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Objectives: Our study evaluated the independent and overall associations of vegetable and fruit consumption at midlife with the likelihood of physical frailty in later life. We also investigated whether specific nutrients in these foods could have accounted for these associations, if present., Design: Prospective cohort study., Setting: A population-based cohort of Chinese adults followed over a period of 20 years in Singapore., Participants: We used data from 11,959 subjects who participated in the baseline (1993-1998) and follow-up 3 (2014-2017) interviews of the Singapore Chinese Health Study., Measurements: At baseline, dietary intake was evaluated using a validated food frequency questionnaire. During the follow-up 3 visits, physical frailty was assessed using a modified Cardiovascular Health Study phenotype that included weakness, slowness, exhaustion and weight loss. Multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations with physical frailty., Results: Participants had mean ages of 52 years at baseline, and 72 years at follow-up 3. Baseline intake of vegetables, but not of fruits, showed a dose-dependent inverse relationship with physical frailty at follow-up 3 (P trend = 0.001). Compared to participants in the lowest quintile of vegetable intake, those in the highest quintile had reduced odds of frailty [OR (95% CI): 0.73 (0.60-0.89)]. Among the components of physical frailty, vegetable intake had the strongest inverse association with weakness defined by handgrip strength [OR (95% CI) between extreme quintiles: 0.62 (0.52-0.73); P trend < 0.001]. In models that were individually adjusted for nutrients, the vegetable-frailty association was attenuated and no longer statistically significant after adjusting for the intake of β-carotene, lutein, folate, α-carotene, and isothiocyanates., Conclusion: Increased midlife intake of vegetables was associated with reduced odds of physical frailty in later life, and the intake of β-carotene, lutein, folate, α-carotene, and isothiocyanates could have accounted for this association., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Adult height has been associated with handgrip strength, which is a surrogate marker of physical frailty. However, it is uncertain if this association is causative or due to confounding bias., Methods: We evaluated pairwise associations among handgrip strength, adult height and genetically determined height [using a polygenic score (PGS) for height in a mediation framework and a two-sample Mendelian randomisation approach] by means of multivariable regression model using a prospective cohort of Chinese living in Singapore. We additionally evaluated pathway enrichments of height-related genes in relation to increased handgrip strength to discover common biological mechanisms underlying associations of genetically determined height with handgrip strength., Results: Height PGS exhibited a positive association with handgrip strength at late life after adjusting for midlife body weight and other baseline exposures (cigarette smoking, education and physical activity status, P=1.2×10-9). Approximately 66.4% of the total effect of height PGS on handgrip strength was mediated through adult height (βindirect-effect=0.034, Pindirect-effect=1.4×10-40). Two-sample Mendelian randomisation evaluations showed a consistent causal relationship between increased height and increased handgrip strength in late life (P between 6.6×10-4 and 3.9×10-18), with insignificant horizontal pleiotropic effects (PMR-Egger  intercept=0.853). Pathway analyses of genes related to both increased adult height and handgrip strength revealed enrichment in ossification and adipogenesis pathways (Padj between 0.034 to 6.8×10-4)., Conclusions: The study highlights on a potentially causal effect between increased adult height and increased handgrip strength at late life, which may be explained by related biological processes underlying preservation of muscle mass and strength in ageing., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR., Methods: Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites., Results: we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%)., Conclusion: In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro / in vivo diagnostic strategies to ascertain drug causality., Trial Registration: ANZCTR ACTRN12619000241134. Registered 19 February 2019., Competing Interests: No relevant conflicts of interest to declare., (© 2024 The Author(s).)

Background: It is unclear if improving diet quality after midlife could reduce the risk of physical frailty at late life. We aimed to associate changes in diet quality after midlife with physical frailty at late life., Methods: Diet quality in 12,580 participants from the Singapore Chinese Health Study was assessed with the Dietary Approaches to Stop Hypertension (DASH) scores at baseline (1993-1998; mean age 53 years) and follow-up 3 (2014-2016; mean age 73 years). Physical frailty was assessed using the modified Cardiovascular Health Study phenotype at follow-up 3. Multivariable logistic regressions examined associations between DASH scores and physical frailty., Results: Comparing participants in extreme quartiles of DASH scores, the odds ratios (OR) [95% confidence interval (CI)] for physical frailty were 0.85 (0.73,0.99) at baseline and 0.49 (0.41, 0.58) at follow-up 3. Compared to participants with consistently low DASH scores, participants with consistently high scores (OR 0.74, 95% CI: 0.59, 0.94) and those with > 10% increase in scores (OR 0.78, 95% CI: 0.64, 0.95) had lower odds of frailty. Compared to those in the lowest DASH tertiles at both time-points, significantly lower odds of physical frailty were observed in those who were in the highest DASH tertiles at both time points [0.59 (0.48, 0.73)], and in those who improved their scores from the lowest [0.68 (0.51, 0.91)] or second tertile at baseline [0.61 (0.48, 0.76)] to the highest tertile at follow-up 3., Conclusions: Maintaining a high diet quality or a substantial improvement in diet quality after midlife could lower the risk of physical frailty at late life., (© 2024. The Author(s).)

Setting: Although age at menopause has been linked to higher risk of physical frailty in later life, little is known about other reproductive factors., Objectives: Our study aimed to investigate the associations between 1) age at menarche, 2) age at natural menopause, 3) duration of reproductive period, 4) number of children, 5) use of oral contraceptives (OCP), and 6) use of hormone replacement therapy (HRT) with the risk of physical frailty in late life., Design: We used data from 5934 women of the Singapore Chinese Health Study who experienced natural menopause, and participated in the third follow-up interviews when physical frailty was assessed. Logistic regression was used to evaluate association of reproductive factors evaluated during baseline and prior follow-up interviews with physical frailty at follow-up 3., Participants: Community-dwelling Chinese women living in Singapore. Participants had a mean age of 52.6 years at baseline (1993-1998), and a mean age of 72.8 years during the third follow-up (2014-2017)., Measurements: Sociodemographic characteristics, level of education, smoking history, physical activity, and history of physician-diagnosed comorbidities were collected. Participants' weight and height were self-reported. We used a modified Cardiovascular Health Study phenotype to assess physical frailty., Results: Age at menarche was inversely associated with the likelihood of physical frailty (P trend  = 0.001); each one-year decrease in age at menarche was associated with a 9% increase (95% CI: 4%-14%) in odds of physical frailty. Age at menopause was also inversely associated with the likelihood of physical frailty (P trend  = 0.009); every one-year decrease in age at menopause was associated with 2% (0%-4%) increased odds. In the assessment of frailty, younger ages at menarche and menopause were associated with greater likelihood of being in the slowest quintile for timed up-and-go and weakest quintile for handgrip strength. Conversely, duration of reproductive period, parity, and use of oral contraceptives or hormone replacement therapy were not significantly associated with the likelihood of physical frailty., Conclusions: In our population-based cohort of Chinese women, younger ages at menarche and menopause were associated with higher likelihood of physical frailty in later life., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: Non-invasive ventilation (NIV), namely continuous positive airway pressure (CPAP) and bi-level positive airway pressure (BiPAP), delivers mechanical ventilation without endotracheal intubation. Short-term NIV (planned for <21 days during initiation) can be used for the management of acute respiratory distress (ARD) among paediatric palliative patients with "Do Not Resuscitate or Intubate" (DNI) as the ceiling of care. This study aimed to describe the usage of short-term NIV among paediatric palliative patients in a woman and child hospital with a paediatric palliative subspecialty., Materials and Methods: A retrospective and observational study was conducted on all paediatric palliative patients who received short-term NIV in Tunku Azizah Hospital Kuala Lumpur, Malaysia, from March 2020 to May 2022., Results: During the study period, short-term NIV was offered on 23 occasions for 20 different children. Indications for short-term NIV include 16 (69.6%) occasions of potentially reversible ARD (NIV Category 1) and 7 (30.4%) occasions of comfort care at the end of life (NIV Category 2). The main cause of ARD was pneumonia (90.3%) due to either aspiration or infection. The modality of NIV used was BiPAP only (14 occasions, 60.9%), CPAP only (three occasions, 13%) and both BiPAP and CPAP (six occasions, 26.1%). The median duration of NIV usage was four days (minimum one day and maximum 15 days). NIV was initiated as an escalation from nasal prong, Ventimask or high-flow mask oxygen on 22 occasions and as weaning down post-extubation on one occasion. For the 22 occasions of escalating therapy, there was significant improvement at six hours compared to pre-NIV in the median heart rate (136 to 121, P =0.002), respiratory rate (40 to 31, P =0.002) and oxygen saturation (96% to 99%, P =0.025). All 17 documented parental impressions of the child's condition post six hours of NIV were that the child had improved. Adverse events during short-term NIV include five episodes (21.7%) of stomach distension, four episodes (17.4%) of skin sores on the face and one episode (4.3%) of excessive drooling. Three patients passed away while on NIV in the hospital. For the other 20 (87%) occasions, patients were able to wean off NIV. Post-weaning off NIV, three patients passed away during the same admission. On 17 occasions, patients were discharged home after weaning off NIV., Conclusion: Usage of short-term NIV in paediatric palliative care, where children have an advanced directive in place indicating DNI, as seen in our study, can be a valuable modality of management for distressing symptoms, in addition to the pharmacological management of breathlessness. This is shown through our study to be of benefit in potentially reversible ARD as well as comfort care at the end of life. Further rigorous studies will need to be conducted for a clearer understanding of short-term NIV that would enable the formulation of guidelines to improve the quality of life and death in children., Competing Interests: There are no conflicts of interest., (© 2024 Published by Scientific Scholar on behalf of Indian Journal of Palliative Care.)

Converging evidence suggests that handgrip strength is linked to cognition in older adults, and this may be subserved by shared age-related changes in brain function and structure. However, the interplay among handgrip strength, brain functional connectivity, and cognitive function remains poorly elucidated. Hence, our study sought to examine these relationships in 148 community-dwelling older adults. Specifically, we examined functional segregation, a measure of functional brain organization sensitive to ageing and cognitive decline, and its associations with handgrip strength and cognitive function. We showed that higher handgrip strength was related to better processing speed, attention, and global cognition. Further, higher handgrip strength was associated with higher segregation of the salience/ventral attention network, driven particularly by higher salience/ventral attention intra-network functional connectivity of the right anterior insula to the left posterior insula/frontal operculum and right midcingulate/medial parietal cortex. Importantly, these handgrip strength-related inter-individual differences in salience/ventral attention network functional connectivity were linked to cognitive function, as revealed by functional decoding and brain-cognition association analyses. Our findings thus highlight the importance of the salience/ventral attention network in handgrip strength and cognition, and suggest that inter-individual differences in salience/ventral attention network segregation and intra-network connectivity could underpin the handgrip strength-cognition relationship in older adults., (© 2024. The Author(s).)

Background: Australian guidelines recommend trimethoprim or nitrofurantoin as first-line agents for uncomplicated urinary tract infections (UTIs). Laboratory surveillance indicates high rates of trimethoprim resistance among urinary bacterial isolates, but there are scant local clinical data about risk factors and impact of trimethoprim resistance., Objectives: To determine the prevalence, risk factors, mechanism and impact of resistance to first-line antibiotic therapy for uncomplicated UTIs in the community setting., Methods: A prospective observational study from October 2019 to November 2021 in four general practices in Melbourne, Australia. Female adult patients prescribed an antibiotic for suspected or confirmed uncomplicated acute cystitis were eligible. Primary outcome was urine isolates with resistance to trimethoprim and/or nitrofurantoin., Results: We recruited 87 participants across 102 UTI episodes with median (IQR) age of 63 (47-76) years. Escherichia coli was the most common uropathogen cultured (48/62; 77%); 27% (13/48) were resistant to trimethoprim (mediated by a dfrA gene) and none were resistant to nitrofurantoin. Isolates with resistance to a first-line therapy were more common among patients reporting a history of recurrent UTIs [risk ratio (RR): 2.08 (95% CI: 1.24-3.51)] and antibiotic use in the previous 6 months [RR: 1.89 (95% CI: 1.36-2.62)]. Uropathogen resistance to empirical therapy was not associated with worse clinical outcomes., Conclusions: Resistance to trimethoprim is common in uncomplicated UTIs in Australia but may not impact clinical outcomes. Further research is warranted on the appropriateness of trimethoprim as empirical therapy, particularly for patients with antimicrobial resistance risk factors., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: Our study evaluated the prospective association between the consumption of caffeine-containing beverages at midlife and the risk of physical frailty at late life within a population-based cohort of Chinese adults living in Singapore over a follow-up period of 20 years., Design: Prospective cohort study., Setting and Participants: We used data from 12,583 participants from the baseline and third follow-up interviews of the Singapore Chinese Health Study (SCHS). Participants had a mean age of 53 years at baseline (1993-1998), and a mean age of 73 years during the third follow-up (2014-2017)., Methods: At baseline, habitual consumption of caffeine-containing beverages was evaluated using a validated semi-quantitative food-frequency questionnaire. During the third follow-up, physical frailty was assessed using the modified Cardiovascular Health Study phenotype., Results: Compared with non-daily drinkers, those who drank 4 or more cups of coffee daily had reduced odds of physical frailty [odds ratio (OR), 0.54; 95% CI, 0.38-0.76]. Similarly, compared with those who hardly drank tea, participants who drank tea everyday also had reduced odds (OR, 0.82; 95% CI, 0.71-0.95). Total daily caffeine intake at midlife was associated with reduced likelihood of frailty at late life in a dose-response relationship (P trend < .001). Relative to their counterparts in the lowest quartile of daily caffeine intake (0-67.6 mg/d), participants in the highest quartile (223.0-910.4 mg/d) had an OR of 0.77 (95% CI, 0.66-0.91). Higher caffeine consumption was associated with lower likelihood of being in the slowest quintile for timed up-and-go (TUG) and weakest quintile for handgrip strength., Conclusions and Implications: In this cohort of Chinese adults, higher consumption of caffeine at midlife, via coffee and tea, was associated with a reduced likelihood of physical frailty in late life., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is limited understanding of the epidemiology of generalized pustular psoriasis (GPP) internationally, with no population-based estimates of GPP in South East Asia., Objectives: To determine the incidence and prevalence of GPP in the Malaysian population and characterize its flares and trigger factors., Methods: We conducted a population-based cohort study using the Teleprimary Care database between January 2010 and December 2020. We identified 230 dermatologist-confirmed GPP cases using International Classification of Diseases, 10th revision, diagnostic codes. Annual prevalence and incidence rates were stratified by age, sex and ethnicity. We compared data regarding flares and trigger factors for patients with GPP who had associated psoriasis vulgaris (PV) with those who did not have associated PV., Results: The prevalence of GPP was 198 per million (267 women, 127 men) and incidence was 27.2 per million person-years [95% confidence interval (CI) 22.8-31.6]; 35.3 (28.4-42.2) per million person-years for women and 18.3 (13.1-23.5) per million person-years for men. Rates were higher in Chinese individuals [prevalence 271 per million; incidence 41.6 per million person-years (28.9-54.3)] than in the Malay population [prevalence 186; incidence 24.6 (19.4-29.7)] or the Indian ethnic group [prevalence 179; incidence 25.0 (13.8-36.3)]. Annual prevalence was consistently higher in women than in men and highest among the Chinese population, followed by the Indian and Malay populations. Overall, 67% of patients with GPP had associated PV. The prevalence and incidence of GPP without PV were lower than GPP with PV at 66 vs. 132 per million and 19.3 (95% CI 15.6-23.0) vs. 8.0 (95% CI 5.6-10.3) per million person-years, respectively. The mean age at GPP onset was 42.7 years (SD 18.4). A bimodal trend in the age of GPP onset was observed, with first and second peaks at age 20-29 years and age 50-59 years, respectively. Disease onset was significantly earlier in patients with GPP without PV than in those with PV [mean age 37.5 years (SD 20.7) vs. 44.9 years (SD 17.0), P = 0.026]. Flares occurred more frequently in patients without PV than in those with PV [mean number of flares per patient per year was 1.35 (SD 0.77) vs. 1.25 (SD 0.58), P = 0.039]. Common triggers of flares in patients with GPP who did not have PV were infections, pregnancy, menstruation and stress, whereas withdrawal of therapy, particularly systemic corticosteroids, was a more frequent trigger in patients with GPP who also had PV., Conclusions: Our findings contribute to the global mapping of GPP, which will help inform the management of this rare condition., Competing Interests: Conflicts of interest: S.E.C. declares paid activities as advisor, speaker or consultant for AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Sanofi and UCB. C.E.M.G. has received honoraria and/or research grants from AbbVie, Almirall, Amgen, AnaptysBio, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Evelo Bioscience, Galderma, GSK, Inmagene, LEO Pharma, Janssen, ONO Pharmaceuticals, Novartis, Pfizer, Sandoz and UCB Pharma. D.M.A. reports research grants from AbbVie, Almirall, Eli Lilly, Janssen, Novartis, UCB, and the LEO Foundation., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: How obesity earlier in life impacts upon mobility dysfunctions in late life is not well understood. Pernicious effects of excess weight on the musculoskeletal system and mobility dysfunctions are well-recognized. However, increasingly more data support the link of obesity to overall motor defects that are regulated in the brain., Objectives: To assess the causal relationship between body mass index (BMI) at midlife and performance of the Timed Up-and-Go test (TUG) in late life among a population-based longitudinal cohort of Chinese adults living in Singapore., Methods: We evaluated genetic predispositions for BMI in 8342 participants who were followed up from measurement of BMI at average 53 years, to TUG test (as a functional mobility measure) 20 years later., Results: A robust 75.83% of genetically determined BMI effects on late-life TUG scores were mediated through midlife BMI (P indirect-effect  = 9.24 × 10 -21 ). Utilizing Mendelian randomization, we demonstrated a causal effect between BMI and functional mobility in late life (β IVW  = 0.180, P IVW  = 0.001). Secondary gene enrichment evaluations highlighted down-regulation of genes at BMI risk loci that were correlated with poorer functional mobility in the substantia nigra and amygdala regions as compared to all other tissues. These genes also exhibit differential expression patterns during human brain development., Conclusions: We report a causal effect of obesity on mobility dysfunction. Our findings highlight potential neuronal dysfunctions in regulating predispositions on the causal pathway from obesity to mobility dysfunction., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Recent experimental work has identified CXCL9 as a promoter for the differentiation of osteoclast progenitors into osteoclasts, with resultant bone resorption. However, no human study has validated an association between this chemokine and osteoporosis or fracture risk. We conducted a matched case-control study nested in the prospective, population-based Singapore Chinese Health Study. Fifty-five men and 119 women with incident hip fractures, occurring median 6.2 years after blood collection, were matched individually to controls by age at recruitment, sex, and duration of blood storage. Serum chemokines, CXCL9 and CXCL10, were measured using immunoassays. Multivariable conditional logistic regression models that included age at blood collection, body mass index, smoking, and diabetes as covariates were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for association with hip fracture risk. Predictive utility of chemokine for hip fracture risk was examined by comparing area under receiver operating characteristic curves (AUC) between prognostic models with and without the chemokine. Increasing CXCL9 levels were associated with increasing hip fracture risk in men but not in women (p interaction  = 0.002); comparing extreme quartiles, the OR (95% CI) in the highest quartile was 10.35 (1.90-56.39) in men (p trend  = 0.002) but 1.46 (0.59-3.60) in women (p trend  = 0.32). Adding CXCL9 to a prognostic model that already incorporated age and other risk factors improved the AUC (95% CI) from 0.65 (0.55-0.76) to 0.74 (0.65-0.83) for the predictive utility of hip fractures in men but not in women. Conversely, the association between CXCL10 and hip fracture risk was not statistically significant in either sex. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Background: Abdominal obesity is associated with functional disability in older adults., Aim: We evaluated whether this association was modified by gender and/or physical frailty., Methods: We used cross-sectional data from 12,583 participants in the third follow-up of the population-based Singapore Chinese Health Study, when participants had mean age of 74 years (range 63-97). Abdominal obesity was defined using waist circumference, physical frailty was established using the modified Cardiovascular Health Study phenotype, and functional disability was determined by the Lawton Instrumental Activities of Daily Living Scale. We used logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between abdominal obesity and disability., Results: Abdominal obesity was associated with increased likelihood of functional disability, and this association was stronger in women than in men [OR (95% CI): 1.27 (1.11-1.46) vs. 1.08 (0.93-1.25); P for interaction < 0.001]. Furthermore, there was a significantly stronger association between abdominal obesity and functional disability in participants who were physically frail compared to those who were not [OR (95% CI): 1.57 (1.19-2.08) vs. 1.11 (0.99-1.23); P for interaction = 0.003], and this phenomenon was observed in both genders. When compared to participants who were neither abdominally obese nor physically frail, participants who were both abdominally obese and physically frail had a synergistically increased risk of functional disability [OR (95% CI): 3.61 (3.03-4.30)]., Conclusions: Women with abdominal obesity had higher risk of functional disability compared to men, and older adults who were both abdominally obese and physically frail had a synergistically increased risk of disability., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Cutaneous adverse drug reactions (cADRs) among people living with HIV (PLWH) are common. Data on drug eruptions among PLWH in Malaysia are limited. Thus, our study aimed to determine the clinical patterns of cADRs among PLWH and the risk factors associated with severe cutaneous adverse reactions (SCAR)., Methods: A cross-sectional study was conducted among PLWH who developed cADRs presenting to our dermatology clinic from June 2020 to December 2020. The Naranjo scale was used for drug causality assessment., Results: A total of 78 PLWH were recruited with a male-to-female ratio of 12:1. The maculopapular eruption was the commonest type of cADRs (75.6%), followed by drug reaction with eosinophilia and systemic symptoms (DRESS) (15.4%). SCAR is defined as a potentially life-threatening, immunologically mediated, drug-induced disease, accounting for 17.9% of the cases. Most of the patients were on antiretroviral therapy (ART) (85.9%), with efavirenz + tenofovir/emtricitabine being the most common combination (80.6%). Efavirenz (51.3%) was the main culprit drug implicated, followed by trimethoprim/sulfamethoxazole (23.1%) and nevirapine (11.5%). CD4 T-cell count <100 cells/μL ( p = 0.006) was the independent risk factor for SCAR. Most cases had probable causal relationships with the culprit drugs (84.6%) and were not preventable (93.6%)., Conclusions: The commonest cADR seen in PLWH was maculopapular eruption, while efavirenz, trimethoprim/sulfamethoxazole, and nevirapine were the three main implicated drugs. Most of the cases had probable drug causality and were not preventable. PLWH with CD4 count <100 cells/μL were particularly at risk of developing SCAR. Overall, this study showed that immune suppression and polypharmacy as a consequence of opportunistic infection prophylaxis are important factors contributing to the increased risk of ADRs among PLWH.

Background: Although obesity can be clinically defined by body mass index (BMI), waist circumference, percent body fat, or visceral fat area, it is unclear which specific measure is best associated with mobility disability in oldest-old adults., Methods: Among 589 Chinese participants aged 85 years and older in a population-based cohort in Singapore, we measured waist circumference, computed BMI, estimated appendicular skeletal muscle mass, percent body fat, and visceral fat area using bioelectrical impedance analysis, and evaluated mobility disability using the Loco-Check questionnaire. We computed areas under the receiver operating characteristic curves (AUC ROC ) to compare how well these measures discriminated between those with and without mobility disability. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations between obesity defined by these measures and mobility disability., Results: Compared to BMI, which had an AUC ROC (95% CI) of 0.68 (0.64-0.72) for the discrimination of mobility disability, only visceral fat area had a significantly higher discriminative performance [AUC ROC (95% CI) of 0.71 (0.67-0.75) (P adjusted  = 0.002)]. The optimal cut-offs of visceral fat area for the discrimination of mobility disability were ≥ 104 cm 2 in men and ≥ 137 cm 2 in women. In fully adjusted models, only obesity defined by visceral fat area was significantly associated with mobility disability [OR (95% CI) of 2.04 (1.10-3.77)]; obesity defined by the other measures were not associated with mobility disability after adjusting for visceral fat., Conclusion: In oldest-old adults, visceral fat area was the best discriminator for obesity associated with mobility disability.

Background: Telomere attrition has been proposed as a hallmark of aging. We previously reported on the association between blood leukocyte telomere length (LTL) at midlife and risk of chronic diseases and mortality., Methods: In this study, we investigated the effect of midlife LTL and genetic proxies on 5 markers of aging outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9581)., Results: We observed a significant association between midlife LTL and handgrip strength later in life (p = .004, padjust = .020), as well as a nominal significant association between midlife LTL and TUG later in life (p = .036, padjust = .180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, p = .010)., Conclusions: Longer midlife LTL was associated with increased handgrip strength later in life., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Asian studies on how physical tests predict short-term mortality in elderly are scarce. We assessed handgrip strength and timed-up-and-go (TUG) as such predictors among elderly Chinese in Singapore., Design: Prospective cohort study., Setting: Community-dwelling Chinese elderly in Singapore., Participants: We used data from 13,789 subjects in the prospective, population-based Singapore Chinese Health Study, who had a mean age of 74 (range 63 to 97) years at time of measurements., Measurements: Subjects underwent assessment for handgrip strength and TUG. They were followed for mortality via linkage with nationwide death registry through 2018., Results: In multivariable analyses, handgrip strength was inversely associated with risk of mortality in a dose-dependent manner: the hazard ratio (HR) [95% confidence interval (CI)] comparing extreme quartiles was 2.05 (1.44-2.90) (Ptrend<0.001). TUG was positively associated with mortality in a stepwise manner: the HR (95% CI) comparing extreme quartiles was 3.08 (2.17-4.38) (Ptrend<0.001). Compared to those with stronger handgrip and faster TUG, participants who either had weaker handgrip or slower TUG had a significant 1.59 to 2.11 fold increase in risk of mortality; while the HR (95% CI) for those who had both weaker handgrip and slower TUG was 3.93 (3.06-5.05). In time-dependent receiver operating characteristic curves, adding handgrip strength and TUG time to a Cox model containing sociodemographic and lifestyle factors, comorbidities, and body measurements significantly improved the area under the curve for the prediction of mortality from 0.5 to 2 years (P≤0.001)., Conclusion: Among elderly in a Chinese population, handgrip strength and TUG test were strong and independent predictors of short-term mortality., Competing Interests: The authors declare no conflict of interest

Objectives: To define the long-term impacts of antibiotic allergy testing (AAT) on patient allergy perception and antibiotic utilization., Methods: Patients were identified from a prospective AAT database as having completed testing during a 15 month period beginning January 2017. Patients were contacted for a follow-up survey at least 12 months post-AAT. For those contacted, baseline demographics, antibiotic allergy label (AAL) history, age-adjusted Charlson comorbidity index, infection history, antibiotic de-labelling (≥1 AAL removed following AAT) and antibiotic usage for 12 months prior to testing (pre-AAT) and 12 months following testing (post-AAT) were recorded for each patient., Results: From the follow-up survey of 112 patients post-AAT, 95.2% (59/62) of patients with complete AAL removal expressed willingness to use 'de-labelled' antibiotics and 91.9% (57/62) were adherent to allergy label modification. Comparing antibiotic utilization 12 months pre-AAT versus 12 months post-AAT, AAT was associated with a significant increase in preferred antibiotic therapy [adjusted odds ratio (aOR) 3.29, 95% CI 1.56-6.92] and reduction in restricted antibiotic utilization (aOR 0.42, 95% CI 0.19-0.93)., Conclusions: An antimicrobial stewardship (AMS)-led AAT programme was safe and effective in the long term in the promotion of preferred and narrow-spectrum antibiotic usage, and favourable patient perception towards the AAT testing results was identified. This study further supports the routine incorporation of AAT into AMS programmes, confirming safety and durability of testing impacts on patients as well as increasing preferred antibiotic utilization., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Antibiotic allergies are reported by up to 1 in 4 cancer patients, almost 50% of which are considered low risk and precede the cancer diagnosis. We demonstrate the successful and safe implementation of a pilot oral penicillin challenge program for cancer patients with low-risk penicillin allergies, increasing the use of penicillin and narrow-spectrum beta-lactams post-testing.

The Blomia tropicalis (Blo t) mite species is considered a storage mite in temperate climate zones and an important source of indoor allergens causing allergic asthma and rhinitis in tropical and subtropical regions. Here, we report the crystal structure of one of the allergens from Blo t, recombinant proBlo t 1 (rproBlo t 1), determined at 2.1 Å resolution. Overall, the fold of rproBlo t 1 is characteristic for the pro-form of cysteine proteases from the C1A class. Structural comparison of experimentally mapped Der f 1/Der p1 IgG epitopes to the same surface patch on Blo t 1, as well as of sequence identity of surface-exposed residues, suggests limited cross-reactivity between these allergens and Blo t 1. This is in agreement with ELISA inhibition results showing that, although cross-reactive human IgE epitopes exist, there are unique IgE epitopes for both Blo t 1 and Der p 1., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Previous studies have highlighted the importance of lung-draining lymph nodes in the respiratory allergic immune response, whereas the lung parenchymal immune system has been largely neglected. We describe a new in vivo model of respiratory sensitization to Blomia tropicalis, the principal asthma allergen in the tropics, in which the immune response is focused on the lung parenchyma by transfer of Th2 cells from a novel TCR transgenic mouse, specific for the major B. tropicalis allergen Blo t 5, that targets the lung rather than the draining lymph nodes. Transfer of highly polarized transgenic CD4 effector Th2 cells, termed BT-II, followed by repeated inhalation of Blo t 5 expands these cells in the lung >100-fold, and subsequent Blo t 5 challenge induced decreased body temperature, reduction in movement, and a fall in specific lung compliance unseen in conventional mouse asthma models following a physiological allergen challenge. These mice exhibit lung eosinophilia; smooth muscle cell, collagen, and goblet cell hyperplasia; hyper IgE syndrome; mucus plugging; and extensive inducible BALT. In addition, there is a fall in total lung volume and forced expiratory volume at 100 ms. These pathophysiological changes were substantially reduced and, in some cases, completely abolished by administration of neutralizing mAbs specific for IL-4 and IL-13 on weeks 1, 2, and 3. This IL-4/IL-13-dependent inducible BALT model will be useful for investigating the pathophysiological mechanisms that underlie asthma and the development of more effective drugs for treating severe asthma., (Copyright © 2016 by The American Association of Immunologists, Inc.)

The role of panfungal polymerase chain reaction (PCR) assays for diagnosis of invasive fungal disease (IFD) is inadequately defined. We describe the use of an internal transcribed spacer 1 (ITS-1) region-directed panfungal PCR in this context at a tertiary referral transplant center. A retrospective review of patients at Alfred Health, Melbourne, Australia (2009-2014) who had clinical samples referred for panfungal PCR testing was conducted. Baseline patient characteristics, antifungal drug history, fungal culture/histopathology, and radiology results were recorded. For bronchoalveolar lavage (BAL) fluid samples, identification of a fungus other than a Candida spp. was defined as a potential pathogen.Of 138 panfungal PCR tests (108 patients), 41 (30%) were positive for a fungal product. Ninety-seven percent (134/138) of specimens were from immunocompromised hosts. Thirteen percent (19/138) of panfungal PCR positive results were for potential pathogens and potential pathogens were detected more frequently in tissue as compared with BAL (12/13 vs. 6/26; P = .0001). No positive panfungal PCR results were obtained from CSF specimens. If histopathology examination was negative, panfungal PCR identified a potential pathogen in only 12% (11/94) of specimens. For the 20 culture negative/histopathology positive specimens, diagnosis of IFD to causative species level by panfungal PCR occurred in 35% (6/20).Sterile site specimens, in particular tissue, were more frequently panfungal PCR positive for potential pathogens than BAL. The utility of panfungal PCR appears greatest in tissue specimens, as an adjunct to histopathology to improve diagnostic sensitivity and specificity. Based on the results of this study we are now only testing tissue specimens by panfungal PCR., (© The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Members of the Mycobacterium abscessus complex are emerging pathogens of increasing importance, causing both respiratory and soft tissue infections, but precise speciation is problematic. This study was performed to examine the subspecies and antibiotic susceptibility of M. abscessus complex isolates collected during 2013 at the statewide New South Wales Mycobacterium Reference Laboratory (NSW MRL), Australia. Mycobacterium abscessus subsp. abscessus accounted for more than half of all M. abscessus isolates (n = 24, 57.1%), and M. abscessus subsp. massiliense comprised the remainder of the isolates (n = 18, 42.9%). There were no M. abscessus subsp. bolletii isolates. The prevalence of antibiotic resistance to all antibiotics, apart from amikacin was high, with 26.3% of isolates being reliably susceptible to only amikacin. Most M. abscessus subsp. abscessus isolates (80%) demonstrated inducible clarithromycin resistance whereas the majority of M. abscessus subsp. massiliense isolates (94.4%) remained susceptible to clarithromycin. There was a good correlation between the erm(41) genotype and clarithromycin susceptibility results after 14 days of incubation for most isolates with only three exceptions. Further studies correlating in vitro susceptibility profiles with clinical outcomes of M. abscessus infections treated with combination antimicrobial therapy are warranted.

Lactate measurement is vital in clinical diagnostics especially among trauma and sepsis patients. In recent years, it has been shown that saliva samples are an excellent applicable alternative for non-invasive measurement of lactate. In this study, we describe a method for the determination of lactate concentration in saliva samples by using a simple and low-cost cotton fabric-based electrochemical device (FED). The device was fabricated using template method for patterning the electrodes and wax-patterning technique for creating the sample placement/reaction zone. Lactate oxidase (LOx) enzyme was immobilised at the reaction zone using a simple entrapment method. The LOx enzymatic reaction product, hydrogen peroxide (H2O2) was measured using chronoamperometric measurements at the optimal detection potential (-0.2 V vs. Ag/AgCl), in which the device exhibited a linear working range between 0.1 to 5 mM, sensitivity (slope) of 0.3169 μA mM(-1) and detection limit of 0.3 mM. The low detection limit and wide linear range were suitable to measure salivary lactate (SL) concentration, thus saliva samples obtained under fasting conditions and after meals were evaluated using the FED. The measured SL varied among subjects and increased after meals randomly. The proposed device provides a suitable analytical alternative for rapid and non-invasive determination of lactate in saliva samples. The device can also be adapted to a variety of other assays that requires simplicity, low-cost, portability and flexibility.

Background: Eczema is a known risk factor for the development of wheeze in childhood. Cord blood T-cell cytokine responses have been shown to be associated with the development of both early childhood eczema and wheeze. Our objective is to study and compare the influence of intrinsic T-cell cytokine responses on the development of wheezing and eczema in the first 2 years of life in a birth cohort of at risk (first degree family with atopic disease) infants., Methods: Cord blood samples were collected from 195 eligible subjects of a birth cohort of 253 subjects. The subjects studied were those who developed either wheezing (n = 34) or eczema (n = 29) in the first 2 years of life, and 65 healthy infants served as control. Cytokines from phytohaemagglutinin stimulated mononuclear cells were analyzed using multiplex cytokine assays and the cytokine profiles in the 3 groups were compared., Results: Most of the subjects were non-atopic with only 3/34 (9%) wheeze and 9/29 (31%) eczema subjects sensitized to the common dietary or inhalant allergens. After adjustment for potential risk factors, wheeze, but not eczema subjects, presented with hyper-responsive cytokine profiles with increased production of T-cell cytokines IL-2 and IL-5. IL-5 was the strongest risk factor associated to the development of wheeze at 2 years of age (OR, 35; 95% CI, 5.0 -246.7)., Conclusion: Cord blood cytokine responses in early onset wheeze and eczema are distinctly different. This suggests that the tendency to develop early onset wheeze may be influenced by preexisting immune factors independent to those for eczema.

Background: The community-associated methicillin-resistant S. aureus (CA-MRSA) ST93 clone is becoming dominant in Australia and is clinically highly virulent. In addition, sepsis and skin infection models demonstrate that ST93 CA-MRSA is the most virulent global clone of S. aureus tested to date. While the determinants of virulence have been studied in other clones of CA-MRSA, the basis for hypervirulence in ST93 CA-MRSA has not been defined., Results: Here, using a geographically and temporally dispersed collection of ST93 isolates we demonstrate that the ST93 population hyperexpresses key CA-MRSA exotoxins, in particular α-hemolysin, in comparison to other global clones. Gene deletion and complementation studies, and virulence comparisons in a murine skin infection model, showed unequivocally that increased expression of α-hemolysin is the key staphylococcal virulence determinant for this clone. Genome sequencing and comparative genomics of strains with divergent exotoxin profiles demonstrated that, like other S. aureus clones, the quorum sensing agr system is the master regulator of toxin expression and virulence in ST93 CA-MRSA. However, we also identified a previously uncharacterized AraC/XylS family regulator (AryK) that potentiates toxin expression and virulence in S. aureus., Conclusions: These data demonstrate that hyperexpression of α-hemolysin mediates enhanced virulence in ST93 CA-MRSA, and additional control of exotoxin production, in particular α-hemolysin, mediated by regulatory systems other than agr have the potential to fine-tune virulence in CA-MRSA.

Staphylococcus aureus is one of the most important human pathogens, causing life-threatening infection in the community and hospital setting. The population genetics of S. aureus and the evolution of virulence is the focus of this review. We describe the various techniques in determining S. aureus population structure and discuss the insights gained from whole genome sequencing of various S. aureus strains. The emergence of community-acquired, methicillin-resistant S. aureus provides a framework for the discussion on evolution of virulence, and the role of horizontal gene transfer in the development of virulence and antibiotic resistance is explored. The knowledge generated from population genetics has the potential to inform strategies to assist in the prevention or treatment of this highly successful human pathogen., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Staphylococcus aureus remains a major opportunistic human pathogen, and while in many individuals it is associated with asymptomatic colonization, it is also capable of causing a range of clinical syndromes from minor skin infections to life-threatening septicemia. Staphylococcus aureus has also demonstrated a remarkable capacity to acquire antimicrobial resistance. Recent technological advances in genomics have led to an avalanche of studies providing deep insights into how S. aureus is evolving globally and within the human host. However, there are still significant experimental barriers in using these insights to try and better understand the biology of S. aureus. Here, we summarize recent advances in the understanding of S. aureus through the use of genomic approaches, and contemplate what the near future holds for truly functional genomics that will allow us to better understand the biology of this pathogen.

During development of the embryonic zebrafish brain, the differential expression of axon guidance molecules directs the growth of axons along defined neuronal tracts. Neurons within the dorsorostral cluster of the presumptive telencephalon project axons ventrally along the supraoptic tract. Brother of Cdo (Boc) is a known axon guidance molecule that is expressed in a broad band lying ventral to the dorsorostral cluster of neurons. Loss of Boc function has previously been shown to perturb the development of the supraoptic tract. We have used live cell imaging of individual growth cones within the living zebrafish embryo to determine how Boc regulates the growth cone dynamics and axon guidance within the supraoptic tract. A plasmid construct encoding elavl3-eGFP was injected into early embryos to selectively label a small number of neurons while the expression of Boc was knocked down by injection of antisense morpholino oligonucleotides. Time-lapse imaging of growth cones within the living embryos revealed that loss of Boc significantly affected the morphology of growth cones in comparison to axons within control embryos. Growth cones navigating along the supraoptic tract in the absence of Boc extended significantly longer filopodia in the rostrocaudal direction. These results indicate that Boc acts to restrict axons and their filopodia within the narrow pathway of the supraoptic tract. The highly selective nature of these pathfinding defects reveal that Boc is likely to be one of many molecules that coordinate the trajectory of axons within the supraoptic tract., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Der p 2, a major allergen of Dermatophagoides pteronyssinus mites, is one of the most clinically relevant allergens to allergic patients worldwide. FIP-fve protein (Fve) from the golden needle mushroom (Flammulina velutipes) is an immunomodulatory protein with potential Th1-skewed adjuvant properties. Here, we produced and immunologically evaluated a Der p 2-Fve fusion protein as a potential immunotherapeutic for allergic diseases. Using an inducible expression system in cultured rice suspension cells, the recombinant Der p 2-Fve fusion protein (designated as OsDp2Fve) was expressed in rice cells under the control of an α-amylase gene (αAmy8) promoter and secreted under sucrose starvation. OsDp2Fve was partially purified from the cultured medium. The conformation of Der p 2 in OsDp2Fve remains intact as reflected by its unaltered allergenicity, as assessed by human IgE ELISA and histamine release assays, compared to non-fusion Der p 2 protein. Furthermore, the Fve protein expressed in OsDp2Fve retains its in vitro lymphoproliferative activity but loses its hemagglutination and lymphoagglutination effects compared to the native protein. Notably, in vivo evaluation showed that mice administered with OsDp2Fve possessed an enhanced production of Der p 2-specific IgG antibodies without potentiating the production of Der p 2-specific IgE and Th2 effector cytokines in comparison with mice co-administered with native Fve and Der p 2 proteins. These results suggest that the recombinant Der p 2-Fve fusion protein produced in rice suspension cell cultures has a great potential for allergy immunotherapy.

In Australia the PVL-positive ST93-IV [2B], colloquially known as "Queensland CA-MRSA" has become the dominant CA-MRSA clone. First described in the early 2000s, ST93-IV [2B] is associated with skin and severe invasive infections including necrotizing pneumonia. A singleton by multilocus sequence typing (MLST) eBURST analysis ST93 is distinct from other S. aureus clones. To determine if the increased prevalence of ST93-IV [2B] is due to the widespread transmission of a single strain of ST93-IV [2B] the genetic relatedness of 58 S. aureus ST93 isolated throughout Australia over an extended period were studied in detail using a variety of molecular methods including pulsed-field gel electrophoresis, spa typing, MLST, microarray DNA, SCCmec typing and dru typing. Identification of the phage harbouring the lukS-PV/lukF-PV Panton Valentine leucocidin genes, detection of allelic variations in lukS-PV/lukF-PV, and quantification of LukF-PV expression was also performed. Although ST93-IV [2B] is known to have an apparent enhanced clinical virulence, the isolates harboured few known virulence determinants. All PVL-positive isolates carried the PVL-encoding phage ΦSa2USA and the lukS-PV/lukF-PV genes had the same R variant SNP profile. The isolates produced similar expression levels of LukF-PV. Although multiple rearrangements of the spa sequence have occurred, the core genome in ST93 is very stable. The emergence of ST93-MRSA is due to independent acquisitions of different dru-defined type IV and type V SCCmec elements in several spa-defined ST93-MSSA backgrounds. Rearrangement of the spa sequence in ST93-MRSA has subsequently occurred in some of these strains. Although multiple ST93-MRSA strains were characterised, little genetic diversity was identified for most isolates, with PVL-positive ST93-IVa [2B]-t202-dt10 predominant across Australia. Whether ST93-IVa [2B] t202-dt10 arose from one PVL-positive ST93-MSSA-t202, or by independent acquisitions of SCCmec-IVa [2B]-dt10 into multiple PVL-positive ST93-MSSA-t202 strains is not known.

Background: Studies have suggested that demographic and lifestyle factors could shape the composition of fecal microbiota in early life. This study evaluated infant stool microbiota signatures in two Asian populations, Singapore (n = 42) and Indonesia (n = 32) with contrasting socioeconomic development, and examined the putative influences of demographic factors on these human fecal associated bacterial signatures., Results: Longitudinal analysis showed associations of geographical origin with Clostridium leptum, Atopobium and Bifidobacterium groups. Mode of delivery had the largest effect on stool microbiota signatures influencing the abundance of four bacterial groups. Significantly higher abundance of bacterial members belonging to the Bacteroides-Prevotella, Bifidobacterium and Atopobium groups, but lower abundance of Lactobacilli-Enterococci group members, were observed in vaginal delivered compared to caesarean delivered infants. Demographic factors influencing the structure of infants stool microbiota during the first year of life included breastfeeding, age of weaning, sibship size and exposure to antibiotics., Conclusions: Differences in stool microbiota signatures were observed in relation to various demographic factors. These features may confound studies relating to the association of the structure of fecal microbiota and the predisposition to human modern disease.

Group 1 allergen from Dermatophagoid pteronyssinus (Der p 1) belongs to the papain-like cysteine protease family and is a major cause of allergic rhinitis and asthma. An anti-Der p 1 monoclonal antibody, mAb W108, was selected and isolated from Der p-specific IgG2b-producing hybridoma clones. Two-dimensional electrophoresis and immunoblotting showed that mAb W108 reacted with four components of Der p extracts with a molecular mass of 35 kDa and pI values varying from 4 to 6; it also reacted with IgE antibodies in the sera of Der p-sensitive patients. In the competitive assay and using azocasein as a substrate, we found that mAb W108 inhibited not only the binding of Der p 1, but also its cysteine protease activity in a dose-dependent manner. The two peptide segments of Der p 1 identified by mAb W108 (aa 151-197 and 286-320) were parts of inter-connecting loops located in the substrate-binding cleft and on the surface of the domain comprising mainly β-sheets. From the predicted interaction between the amino acid sequence in the CDR3 of mAb W108 and Der p 1-binding epitopes, the possible binding sites for mAb W108 to Der p 1 may sterically hinder the IgE epitope and the active site of cysteine protease activity. Administration of mAb W108 in the Der p-sensitized murine model of asthma alleviated allergen-induced airway inflammation and the Th2 cytokine immune response, suggesting its therapeutic potential. These findings can provide new insights into understanding IgE-mediated disease and the design of modified allergen vaccines for future allergen-specific immunotherapy.

CD4(+) memory/effector T cells play a central role in orchestrating the rapid and robust immune responses upon re-encounter with specific Ags. However, the immunologic mechanism(s) underlying these responses are still not fully understood. To investigate this, we generated an allergen (major house dust mite allergen, Blo t 5)-specific murine Th2 cell line that secreted IL-4, IL-5, IL-10, and IL-13, but not IL-9 or TNF-α, upon activation by the cognate Ag. These cells also exhibited CD44(high)CD62L(-) and CD127(+) (IL-7Rα(+)) phenotypes, which are characteristics of memory/effector T cells. Experiments involving adoptive transfer of this Th2 cell line in mice, followed by three intranasal challenges with Blo t 5, induced a dexamethasone-sensitive eosinophilic airway inflammation. This was accompanied by elevation of Th2 cytokines and CC- and CXC-motif chemokines, as well as recruitment of lymphocytes and polymorphic mononuclear cells into the lungs. Moreover, Blo t 5-specific IgE was detected 4 d after the last intranasal challenge, whereas elevation of Blo t 5-specific IgG1 was found at week two. Finally, pulmonary delivery of the pVAX-IL-35 DNA construct effectively downregulated Blo t 5-specific allergic airway inflammation, and i.m. injection of pVAX-IL-35 led to long-lasting suppression of circulating Blo t 5-specific and total IgE. This model provides a robust research tool to elucidate the immunopathogenic role of memory/effector Th2 cells in allergic airway inflammation. Our results suggested that IL-35 could be a potential therapeutic target for allergic asthma through its attenuating effects on allergen-specific CD4(+) memory/effector Th2 cell-mediated airway inflammation.

Background: Neonates with a family history of atopy are at higher risk for developing wheezing in early life., Objective: From a birth cohort of at risk infants (first-degree family with atopic disease), we evaluated the influence of distinct intrinsic immunologic risk factors on wheezing disorders in the first 2 years of life., Methods: Cord blood samples were collected from 195 eligible subjects of a birth cohort of 253 subjects. The subjects studied were those who developed wheezing (n=34) or eczema (n=29) in the first 2 years of life, and 65 healthy control infants. At the time of thawing the viability of the cells were median 70% (range 67.5%-72.5%). Cytokines from lipopolysaccharide (LPS)-stimulated mononuclear cells were analysed using fluorescent-activated cell sorting-array and their profiles were evaluated using factor analysis., Results: Infants with wheeze were significantly associated with enhanced combined LPS stimulated IL-1β, IL-6, and IL-12/IL-23p40 compared with healthy controls (P=0.003). This profile was also associated with the increased risk for wheeze at 2 years of age (OR=2.45; 95% CI=1.50-3.93, P=0.001). LPS-stimulated cytokine IL-8 was also significantly higher in the wheeze group compared with healthy controls and eczema (P=0.003). Intracellular staining showed that monocytes are main producers of IL-6 and IL-8 from cord blood mononuclear cells. Most of the subjects were non-atopic with 3/34 (9%) wheeze and 9/29 (31%) eczema subjects sensitized to the common dietary or inhalant allergens., Conclusion and Clinical Relevance: In infants at genetic risk of atopy, wheeze but not eczema in the first 2 years of life is associated with intrinsic hyperresponsive innate cytokine responses which might predispose infants to wheeze development. Distinct pre-symptomatic hyperresponsive innate immune responses risk factors were found to be associated with early onset wheeze disorders, but not eczema., (© 2011 Blackwell Publishing Ltd.)

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 has spread rapidly across North America, and CA-MRSA is also increasing in Australia. However, the dominant Australian CA-MRSA strain, ST93-IV [2B] appears distantly related to USA300 despite strikingly similar clinical and epidemiological profiles. Here, we compared the virulence of a recent Australian ST93 isolate (JKD6159) to other MRSA, including USA300, and found that JKD6159 was the most virulent in a mouse skin infection model. We fully sequenced the genome of JKD6159 and confirmed that JKD6159 is a distinct clone with 7616 single nucleotide polymorphisms (SNPs) distinguishing this strain from all other S. aureus genomes. Despite its high virulence there were surprisingly few virulence determinants. However, genes encoding α-hemolysin, Panton-Valentine leukocidin (PVL) and α-type phenol soluble modulins were present. Genome comparisons revealed 32 additional CDS in JKD6159 but none appeared to encode new virulence factors, suggesting that this clone's enhanced pathogenicity could lie within subtler genome changes, such as SNPs within regulatory genes. To investigate the role of accessory genome elements in CA-MRSA epidemiology, we next sequenced three additional Australian non-ST93 CA-MRSA strains and compared them with JKD6159, 19 completed S. aureus genomes and 59 additional S. aureus genomes for which unassembled genome sequence data was publicly available (82 genomes in total). These comparisons showed that despite its distinctive genotype, JKD6159 and other CA-MRSA clones (including USA300) share a conserved repertoire of three notable accessory elements (SSCmecIV, PVL prophage, and pMW2). This study demonstrates that the genetically distinct ST93 CA-MRSA from Australia is highly virulent. Our comparisons of geographically and genetically diverse CA-MRSA genomes suggest that apparent convergent evolution in CA-MRSA may be better explained by the rapid dissemination of a highly conserved accessory genome from a common source.

Growing interest in cognitive deficits associated with schizophrenia has led to the need for a clinician-friendly cognitive instrument. The Schizophrenia Cognition Rating Scale (SCoRS), recognized for its brevity and ease of administration, has proven to be a valid and reliable measure of overall cognition in schizophrenia patients. However, there has been no such validation in an Asian context. This SCoRS validation study involved 103 patient and 48 control subjects within an Asian population. Test-retest reliability, sensitivity of the instrument to cognitive differences between patients with schizophrenia and healthy controls as well as validity by comparing with a standardised performance-based cognitive battery, the Brief Assessment of Cognition in Schizophrenia (BACS) were assessed. Our findings indicated that SCoRS is highly reliable (ICC=0.984) and sensitive to cognitive dysfunction. SCoRS is significantly correlated with BACS composite scores and predicted functional outcomes as measured by Global Assessment of Functioning (GAF) and World Health Organisation-Quality of Life (WHO QOL) within an Asian population. SCoRS represents a clinician-friendly cognitive assessment tool that incorporates third-party feedback and might be employed in clinical practice to better evaluate and manage schizophrenia.

Sensitization to house dust mites (HDM) is highly prevalent among the young atopic population in Singapore. Previously published data suggest that individuals with skin allergies show preferred sensitization to Dermatophagoides pteronyssinus while individuals with pure respiratory allergies show preferred sensitization to Blomia tropicalis. The aim of our study was to compare the sensitization profiles between children with asthma and those with eczema to D. pteronyssinus and B. tropicalis and their specific allergens. A total of 60 children, 30 with asthma and 30 with eczema were recruited. IgE levels specific for a panel of HDM allergens from the two mite species were measured using enzyme-linked immunosorbent assay. The asthma group showed highest sensitization to Blo t5 while the eczema group showed highest sensitization to Der p5. Comparison between the two disease groups showed that the eczema group had significantly higher IgE levels for Der p (p = 0.042) and its allergens Der p1 (p = 0.019) and Der p5 (p = 0.001). Generally, the eczema group was more sensitized to the panel of allergens compared to the asthma group. Individuals with asthma and those with eczema showed different sensitization profiles to HDM. These findings highlighted possible mechanisms for different manifestation of allergy.

Eczema is a chronic form of childhood disorder that is gaining in prevalence in affluent societies. Previous studies hypothesized that the development of eczema is correlated with changes in microbial profile and composition of early life endemic microbiota, but contradictory conclusions were obtained, possibly due to the lack of minimization of apparent non-health related confounders (e.g., age, antibiotic consumption, diet and mode of delivery). In this study, we recruited seven caesarean-delivered and total formula-fed infants, and comparatively examined the early-life endemic microbiota in these infants with and without eczema. Using 16S pyrosequencing, infants' fecal microbiota were observed to comprise Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes as the four main phyla, and the presence and absence of specific populations within these four phyla are primarily mediated by ageing. Quantitative analysis of bacterial targets on a larger sample size (n = 36 at 1, 3, and 12 months of age) revealed that the abundances of Bifidobacterium and Enterobacteriaceae were different among caesarean-delivered infants with and without eczema, and the bacterial targets may be potential biomarkers that can correlate to the health status of these infants. Our overall findings suggest that the minimization of possible confounders is essential prior to comparative evaluation and correlation of fecal microbiota to health status, and that stool samples collected from caesarean-delivered infants at less than 1 year of age may represent a good cohort to study for potential biomarkers that can distinguish infants with eczema from those without. These findings would greatly facilitate future efforts in understanding the possible pathogenesis behind certain bacterial targets, and may lead to a timely intervention that reduces the occurrence of early life eczema and possibly allergic disorders in later life.

Background: Ingestion of flour contaminated with dust mite may trigger severe anaphylaxis in tropical and sub-tropical regions., Aims: This study aimed to evaluate environmental factors that affect dust mite propagation in the tropics., Materials & Methods: Dust mites were introduced to a variety of flour samples and incubated at two different environmental conditions., Results: It was found that dust mites populations flourished best in wheat flour compared to other varieties of flour, and at ambient temperatures with high humidity instead of the air conditioned environment., Conclusion: Dust mite infestation of flour is dependent on the presence of wheat and high ambient temperature in the tropics.

Background: Analysis of cross-reactivity between the nematode Ascaris ssp. and dust mites, two important allergen sources in the tropics, will contribute in understanding their influence on asthma and atopy. The objective of this study was to investigate immunoglobulin E (IgE) cross-reactivity between Ascaris and two domestic mites in the tropics., Methods: Sera from 24 asthmatic patients were used in ELISA and immunoblotting IgE-binding inhibition assays using Ascaris, Blomia tropicalis and Dermatophagoides pteronyssinus extracts and the recombinants Blo t 10, ABA-1 and Blo t 13 as competitors. Identification of Ascaris allergens was confirmed by mass spectrometry (LC-MS/MS)., Results: We detected at least 12 human IgE-binding components in Ascaris extract. Blomia tropicalis and D. pteronyssinus inhibited 83.3% and 79% of IgE-binding to Ascaris, while Ascaris inhibited 58.3% and 79.3% to B. tropicalis and D. pteronyssinus respectively. Mite tropomyosin inhibited 85% of IgE-binding to Ascaris. Affinity-purified human IgE to rBlo t 10 identified an allergen of 40 kDa in Ascaris extract, further confirmed as tropomyosin by LC-MS/MS. We found no evidence of IgE cross-reactivity between rABA-1 and any allergen component in mite extracts, including rBlo t 13., Conclusions: There is cross-reactivity between Ascaris and mites, determined by several allergens including tropomyosin and glutathione-S-transferase. In addition to its potential impact on asthma pathogenesis, Ascaris infection and mite allergy diagnosis relying on the determination of specific IgE could be affected by this cross-reactivity. ABA-1 has no cross-reactive counterpart in mite extracts, suggesting its usefulness as a more specific marker of Ascaris infection.

Fve is a fungal protein isolated from the golden needle mushroom Flammulina velutipes and has previously been reported to trigger immunological responses in both mouse and human lymphocytes. In this study, we evaluated the potential application of Fve as an adjuvant for tumour immunotherapy and examined the underlying mechanism(s). When the human papillomavirus (HPV)-16 E7 oncoprotein was used as a model antigen, mice coimmunized with HPV-16 E7 and Fve showed enhanced production of HPV-16 E7-specific antibodies as well as expansion of HPV-16 E7-specific interferon (IFN)-gamma-producing CD4(+) and CD8(+) T cells as compared with mice immunized with HPV-16 E7 alone. Tumour protection assays showed that 60% of mice coimmunized with HPV-16 E7 plus Fve, as compared with 20% of those immunized only with HPV-16 E7, remained tumour-free for up to 167 days after challenge with the tumour cells. Tumour therapeutic assays showed that HPV-16 E7 plus Fve treatment significantly prolonged the survival of tumour-bearing mice as compared with those treated only with HPV-16 E7. In vivo cell depletion and adoptive T-cell transfer assays showed that CD4(+) and CD8(+) T cells and IFN-gamma played critical roles in conferring the antitumour effects. Interestingly, Fve could stimulate the maturation of splenic dendritic cells in vivo and induce antigen-specific CD8(+) T-cell immune responses. In summary, Fve has potent adjuvant properties that enhance T helper type 1 antigen-specific humoral and cellular immune responses which confer strong antitumour effects. The use of Fve as an adjuvant could be an attractive alternative to the current vaccination strategy for cancer immunotherapy.