertiary care centre in northern Malaysia. Methods A retrospective study of open globe injuries in a period of three years between June 2017 and May 2020. Patients presenting with open globe injuries were identified and recruited from hospital census. Case records were retrieved and analysed after recruitment. Results A total of 114 patients with 118 open globe injuries were included in the study. Four patients had bilateral eye involvement. Men were found to have seven and a half times higher rate of ocular injuries than women. The predominant age group of ocular trauma presentation was in younger adults between the age of 21 and 30 years old. Work-related injuries account for almost half of the globe injuries (48.7%) followed by motor vehicle accident-related, domestic accident-related, and others. The significant factors related to the visual outcome are presenting visual acuity (VA), presence of relative afferent pupillary defect (RAPD) and vitreous loss. Conclusion The factors related to visual outcomes in this study may aid the clinician in determining the visual prognosis of ocular injuries. Young working males were the most susceptible group to sustain penetrating ocular injuries due to their job nature. Health education and safety at workplace are essential to reduce the occurrence of ocular injuries.

Background: A diagnosis of ankylosing spondylitis (AS) is challenging and often delayed despitebpatients being symptomatic. Low back pain is the most common initial symptom, appearing in the second and third decades of life. Acute anterior uveitis (AAU) occurs much later in the course of the disease, often when the destruction of the spine is already debilitating. Objective: Here, we report three cases of AS that were diagnosed after the patients developed AAU. Methods: A case series illustrated AAU leading to the diagnosis of AS years after the initial episode of low back pain. A comparison of the clinical presentation, diagnosis, and outcomes was also illustrated. Result: We report three cases of acute anterior uveitis (AAU)-associated AS diagnosed only after many visits to the primary health care provider with the complaint of chronic low back pain. All three patients had irreversible radiological changes upon diagnosis of AS. The AAU resolved with topical steroids, and one patient developed cataract. Conclusion: A high index of suspicion of AS in a young adult with chronic back pain before the development of AAU may prevent further functional loss and provide a better prognosis. Diagnosis of AS following AAU is not only associated with dependency but also may rob the vision of a young adult.

Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vasculature, plays critical roles in disease, including in cancer metastasis and chronic inflammation. Preclinical and recent clinical studies have now demonstrated therapeutic utility for several anti-lymphangiogenic agents, but optimal agents and efficacy in different settings remain to be determined. We tested the anti-lymphangiogenic property of 3,4-Difluorobenzocurcumin (CDF), which has previously been implicated as an anti-cancer agent, using zebrafish embryos and cultured vascular endothelial cells. We used transgenic zebrafish labelling the lymphatic system and found that CDF potently inhibits lymphangiogenesis during embryonic development. We also found that the parent compound, Curcumin, does not inhibit lymphangiogenesis. CDF blocked lymphatic and venous sprouting, and lymphatic migration in the head and trunk of the embryo. Mechanistically, CDF impaired VEGFC-VEGFR3-ERK signalling in vitro and in vivo. In an in vivo pathological model of Vegfc-overexpression, treatment with CDF rescued endothelial cell hyperplasia. CDF did not inhibit the kinase activity of VEGFR3 yet displayed more prolonged activity in vivo than previously reported kinase inhibitors. These findings warrant further assessment of CDF and its mode of action as a candidate for use in metastasis and diseases of aberrant lymphangiogenesis.

Though vegetarians own the privilege of a wide range of health benefits and of much lower risk of many diseases, they are also cut off many essential nutritional values. This study aimed to determine the vegetarian practices, body composition and dietary intake of vegetarians among Hindus and Buddhists in Kuching, Sarawak. Using questionnaire and anthropometric measurement, this cross-sectional study was carried out in Hindu and Buddhist temples in Kuching. Data was entered and analysed using SPSS version 22. A total of 114 respondents participated in the study, with mean age of 45.8 years (SD±16.01), females (57%), and majority Buddhists (81.6%). Majority of the respondents were on lacto-ovo vegetarian diet (71%) with more among the Hindus. More than half of the respondents were overweight and obese (64.1%). About 58% of the respondents were found to have abnormal waist circumference and 78.1% with over fat percentage. Buddhist respondents consumed more carbohydrates than Hindus. Hindu respondents consume more macro-nutrients such as protein and fat with a mean intake of 102.9 g (SD ±34.60) and 20.9 % of total energy intake respectively and more micro-nutrients. Vegetarian diet does not warranty healthy body as the quality and quantity of the food intake can influence the nutritional status of a person. Knowledge on choice of food should be imparted to improve their health status. South East Asia Journal of Public Health Vol.8(1) 2018: 3-9

Background The prevalence rate of reflux esophagitis (RE) in Asia, including Taiwan, has increased dramatically in recent years. However, few studies have discussed on its relationship with metabolic syndrome (MetS). This study aimed to evaluate the correlation between RE and MetS and its components. Methods We conducted a cross-sectional study during 2013 to 2014 in Taiwan. A total of 4895 subjects who completed upper gastrointestinal endoscopy at the Health Examination Center of Changhua Christian Hospital were enrolled. RE was defined according to the upper gastrointestinal endoscopic findings and MetS was defined according to the Taiwanese criteria. Univariate and multivariate logistic regression analyses were applied to calculate odds ratios and 95% confidence intervals for each variable to assess the associated features for RE. We analyzed the relationship between the number of MetS components and the severity of RE using the chi-square test for trend. Results The prevalence rates of MetS and RE were respectively 28.5 and 59.6%. According to univariate logistic regression analysis, MetS was significantly associated with RE and remained a positive association in multivariate logistic regression analysis (adjusted ORß = 1.251; 95% CI = 1.071–1.462; p = 0.005). Furthermore, among the five MetS components, elevated blood pressure (adjusted ORγ = 1.163; 95% CI = 1.023–1.323; p = 0.021), abdominal obesity (adjusted ORγ = 1.173; 95% CI = 1.020–1.349; p = 0.026) and hyperglycemia (adjusted ORγ = 1.306; 95% CI = 1.142–1.495; p

Both asymptomatic (ASB) and symptomatic bacteriuria during pregnancy increase the risk of adverse fetal or maternal outcomes. Our study aims to determine the prevalence of bacteriuria, the etiological agents with their susceptibility to antimicrobials, and the risk factors for therapeutic failure among pregnant women for antenatal care in the primary health care of Macau, China. Methods: This is a cross-sectional survey involving 5101 antenatal care pregnant women from 1st Jan to 31st Dec., 2017. The mid-stream clean-catch urine specimens were routinely examined microscopically and cultured following the first consultation. Other data were collected from the computerized medical records. Results: The mean age of the pregnant women was 31.4 ± 5.04 years. We followed 130 women with positive cultures on first consultation, of whom 35 (26.9%) were found to have contaminated cultures. 95 pregnant women were confirmed to have UTI. The prevalence of bacteriuria was 1.86% (n = 95), of which 83 (87.4%) were asymptomatic. ASB was mainly in the younger age-group (20 - 30 years) and the primipara. Of 196 positive cultures, the commonest bacterium was Escherichia coli (n = 111 or 56.6%, 98.2% susceptible to nitrofurantoin), followed by Klebsiella pneumonia (n = 20 or 10.2%, 90% susceptible to 2nd generation cephalosporin), and Streptococcus agalactiae (n = 16 or 8.2%, 100% susceptible to nitrofurantoin). After treatment, there were 80 (84.2%) therapeutic successes and 15 (15.8%) failures. Symptomatic infection and later trimester were significantly associated with therapeutic failure (P ≤ 0.05). Conclusions: ASB is common in the young age group and primipara. Nitrofuranton and 2nd generation cephalosporin are effective antibiotics against UTI in pregnancy. Symptomatic infection and occurrence in later trimester were significantly associated with treatment failure.

Objective To determine the extent of self-management support (SMS) provided to primary care patients with type 2 diabetes (T2D) and hypertension and its associated factors. Design Cross-sectional survey conducted between April and May 2017. Setting Forty public clinics in Malaysia. Participants A total of 956 adult patients with T2D and/or hypertension were interviewed. Main Outcome Measures Patient experience on SMS was evaluated using a structured questionnaire of the short version Patient Assessment of Chronic Illness Care instrument, PACIC-M11. Linear regression analysis adjusting for complex survey design was used to determine the association of patient and clinic factors with PACIC-M11 scores. Results The overall PACIC-M11 mean was 2.3(SD,0.8) out of maximum of 5. The subscales’ mean scores were lowest for patient activation (2.1(SD,1.1)) and highest for delivery system design/decision support (2.9(SD,0.9)). Overall PACIC-M11 score was associated with age, educational level and ethnicity. Higher overall PACIC-M11 ratings was observed with increasing difference between actual and expected consultation duration [β = 0.01; 95% CI (0.001, 0.03)]. Better scores were also observed among patients who would recommend the clinic to friends and family [β = 0.19; 95% CI (0.03, 0.36)], when health providers were able to explain things in ways that were easy to understand [β = 0.34; 95% CI (0.10, 0.59)] and knew about patients’ living conditions [β = 0.31; 95% CI (0.15, 0.47)]. Conclusions Our findings indicated patients received low levels of SMS. PACIC-M11 ratings were associated with age, ethnicity, educational level, difference between actual and expected consultation length, willingness to recommend the clinic and provider communication skills.

A 54-year-old autoclave technician was referred to the ambulatory care department of a UK district general hospital via his general practitioner (GP) with a 5-week history of a ‘profuse, papery’ rash ([figure 1A][1]), left groin lymphadenopathy, malaise, myalgia and fevers. He had a medical

Background To evaluate the effectiveness of the Enhanced Primary Healthcare (EnPHC) interventions on process of care and intermediate clinical outcomes among type 2 diabetes patients. Research Design and Methods This was a quasi-experimental controlled study of multi-pronged interventions conducted in 20 intervention and 20 control public primary care clinics in Malaysia from November 2016 to June 2019. Malaysian patients aged 30 years and above with a diagnosis of type 2 diabetes were selected via systematic random sampling. We conducted difference-in-differences analyses of data on process of care and intermediate clinical outcomes extracted from medical records. Results We reviewed 12,017 medical records of patients with type 2 diabetes. Process of care measures improved: HbA1c tests performed within the past three months (odds ratio (OR) 3.31, 95% CI 2.13, 5.13); lipid test (OR 4.59, 95% CI 2.64, 7.97), LDL (OR 4.33, 95% CI 2.16, 8.70), and urine albumin (OR 1.99, 95% CI 1.12, 3.55) tests within the past year; BMI measured within the past six months (OR 15.80, 95% CI 4.78, 52.24); cardiovascular risk assessment (OR 174.65, 95% CI 16.84, 1810.80); and exercise counselling (OR 1.18, 95% CI 1.04, 1.33). We found no statistically significant changes in intermediate clinical outcomes. Conclusions EnPHC interventions were effective in improving process of care but not intermediate clinical outcomes for type 2 diabetes patients. The intervention package was successful in enhancing the quality of care in diabetes from the health provider perspective. Patient engagement and self-management support may be needed to bring forth changes in patient outcomes.

Anoikis is the cell death induced by inappropriate, or lack of, cell adhesion. Many of the previous investigations have focused on the mechanisms leading to anoikis resistance of epithelial-derived tumor cells, and on determining pathways leading to cell survival. While not derived from epithelial tissue, primary melanoma cells are clearly able to avoid cell death induced by loss of adherence from the basement membrane of the epidermis when invading. The melanocytic lineage originates from neural crest cells, a population of highly migratory embryonic cells. Therefore, melanoma is a neoplasm of neuroectodermal origin and not epithelial in nature. As such, melanoma cells show key differences in specific parts of pathways leading to anoikis resistance. This chapter will focus on the specific mechanisms involved in anoikis resistance in cutaneous melanoma, a poorly studied tumor in this area.

Headache can be a primary or secondary disorder. The characteristics of headache and its associated features, especially the presence of red flag signs, are important in distinguishing secondary from primary causes. Hemicrania continua is a type of primary headache disorder characterized by a continuous unilateral headache with episodes of exacerbations and association with cranial autonomic symptoms, which include several ocular symptoms. The absolute response to indomethacin remains the hallmark of this disease. We would like to report a rare case of hemicrania continua with scintillating scotoma during exacerbations apart from the typical autonomic features of conjunctival injection, ptosis, eyelid edema, and lacrimation.

Background: In severe eosinophilic asthma (SEA), mepolizumab, an anti-interleukin 5 (IL-5) monoclonal antibody (mAb) can reduce asthma exacerbations and oral corticosteroid (OCS) requirements, but effect on nasal polyps (NP) recurrence and need for surgery is uncertain. We aimed to study the treatment (Rx) response in SEA patients with NP (SEAwNP) and assess for predictors of suboptimal Rx response individually for the asthma and NP components. Method: We measured sputum cell counts, cytokines, autoantibodies and nasoendoscopic total polyp score (TPS) in 6 patients with SEAwNP on mepolizumab (100mcg q4weeks) over 15 months, every 3 months. Optimal Rx response to the SEA component was defined as sputum eosinophil counts ≤ 3% after 4 months of treatment and >1 of the following: a) ACT score ≥20, b) Reduction of OCS dosage by ≥50%, c) 0 exacerbation requiring an OCS burst. Rx response for NP was defined as a) reduction in TPS by ≥1, (b) no recurrence. Results: There was optimal Rx response in 3/6(50%) patients with respect to their SEA component, while only 30% for NP. The suboptimal response in SEAwNP is predicted by sputum eosinophil counts (>3%), even when asthma controlled (ACT≥20). Suboptimal response in SEA and NP is associated with rise in sputum IL-5 and IL-13 respectively; baseline levels cannot predict treatment response. IL-5 is correlated with anti-EPX antibodies (r=0.52,p=0.0026) in individual patients. However collectively, anti-EPX levels remained constant, regardless of treatment response. Conclusions: Mepolizumab has differential Rx response to the nasal polyp component in SEAwNP patients. Trends in sputum eosinophil and IL-5 and IL13 can predict suboptimal treatment response.

Introduction There are few sources of published data on intra-cluster correlation coefficients (ICCs) amongst patients with type 2 diabetes (T2D) and/or hypertension in primary care, particularly in low- and middle-income countries. ICC values are necessary for determining the sample sizes of cluster randomized trials. Hence, we aim to report the ICC values for a range of measures from a cluster-based interventional study conducted in Malaysia. Method Baseline data from a large study entitled Evaluation of Enhanced Primary Health Care interventions in public health clinics (EnPHC-EVA: Facility) were used in this analysis. Data from 40 public primary care clinics were collected through retrospective chart reviews and a patient exit survey. We calculated the ICCs for processes of care, clinical outcomes and patient experiences in patients with T2D and/or hypertension using the analysis of variance approach. Results Patient experience had the highest ICC values compared to processes of care and clinical outcomes. The ICC values ranged from 0.01 to 0.48 for processes of care. Generally, the ICC values for processes of care for patients with hypertension only are higher than those for T2D patients, with or without hypertension. However, both groups of patients have similar ICCs for antihypertensive medications use. In addition, similar ICC values were observed for clinical outcomes, ranging from 0.01 to 0.09. For patient experience, the ICCs were between 0.03 (proportion of patients who are willing to recommend the clinic to their friends and family) and 0.25 (for Patient Assessment of Chronic Illness Care item 9, Given a copy of my treatment plan). Conclusion The reported ICCs and their respective 95% confidence intervals for T2D and hypertension will be useful for estimating sample sizes and improving efficiency of cluster trials conducted in the primary care setting, particularly for low- and middle-income countries.

Aim: This paper describes the study protocol, which aims to evaluate the effectiveness of a multifaceted intervention package called ‘Enhanced Primary Healthcare’ (EnPHC) on the process of care and intermediate clinical outcomes among patients with Type 2 diabetes mellitus (T2DM) and hypertension. Other outcome measures include patients’ experience and healthcare providers’ job satisfaction. Background: In 2014, almost two-thirds of Malaysia’s adult population aged 18 years or older had T2DM, hypertension or hypercholesterolaemia. An analysis of health system performance from 2016 to 2018 revealed that the control and management of diabetes and hypertension in Malaysia was suboptimal with almost half of the patients not diagnosed and just one-quarter of patients with diabetes appropriately treated. EnPHC framework aims to improve diagnosis and effective management of T2DM, hypertension or hypercholesterolaemia and their risk factors by increasing prevention, optimising management and improving surveillance of diagnosed patients. Methods: This is a quasi-experimental controlled study which involves 20 intervention and 20 control clinics in two different states in Malaysia, namely Johor and Selangor. The clinics in the two states were matched and randomly allocated to ‘intervention’ and ‘control’ arms. The EnPHC framework targets different levels from community to primary healthcare clinics and integrated referral networks. Data are collected via a retrospective chart review (RCR), patient exit survey, healthcare provider survey and an intervention checklist. The data collected are entered into tablet computers which have installed in them an offline survey application. Interrupted time series and difference-in-differences (DiD) analyses will be conducted to report outcomes.

Patients with severe asthma that remain uncontrolled incur significant medical burden and healthcare costs. Severe asthma is a heterogeneous airway disorder with complex pathophysiological mechanisms which can be broadly divided into type 2 (T2)-high and T2-low inflammatory pathways. Recent advances in asthma therapeutics with the advent of biologics have heralded an era of promising targeted therapy in this group of patients. The current available biologics, including anti-IgE mAb, anti-IL-5/IL-5R mAb and anti-IL-4Rα mAb, mainly target patients with an asthma endotype characterised by T2-high inflammation. While they have delivered positive outcomes in terms of reduction in exacerbations, improving lung function and quality of life, as well as reducing the dependence on oral corticosteroids, they have not functioned as the "panacea" as a significant proportion of patients do not respond completely to these targeted therapies. In addition, there is a lack of markers that can predict treatment response and clinicians are guided only by subjective asthma symptom scores. Suboptimal treatment response is common for individual patients. There has also been a dearth of effective targeted therapy for patients with T2-low asthma and treatment options remain limited for these patients. There is a pipeline of newer biologics targeting cytokines that operate at the interface between innate and adaptive immunity (e.g. IL-17A, thymic stromal lymphopoietin (TSLP), IL-25, IL-33, IL-32 and IL-36γ) with potential of modifying and reducing the severity of asthma. This commentary provides an overview of treatment with the current biologics and highlights the limitations, challenges and unmet needs in clinical management. We also summarise up-and-coming potential targets and therapeutic biologics for severe asthma.

The 2019 coronavirus (COVID-19) pandemic has now involved numerous low-to-middle-income countries (LMICs). The healthcare systems in LMICs face serious constraints in capacity and accessibility during normal times. This would be aggravated during an outbreak, leading to worse clinical outcomes. Moreover, 69% of the global population aged 60 and above live in LMICs. These older persons are at increased risk of severe COVID-19 and mortality [1]. LMICs lack time and finances for swift uptake of new technologies (e.g., rapid test kits, vaccines, and antivirals). From a more urgent and pragmatic perspective, we believe creative use of existing resources and repurposing others for human medical care are needed (Table 1). We acknowledge that our suggestions may be perceived as controversial, and we wish to emphasize that maximization of conventional healthcare assets should always be done before turning to unconventional solutions.

Globally, group A streptococcal infections are responsible for over 500,000 deaths per year. A safe vaccine that does not induce autoimmune pathology and that affords coverage for most GAS serotypes is highly desired. We have previously demonstrated that a vaccine based on the conserved M-protein epitope, J8 was safe and immunogenic in a pilot Phase I study. We subsequently improved vaccine efficacy by incorporation of a B-cell epitope from the IL-8 protease, SpyCEP, which protected IL-8 and enhanced neutrophil ingress to the site of infection. We have now substituted the carrier protein, diphtheria toxoid with its superior analogue, CRM197 which provides better immunogenicity and is widely used in licenced human vaccines. The new vaccine was compared with the DT conjugate vaccine to confirm that these modifications have not altered the physicochemical properties of the vaccine. This vaccine, when tested in an animal model of GAS infection, demonstrated significant reduction in systemic and local GAS burden, with comparable efficacy to the DT conjugate vaccine. The vaccine was shown to be equally effective in the presence of human plasma and in the presence of pre-existing DT-specific antibodies, thus minimising concerns regarding its potential efficacy in humans.

Babesia spp. are tick-transmitted intra-erythrocytic protozoan parasites that infect humans and animals, causing a flu-like illness and hemolytic anemia. There is currently no human vaccine available. People most at risk of severe disease are the elderly, immunosuppressed, and asplenic individuals. B. microti and B. divergens are the predominant species affecting humans. Here, we present a whole-parasite Babesia vaccine. To establish proof-of-principle, we employed chemically attenuated B. microti parasitized red blood cells from infected mice. To aid clinical translation, we produced liposomes containing killed parasite material. Vaccination significantly reduces peak parasitemia following challenge. B cells and anti-parasite antibodies do not significantly contribute to vaccine efficacy. Protection is abrogated by the removal of CD4+ T cells or macrophages prior to challenge. Importantly, splenectomized mice are protected by vaccination. To further facilitate translation, we prepared a culture-based liposomal vaccine and demonstrate that this performs as a universal vaccine inducing immunity against different human Babesia species.

Reciprocal epithelial-mesenchymal signaling is essential for morphogenesis, including branching of the lung. In the mouse, mesenchymal cells differentiate into airway smooth muscle that wraps around epithelial branches, but this contractile tissue is absent from the early avian lung. Here, we found that branching morphogenesis in the embryonic chicken lung requires extracellular matrix (ECM) remodeling driven by reciprocal interactions between the epithelium and mesenchyme. Before branching, the basement membrane wraps the airway epithelium as a spatially uniform sheath. After branch initiation, however, the basement membrane thins at branch tips; this remodeling requires mesenchymal expression of matrix metalloproteinase-2, which is necessary for branch extension but not branch initiation. As branches extend, tenascin-C (TNC) accumulates in the mesenchyme several cell diameters away from the epithelium. Despite its pattern of accumulation, TNC is expressed exclusively by epithelial cells. Branch extension coincides with deformation of adjacent mesenchymal cells, which correlates with an increase in mesenchymal fluidity at branch tips that may transport TNC away from the epithelium. These data reveal novel epithelial-mesenchymal interactions that direct ECM remodeling during airway branching morphogenesis.

The development of a blood-stage malaria vaccine has largely focused on the subunit approach. However, the limited success of this strategy, mainly due to antigenic polymorphism and the failure to maintain potent parasite-specific immune responses, indicates that other approaches must be considered. Whole parasite (WP) vaccines offer many advantages over sub-units; they represent every antigen on the organism, thus limiting the effects of antigenic polymorphism, and similarly they compensate for individual Immune-Response (Ir) gene-regulated non-responsiveness to any particular antigen. From a development perspective, they negate the need to identify and compare the relative efficacies of individual candidate antigens. WP vaccines induce protective immunity that is largely cell-mediated. However, WP blood-stage vaccines present a number of challenges for the development pathway. Key issues are cryopreservation and storage and the possible induction of antibodies against red blood cell surface antigens, even if the parasites are grown in blood group O, Rh negative blood. Here, we used a novel adaptation of an immunomagnetic method from STEMCELL™ Technologies to remove the red cell membranes from human red blood cells parasitized with P. falciparum. We then used these antigens to construct liposomes which were modified to present mannose on their membrane to target the liposome to antigen presenting cells. We then compared the immunogenicity of freshly prepared and lyophilized liposome vaccines. Following vaccination of mice, liposomes induced significantly lower antibody responses to human red cells but potent strain- and species-transcending cell-mediated immune responses to parasite antigens. These data support transitioning the P. falciparum liposomal vaccine into clinical studies.

Background A major outbreak of the Zika virus (ZIKV) has been reported in Brazil in 2015. Since then, it spread further to other countries in the Americas and resulted in declaration of the Public Health Emergency of International Concern (PHEIC) by World Health Organization. In 2016, Singapore reported its first minor ZIKV epidemic. Malaysia shares similar ecological environment as Brazil and Singapore which may also favor ZIKV transmission. However, no ZIKV outbreak has been reported in Malaysia to date. This study aimed to discuss all confirmed ZIKV cases captured under Malaysia ZIKV surveillance system after declaration of the PHEIC; and explore why Malaysia did not suffer a similar ZIKV outbreak as the other two countries. Methods This was an observational study reviewing all confirmed ZIKV cases detected in Malaysia through the ZIKV clinical surveillance and Flavivirus laboratory surveillance between June 2015 and December 2017. All basic demographic characteristics, co-morbidities, clinical, laboratory and outcome data of the confirmed ZIKV cases were collected from the source documents. Results Only eight out of 4043 cases tested positive for ZIKV infection during that period. The median age of infected patients was 48.6 years and majority was Chinese. Two of the subjects were pregnant. The median interval between the onset of disease and the first detection of ZIKV Ribonucleic Acid (RNA) in body fluid was 3 days. Six cases had ZIKV RNA detected in both serum and urine samples. Phylogenetic analysis suggests that isolates from the 7 cases of ZIKV infection came from two clusters, both of which were local circulating strains. Conclusion Despite similar ecological background characteristics, Malaysia was not as affected by the recent ZIKV outbreak compared to Brazil and Singapore. This could be related to pre-existing immunity against ZIKV in this population, which developed after the first introduction of the ZIKV in Malaysia decades ago. A serosurvey to determine the seroprevalence of ZIKV in Malaysia was carried out in 2017. The differences in circulating ZIKV strains could be another reason as to why Malaysia seemed to be protected from an outbreak.

Naturally acquired immunity to malaria is robust and protective against all strains of the same species of Plasmodium. This develops as a result of repeated natural infection, taking several years to develop., Naturally acquired immunity to malaria is robust and protective against all strains of the same species of Plasmodium. This develops as a result of repeated natural infection, taking several years to develop. Evidence suggests that apoptosis of immune lymphocytes due to uncontrolled parasite growth contributes to the slow acquisition of immunity. To hasten and augment the development of natural immunity, we studied controlled infection immunization (CII) using low-dose exposure to different parasite species (Plasmodium chabaudi, P. yoelii, or P. falciparum) in two rodent systems (BALB/c and C57BL/6 mice) and in human volunteers, with drug therapy commencing at the time of initiation of infection. CIIs with infected erythrocytes and in conjunction with doxycycline or azithromycin, which are delayed death drugs targeting the parasite’s apicoplast, allowed extended exposure to parasites at low levels. In turn, this induced strong protection against homologous challenge in all immunized mice. We show that P. chabaudi/P. yoelii infection initiated at the commencement of doxycycline therapy leads to cellular or antibody-mediated protective immune responses in mice, with a broad Th1 cytokine response providing the best correlate of protection against homologous and heterologous species of Plasmodium. P. falciparum CII with doxycycline was additionally tested in a pilot clinical study (n = 4) and was found to be well tolerated and immunogenic, with immunological studies primarily detecting increased cell-associated immune responses. Furthermore, we report that a single dose of the longer-acting drug, azithromycin, given to mice (n = 5) as a single subcutaneous treatment at the initiation of infection controlled P. yoelii infection and protected all mice against subsequent challenge.

Background The continuing morbidity and mortality associated with infection with malaria parasites highlights the urgent need for a vaccine. The efficacy of sub-unit vaccines tested in clinical trials in malaria-endemic areas has thus far been disappointing, sparking renewed interest in the whole parasite vaccine approach. We previously showed that a chemically attenuated whole parasite asexual blood-stage vaccine induced CD4+ T cell-dependent protection against challenge with homologous and heterologous parasites in rodent models of malaria. Methods In this current study, we evaluated the immunogenicity and safety of chemically attenuated asexual blood-stage Plasmodium falciparum (Pf) parasites in eight malaria-naïve human volunteers. Study participants received a single dose of 3 × 107 Pf pRBC that had been treated in vitro with the cyclopropylpyrolloindole analogue, tafuramycin-A. Results We demonstrate that Pf asexual blood-stage parasites that are completely attenuated are immunogenic, safe and well tolerated in malaria-naïve volunteers. Following vaccination with a single dose, species and strain transcending Plasmodium-specific T cell responses were induced in recipients. This included induction of Plasmodium-specific lymphoproliferative responses, T cells secreting the parasiticidal cytokines, IFN-γ and TNF, and CD3+CD45RO+ memory T cells. Pf-specific IgG was not detected. Conclusions This is the first clinical study evaluating a whole parasite blood-stage malaria vaccine. Following administration of a single dose of completely attenuated Pf asexual blood-stage parasites, Plasmodium-specific T cell responses were induced while Pf-specific antibodies were not detected. These results support further evaluation of this chemically attenuated vaccine in humans. Trial registration Trial registration: ACTRN12614000228684. Registered 4 March 2014.

Bilateral optic disc swelling with bilateral abducens nerve palsy as the first presenting signs of sporadic primary Burkitt's lymphoma (BL) is very rare. We report this in a young immunocompetent individual. Initial misdiagnosis of idiopathic intracranial hypertension was made due to normal brain imaging with elevated opening pressure on lumbar puncture. After 2 months, he developed neurological deficits and neck swellings. Biopsy of swelling revealed BL. He received chemotherapy but succumbed before the second cycle. Signs of raised intracranial pressure warrant meticulous investigation. Multiple high-volume taps of lumbar puncture are advised if clinical suspicion of neurolymphomatosis is high.

Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK, and CSC markers, insofar as ILK and CD44 were expressed in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development in response to tissue mechanics and oxygen tension. Cancer Res; 76(18); 5277–87. ©2016 AACR.

Central serous chorioretinopathy (CSCR) is a retinal condition characterized by fluid accumulation in the subretinal space, resulting in neurosensory detachment or pigment epithelial detachment. The risk factors associated with this condition include male gender, middle age, smoking, stress and use of corticosteroids. We report a case of CSCR in a 37-year-old policeman with hypertension and bronchial asthma. He presented with sudden onset of bilateral blurring of central vision for 1 day, worse over the left eye. There were no other significant eye complaints. He is an active smoker and has been on long-term corticosteroids for asthma. On examination, the visual acuity was 6/9 bilaterally. The anterior segment of both eyes was normal. Examination of the right fundus revealed a dome-shaped swelling inferior to the fovea, while the left fundus showed circular detachment of the neurosensory retina at the macula. He was diagnosed to have bilateral central serous chorioretinopathy. He was also counseled to stop smoking. The corticosteroids were continued due to the risk of precipitating an asthma attack if they were withheld. Upon his next review two months later, his condition remained stable. CSCR is usually a self-limited condition, with good visual outcome. A thorough medical, social and drug history should be obtained, and patients advised to modify their lifestyle to eliminate or reduce risk factors such as smoking, stress and corticosteroid use.