Ocular co-morbidities in patients with atopic dermatitis - a cross-sectional study from a tertiary referral hospital, Malaysia.

INTRODUCTION: Atopic dermatitis (AD) is a chronic relapsing pruritic inflammatory skin disease that commonly occurs among children as well as adults. AD patients were reported to have high prevalence of ocular manifestations, which may be due to the disease nature or drug complications. This study aimed to determine the prevalence of ocular manifestations in patients with AD. MATERIALS AND METHODS: Eighty patients who fulfilled the UK Working Party's Diagnostic Criteria for Atopic Dermatitis were included in the cross-sectional study. A standardized case report form was formulated to collect the demographic data and disease profile of the participants. AD severity was evaluated using the EASI and SCORAD score. All patients underwent a complete ophthalmological evaluation. RESULTS: The prevalence of ocular manifestations among the patients with AD was 48.8%. Fifty-four (67.5%) patients had facial dermatitis and 37 (46.2%) showed periorbital signs. The mean AD disease duration was 10.99 ± 11.20 years. Majority of the patients had mild to moderate AD. The most frequent ocular manifestation was allergic conjunctivitis (18.75%) followed by cataract (8.75%) and ocular hypertension (8.75%). Among the patients with ocular manifestations, 27 (69.2%) patients regularly applied topical corticosteroids on the face. The use of systemic corticosteroids was seen in 19 (42.2%) patients. Prolonged AD duration was significantly associated with the development of ocular manifestations. CONCLUSIONS: Nearly half of the patients with AD were complicated with ocular disease regardless of the AD severity, facial dermatitis and presence of periorbital signs. Long disease duration is associated with ocular manifestations, especially steroid related complications.

Melanoma-associated glycosyltransferase GCNT2 as an emerging biomarker and therapeutic target.

In metastatic melanoma, with a dismal survival rate and propensity for treatment resistance and recurrence, it is critical to establish biomarkers that better predict treatment response and disease severity. The melanoma glycome, composed of complex carbohydrates termed glycans, is an under-investigated area of research, although it is gaining momentum in the cancer biomarker and therapeutics field. Novel findings suggest that glycans play a major role in influencing melanoma progression and could be exploited for prognosticating metastatic activity and/or as therapeutic targets. In this review, we discuss the role of aberrant glycosylation, particularly the specialized function of ß1,6 N-acetylglucosaminyltransferase 2 (GCNT2), in melanoma pathogenesis and summarize mechanisms of GCNT2 regulation to illuminate its potential as a predictive marker and therapeutic target.

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Faecal microbiota transplantation for treatment of recurrent or refractory Clostridioides difficile infection in Hong Kong.

INTRODUCTION: Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated infection globally, causing significant morbidity and mortality. Faecal microbiota transplantation (FMT) has emerged as a promising option for recurrent and refractory CDI. This study aimed to assess the safety, efficacy, and feasibility of FMT for CDI in Hong Kong. METHODS: We conducted a single-centre, retrospective study for all consecutive cases of recurrent or refractory CDI who underwent FMT from 2013 to 2018. Clinical demographics, outcome, and safety parameters were collected. RESULTS: A total of 24 patients with recurrent or refractory CDI (median age 70 years, interquartile range=45.0-78.3 years; 67% male) were included. Over 80% had been recently hospitalised or were long-term care facility residents. Faecal microbiota transplantation was delivered by feeding tube in 11 (45.8%), oesophagogastroduodenoscopy in eight (33.3%), and colonoscopy in six (25%) of the patients. Resolution of diarrhoea without relapse within 8 weeks was achieved in 21 out of 24 patients (87.5%) after FMT. No deaths occurred within 30 days. The FMT was well tolerated and no serious adverse events attributable to FMT were reported. CONCLUSION: Our results confirm that FMT is a safe, efficacious, and feasible intervention for patients with refractory or recurrent CDI in Hong Kong. Given the increasing disease burden and the lack of effective alternatives in Hong Kong for difficult-to-treat cases of CDI, we recommend that a territory-wide FMT service be established to address increasing demand for this treatment.

Alzheimer's disease: insights for risk evaluation and prevention in the Chinese population and the need for a comprehensive programme in Hong Kong/China.

With the ageing of the global population, China is projected to be impacted significantly by the rising number of patients with Alzheimer's disease (AD). A cure for AD is not yet available, so society should be prepared for an increasing AD-related burden. In this review, we examine this impending problem and provide overviews on (a) the magnitude of the problem of AD in Hong Kong/China in the near future; (b) the genetic and lifestyle risk factors that contribute to AD; (c) current diagnostic approaches and the potential of newly discovered genetic biomarkers for early detection; (d) medications, non-pharmacological interventions, and possible preventive measures; and (e) the need for social and psychological care from the community. In Hong Kong, primary care and AD-related support for at-risk individuals, patients, and caregivers are inadequate. A joint effort from the medical community, government, universities, non-governmental organisations/charities, and industry should initiate the development of a long-term programme for AD. Finally, we outline recommendations for the relevant parties to consider.

The importance of international collaboration for rare diseases research: a European perspective.

Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease.

Immunoglobulin G4-related disease in Hong Kong: clinical features, treatment practices, and its association with multisystem disease.

INTRODUCTION: Immunoglobulin G4-related disease remains an under-recognised and evolving disease. Local data are sparse and previous publications have been limited to individual case reports or case series only. We conducted this study to review the clinical features, treatment practices, and factors associated with multisystem involvement in Hong Kong. We described the clinical features and treatment modalities of the largest cohort of immunoglobulin G4-related disease in our locality thus far. METHODS: We retrospectively evaluated all patients with immunoglobulin G4-related disease between January 2003 and December 2015 in Queen Mary Hospital and combined this with patient data extracted from previous local publications. We analysed the clinical features, treatment practices, and factors associated with the number of organ systems involved. RESULTS: A total of 104 patients (55 from Queen Mary Hospital and 49 from literature review) were identified. Patients were predominantly older men (mean [standard deviation] age, 61.9 [12.7] years; male-to-female ratio=3:1) and 94.4% had elevated pre-treatment serum immunoglobulin G4 levels. Hepatobiliary and pancreatic system (40.4%), salivary gland (33.7%), lymph node (29.8%), and eye (19.2%) were the most common organ systems involved. Lymphadenopathy was associated with glucocorticoid use (odds ratio=2.65; 95% confidence interval, 1.08-6.54; P=0.034). Pre-treatment serum immunoglobulin G4 levels correlated with the number of organ systems involved (ß=0.347; P=0.004) and, specifically, more associated with patients having salivary gland involvement than those without (mean, 1109 mg/dL vs 599 mg/dL; P=0.012). CONCLUSION: We identified pre-treatment serum immunoglobulin G4 to be associated with multisystem disease, especially with salivary gland involvement, highlighting its potential for disease prognostication and monitoring. Increased physician awareness and multidisciplinary efforts are required for early diagnosis and optimal management of this masquerading disease.

The clinical utility of conventional karyotyping in the detection of cytogenetic abnormalities in soft tissue tumours: an Asian institutional experience.

OBJECTIVES: To assess the clinical utility of conventional karyotyping as a diagnostic tool in soft tissue tumours amidst the increasing use of molecular cytogenetics. DESIGN: Case series. SETTING: Singapore General Hospital, an Asian institution. PARTICIPANTS: A total of 35 participants (18 male and 17 female) aged 15 to 81 years were included in this study. Conventional karyotyping of 35 consecutive fresh soft tissue tumour specimens was performed over 4 years and the results were analysed. RESULTS: Of the 35 cases of soft tissue tumours reviewed, chromosome abnormalities were detected in 22 (63%) cases, 11 (31%) showed a normal karyotype, and 2 (6%) had culture failure. Of the 22 cases with abnormal karyotype, nine (41%) cases showed recurring aberrations: Ewing's sarcomas (n=2), desmoplastic small round cell tumour (n=1), synovial sarcomas (n=3), myxoid liposarcomas (n=2), and lipoma (n=1). One lipoma case had a t(2;12)(q23;q15) in which 2q23 breakpoint was not reported before. Chromosomal aberration involving 12q15 breakpoint has been shown in a previous study to be indicative of a lipoma-like liposarcoma. Another lipoma case had addition of 5q15 and 9p13 together with a balanced aberration of t(12;13) (q13;q12) which were novel aberrations. One synovial sarcoma case showed t(3;7)(q21;p13) which was an uncharacteristic aberration. CONCLUSION: Conventional karyotyping demonstrated utility as a genome-wide screening tool for soft tissue tumours and an adjunct diagnostic tool in the event histopathology results were doubtful. With the more widespread use of karyotyping, novel recurring chromosomal aberrations may be discovered.

High throughput screening aids clinical decision-making in refractory acute myeloid leukaemia.

BACKGROUND: Despite advances in therapeutics for adverse-risk acute myeloid leukaemia (AML), overall survival remains poor, especially in refractory disease. Comprehensive tumour profiling and pre-clinical drug testing can identify effective personalised therapies. CASE: We describe a case of ETV6-MECOM fusion-positive refractory AML, where molecular analysis and in vitro high throughput drug screening identified a tolerable, novel targeted therapy and provided rationale for avoiding what could have been a toxic treatment regimen. Ruxolitinib combined with hydroxyurea led to disease control and enhanced quality-of-life in a patient unsuitable for intensified chemotherapy or allogeneic stem cell transplantation. CONCLUSION: This case report demonstrates the feasibility and role of combination pre-clinical high throughput screening to aid decision making in high-risk leukaemia. It also demonstrates the role a JAK1/2 inhibitor can have in the palliative setting in select patients with AML.

Synaptic targeting of glutamate receptors.

The proper targeting and clustering of neurotransmitter receptors at appropriate postsynaptic sites are principal requirements for the formation of functional synapses. Recently, new studies have begun to elucidate the mechanisms underlying the targeting and clustering of glutamate receptors at excitatory synapses in the brain. Members of the SAP90/PSD-95 family of proteins have emerged as potential regulators of glutamate-receptor membrane distribution. Further, targeting motifs within glutamate receptor subunits have been identified. These findings provide important clues in the effort to understand the molecular features of synaptic organization.

Implications of attendance patterns in Northern Ireland for abdominal aortic aneurysm screening.

INTRODUCTION: Evidence supports the introduction of an abdominal aortic aneurysm (AAA) screening programme. The aims of this study were to estimate future disease patterns and to determine the effect of the proportion attending on the programme's cost-effectiveness. PATIENTS AND METHODS: The results of the local AAA screening programme were reviewed. Ultrasonic infrarenal aortic diameter of 30 mm was considered aneurysmal. Projected population numbers from the Department of Health and current disease prevalence were used to estimate future number of potential patients. The Multi-centre Aneurysm Screening Study (MASS) Markov model was used to calculate an incremental cost-effectiveness ratio (ICER) and 95% uncertainty intervals (UI), using a 30-year time horizon and 3.5% per annum discount, to determine the effect of attendance. RESULTS: Men were recruited from August 2004 to May 2010. 13316 were invited for a scan and 5931 (44.5%) attended. 321 AAA were diagnosed, giving a prevalence of 5.4%, while 27 large AAA (0.46%) were repaired. The annual incidence of AAA until 2021 will range from 441 to 526, with an incidence of 40-48 large AAA, with both showing a gradual increase with time. Using this attendance rate, the ICER was calculated at £2350 per life-year gained (95% UI: £1620-£4290), or £3020 per quality-adjusted life-year gained (95% UI: £2080-£5500). CONCLUSIONS: The prevalence of disease in this local AAA screening was similar to other studies. The low attendance will result in many AAA being missed, but will not impact greatly on the long-term cost-effectiveness.

Obesity Measures and Definitions of Sarcopenic Obesity in Singaporean Adults - the Yishun Study.

OBJECTIVES: Due to the lack of a uniform obesity definition, there is marked variability in reported sarcopenic obesity (SO) prevalence and associated health outcomes. We compare the association of SO with physical function using current Asian Working Group for Sarcopenia (AWGS) guidelines and different obesity measures to propose the most optimal SO diagnostic formulation according to functional impairment, and describe SO prevalence among community-dwelling young and old adults. DESIGN: Obesity was defined according to waist circumference (WC), percentage body fat (PBF), fat mass index (FMI), fat mass/fat-free mass ratio (FM/FFM), or body mass index (BMI). SO was defined as the presence of both obesity and AWGS sarcopenia. Muscle function was compared among phenotypes and obesity definitions using ANOVA. Differences across obesity measures were further ascertained using multiple linear regressions to determine their associations with the Short Physical Performance Battery (SPPB). SETTING: Community-dwelling adults 21 years old and above were recruited from a large urban residential town in Singapore. PARTICIPANTS: 535 community-dwelling Singaporeans were recruited (21-90 years old, 57.9% women), filling quotas of 20-40 participants in each sex- and age-group. MEASUREMENTS: We took measurements of height, weight, BMI, waist and hip circumferences, body fat, muscle mass, muscle strength, and functional assessments. Questionnaire-based physical and cognitive factors were also assessed. RESULTS: Overall prevalence of SO was 7.6% (WC-based), 5.1% (PBF-based), 2.7% (FMI-based), 1.5% (FM/FFM-based), and 0.4% (BMI-based). SO was significantly associated with SPPB only in the FMI model (p<0.05), and total variance explained by the different regression models was highest for the FMI model. CONCLUSIONS: Our findings suggest FMI as the most preferred measure for obesity and support its use as a diagnostic criteria for SO.

Malnutrition and Sarcopenia in Community-Dwelling Adults in Singapore: Yishun Health Study.

OBJECTIVES: To determine the overlapping prevalence of malnutrition and sarcopenia and the association between parameters of malnutrition with muscle mass and strength in a community-dwelling Singaporean adult population. DESIGN: This was a cross-sectional study. SETTING: Large north-eastern residential town of Yishun in Singapore. PARTICIPANTS: Random sampling of community-dwelling Singaporeans aged 21-90 years old (n=541). MEASUREMENTS: Anthropometry, body composition and handgrip strength (muscle strength) were measured. Sarcopenia was identified using dual-energy x-ray absorptiometry scan (muscle mass). Nutritional status was measured using Mini Nutritional Assessment (MNA-SF). Other questionnaires collected included physical activity and cognition. Associations between nutritional status with sarcopenia as well as with muscle mass and strength were analysed using multinomial logistics and linear regressions. RESULTS: The overall population-adjusted prevalence of those at nutritional risk and malnourished were 18.5% and 0.1% respectively. More than a third of participants (35%) who were at nutritional risk were sarcopenic. Malnourished participants were all sarcopenic (100%, N=2) whereas those who were sarcopenic, 27.0% (N=37) were at nutritional risk/malnourished. Being at nutritional risk/malnourished was significantly associated with 2 to 3 times increased odds of sarcopenia in multivariate analyses adjusting for age, gender, physical activity level and cognition, and fat mass index. Favourable MNA parameter scores on food intake and BMI were positively associated with greater muscle mass and handgrip strength (p<0.05). CONCLUSION: Given the overlapping clinical presentation of malnutrition and sarcopenia, community screening protocols should include combination screening of nutritional status and sarcopenia with appropriate interventions to mitigate risk of adverse health outcomes.

Interleukin 1 production during accessory cell-dependent mitogenesis of T lymphocytes.

We have studied the control and significance of IL-1 production in human leukocyte cultures during accessory cell-dependent, T lymphocyte mitogenesis using sensitive bioassays and immunolabeling techniques. In primary antigen-dependent systems like the MLR, IL-1 production was not detected in accessory cells (monocytes, dendritic cells) or T cells, suggesting that it is not an early product in these responses. However, monocytes could be induced to make IL-1 after interacting with sensitized antigen-specific T cells. Both alloreactive T cell clones or freshly prepared lymphoblasts induced IL-1 provided the monocytes carried the HLA-DR antigens to which the T cells were initially sensitized. Even in these circumstances, dendritic cells and B cells failed to make IL-1. The mechanism whereby activated T cells induce IL-1 in monocytes was explored. Supernatants from cocultures of monocytes and T cells or several recombinant cytokines induced little or no IL-1. A more potent antigen independent pathway of IL-1 induction was identified. IL-1 could be induced in third-party HLA-DR nonspecific monocytes in cocultures of alloreactive T cell clones or blasts and HLA-DR-specific dendritic cells. The induction was factor independent since dendritic cells and T blasts placed in a chamber separate from third-party monocytes by a semipermeable membrane did not induce monocyte IL-1. These results suggest that a cell contact mechanism rather than an IL-1-inducing factor leads to IL-1 production. The role of IL-1 in T cell proliferation was tested with a polyclonal anti-IL-1 antibody. The antibody failed to block the proliferation of primary T cells, or alloreactive T cell clones and blasts stimulated with HLA-specific monocytes or dendritic cells, even though IL-1 in the medium was neutralized.

The allergen specificity of the late asthmatic reaction.

BACKGROUND: Allergen inhalation challenge in asthma may induce both early (EAR) and late (LAR) asthmatic reactions. The EAR is IgE and mast cell dependent. The mechanism of the LAR is less well defined and we have hypothesized may be allergen dependent. The aim of this study was to investigate the allergen specificity of the LAR to allergen inhalation in asthma. METHODS: In a randomized, double-blind, crossover design six asthmatic volunteers with dual sensitization to house dust mite (HDM) allergen and grass pollen (GP) allergen underwent inhalation allergen challenge with these separate allergens on two occasions separated by 14 days. Lung function changes were followed for 8-h postchallenge. Bronchial reactivity (histamine PC(20)) and airway inflammation, assessed by induced sputum differential cell count, were measured 24-h pre and postallergen challenge. The allergen inhalation challenges were matched to achieve the same magnitude of EAR. RESULTS: Despite comparable group mean EAR percent falls in FEV(1) (25.8% following GP and 28.0% following HDM (P = 0.917), the LAR was statistically greater on the HDM challenge day (13.0%vs 22.8% [P = 0.046]) and was associated with a significant airway eosinophil recruitment (mean (SD) of 5.4 (4.8)% to 22.1 (18.2)% (P = 0.028) that was not evident on the GP allergen challenge day. CONCLUSIONS: These findings identify the allergen specificity of the LAR and indicate that factors independent of IgE contribute to the LAR. Such findings have relevance both to the understanding of the allergen-induced airway responses in asthma and the need for homogeneity in inhaled-allergen challenge studies in asthma.

An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era.

Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several high-risk features of myeloma, the validity of conventional risk-stratification and prognostication systems needs to be reevaluated. We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure. Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still discriminating of long-term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in predicting for a worse outcome on multivariate analysis (median survival 2.6 years, P = 0.001), suggesting that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyping provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high-risk FISH markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation.

Anogenital herpes simplex suppressive therapy: an audit of transfer of care to general practitioners.

A central London genitourinary medicine clinic introduced a policy of transfer to general practitioners (GPs) the care of all patients on successful suppressive treatment of recurrent herpes simplex virus (HSV) infection. An audit showed the initiation of transfer of care to GPs was 65%.

Short- and potential long-term adverse health outcomes of COVID-19: a rapid review.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of patients infected worldwide and indirectly affecting even more individuals through disruption of daily living. Long-term adverse outcomes have been reported with similar diseases from other coronaviruses, namely Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). Emerging evidence suggests that COVID-19 adversely affects different systems in the human body. This review summarizes the current evidence on the short-term adverse health outcomes and assesses the risk of potential long-term adverse outcomes of COVID-19. Major adverse outcomes were found to affect different body systems: immune system (including but not limited to Guillain-Barré syndrome and paediatric inflammatory multisystem syndrome), respiratory system (lung fibrosis and pulmonary thromboembolism), cardiovascular system (cardiomyopathy and coagulopathy), neurological system (sensory dysfunction and stroke), as well as cutaneous and gastrointestinal manifestations, impaired hepatic and renal function. Mental health in patients with COVID-19 was also found to be adversely affected. The burden of caring for COVID-19 survivors is likely to be huge. Therefore, it is important for policy makers to develop comprehensive strategies in providing resources and capacity in the healthcare system. Future epidemiological studies are needed to further investigate the long-term impact on COVID-19 survivors.

Plasma vitamin B12 status and cerebral white-matter lesions.

BACKGROUND AND OBJECTIVE: Elevated homocysteine has been associated with a higher prevalence of cerebral white-matter lesions and infarcts, and worse cognitive performance. This raises the question whether factors involved in homocysteine metabolism, such as vitamin B(12), are also related to these outcomes. This study examined the association of several markers of vitamin B(12) status with cerebral white-matter lesions, infarcts and cognition. METHODS: The study evaluated the association of plasma concentrations of vitamin B(12), methylmalonic acid, holotranscobalamin and transcobalamin saturation with cerebral white-matter lesions and infarcts at baseline and cognition at baseline and during follow-up among 1019 non-demented elderly participants of the population-based Rotterdam Scan Study. Analyses were adjusted for several potential confounders, including homocysteine and folate concentration. RESULTS: Poorer vitamin B(12) status was significantly associated with greater severity of white-matter lesions, in particular periventricular white-matter lesions, in a concentration-related manner. Adjustment for common vascular risk factors (including blood pressure, smoking, diabetes and intima media thickness) did not alter the associations. Adjustment for homocysteine and folate modestly weakened the associations. No association was observed for any of the studied markers of vitamin B(12) status with presence of brain infarcts and baseline cognition or cognitive decline during follow-up. CONCLUSIONS: These results indicate that vitamin B(12) status in the normal range is associated with severity of white-matter lesions, especially periventricular lesions. Given the absence of an association with cerebral infarcts, it is hypothesised that this association is explained by effects on myelin integrity in the brain rather than through vascular mechanisms.