Detection of Bacterial Neutral Ceramidase in Diabetic Foot Ulcers with an Optimized Substrate and Chemoenzymatic Probes.

Ceramidases (CDases) are important in controlling skin barrier integrity by regulating ceramide composition and affording downstream signal molecules. While the functions of epidermal CDases are known, roles of neutral CDases secreted by skin-residing microbes are undefined. Here, we developed a one-step fluorogenic substrate, S-B, for specific detection of bacterial CDase activity and inhibitor screening. We identified a non-hydrolyzable substrate mimic, C6, as the best hit. Based on C6, we designed a photoaffinity probe, JX-1, which efficiently detects bacterial CDases. Using JX-1, we identified endogenous low-abundance PaCDase in a P. aeruginosa monoculture and in a mixed skin bacteria culture. Harnessing both S-B and JX-1, we found that CDase activity positively correlates with the relative abundance of P. aeruginosa and is negatively associated with wound area reduction in clinical diabetic foot ulcer patient samples. Overall, our study demonstrates that bacterial CDases are important regulators of skin ceramides and potentially play a role in wound healing.

A wireless and battery-free wound infection sensor based on DNA hydrogel.

The confluence of wireless technology and biosensors offers the possibility to detect and manage medical conditions outside of clinical settings. Wound infections represent a major clinical challenge in which timely detection is critical for effective interventions, but this is currently hindered by the lack of a monitoring technology that can interface with wounds, detect pathogenic bacteria, and wirelessly transmit data. Here, we report a flexible, wireless, and battery-free sensor that provides smartphone-based detection of wound infection using a bacteria-responsive DNA hydrogel. The engineered DNA hydrogels respond selectively to deoxyribonucleases associated with pathogenic bacteria through tunable dielectric changes, which can be wirelessly detected using near-field communication. In a mouse acute wound model, we demonstrate that the wireless sensor can detect physiologically relevant amounts of Staphylococcus aureus even before visible manifestation of infection. These results demonstrate strategies for continuous infection monitoring, which may facilitate improved management of surgical or chronic wounds.

Primary Care Prognostic (PCP) Index of 11-Year Mortality Risk: Development and Validation of a Brief Prognostic Tool.

BACKGROUND: Healthcare providers use a life expectancy of at least 5 to 10 years in shared clinical decision-making with older adults about cancer screening, major surgeries, and disease prevention interventions. At present, few prognostic indexes predict long-term mortality beyond 10 years or are suited for use in primary care settings. OBJECTIVE: We developed and validated an 8-item multidimensional index predicting 11-year mortality for use in primary care. DESIGN, SETTING, AND PARTICIPANTS: Using data from the Singapore Longitudinal Ageing Studies (SLAS), we developed a Primary Care Prognostic (PCP) Index for predicting 11-year mortality risk in a development cohort (n = 1550) and validated it in a geographically different cohort (n = 928). MAIN MEASURES: The PCP Index was derived from eight indicators (body mass loss, weakness, slow gait, comorbidity, polypharmacy, IADL/BADL dependency, low albumin, low total cholesterol, out of 25 candidate indicators) using stepwise Cox proportional hazard models. KEY RESULTS: In the developmental cohort, the mortality hazard ratio increased by 53% per PCP point score increase, independent of age and sex. Across risk categories, absolute risks of mortality increased from 5% (score 0) to 67.9% (scores 7-9), with area under curve (AUC = 0.77 (95% CI 0.73-0.80)). The PCP Index also predicted mortality in the validation cohort, with AUC = 0.70 (95% CI 0.64-0.75). CONCLUSIONS: The PCP Index using simple clinical assessments and point scoring is a potentially useful prognostic tool for predicting long-term mortality and is well suited for risk stratification and shared clinical decision-making with older adults in primary care.

Increasing Influenza and Pneumococcal Vaccination Uptake in Seniors Using Point-of-Care Informational Interventions in Primary Care in Singapore: A Pragmatic, Cluster-Randomized Crossover Trial.

Objectives. To evaluate the effectiveness of point-of-care informational interventions in general practitioner clinics to improve influenza and pneumococcal vaccination uptake among elderly patients.Methods. We conducted a pragmatic, cluster-randomized crossover trial in 22 private general practitioner clinics in Singapore, from November 2017 to July 2018. We included all patients aged 65 years or older. Clinics were assigned to a 3-month intervention (flyers and posters encouraging vaccination) plus 1-month washout period, and a 4-month control period (usual care). Primary outcomes were differences in vaccination uptake rates between periods. Secondary outcomes were identification of other factors associated with vaccination uptake.Results. A total of 4378 and 4459 patients were included in the intervention and control periods, respectively. Both influenza (5.9% vs 4.8%; P = .047) and pneumococcal (5.7% vs 3.7%; P = .001) vaccination uptake rates were higher during the intervention period compared with the control period. On multilevel logistic regression analysis, follow-up for hypertension, diabetes mellitus, hyperlipidemia, or any combination of the 3 was associated with uptake of both vaccines.Conclusions. Point-of-care informational interventions likely contributed to increased influenza and pneumococcal vaccination uptake. Patients on follow-up for hypertension, diabetes mellitus, hyperlipidemia, or any combination of the 3 were more likely to receive influenza and pneumococcal vaccination and should be actively engaged by physicians.Trial Registration. ClinicalTrials.gov Identifier: NCT03445117.

Hallmark trials in ANCA-associated vasculitis (AAV) for the pediatric rheumatologist.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a complex group of systemic vasculitides that are characterized by primary small-to-medium sized blood vessel inflammation with the presence of autoantibodies known as ANCA. AAV diseases include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), and Microscopic Polyangiitis (MPA). AAVs are challenging conditions associated with high cumulative disease and treatment related morbidity and mortality. Given its rarity and the resulting paucity of pediatric-specific clinical trial evidence, pediatric rheumatologists have had to often extrapolate from adult literature for management and therapeutic decisions. The aim of this review is to provide a comprehensive overview of the important findings and overall conclusions of critical landmark clinical trials in the induction and maintenance treatments in adult AAV for the pediatric rheumatologist. This review also highlights the outcomes of recent pediatric AAV observational studies and discusses the future research priorities in pediatric AAV management.

Determinants of poor sleep quality in elderly patients with diabetes mellitus, hyperlipidemia and hypertension in Singapore.

AimThe objective of this study was to assess determinants of poor sleep quality which is an under-diagnosed and under-treated problem in elderly patients with diabetes mellitus, hyperlipidemia and hypertension. BACKGROUND: Poor sleep quality is linked to decreased quality of life, increased morbidity and mortality. Poor sleep quality is common in the elderly population with associated cardiometabolic risk factors such as diabetes, hyperlipidemia and hypertension. METHODS: This is a cross-sectional study undertaken in the primary healthcare setting (Singhealth Polyclinics-Outram) in Singapore. Singaporeans aged 65 years and above who had at least one of the three cardiometabolic risk factors (diabetes, hypertension and hyperlipidemia) were identified. Responders' sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire and were divided into those with good quality sleep and those with poor quality sleep, based on the PSQI score. Information on demographics, co-morbidities and lifestyle practices were collected. Descriptive and multivariate analyses of determinants of poor sleep were determined.FindingsThere were 199 responders (response rate 88.1%). Nocturia (adjusted prevalence rate ratio 1.54, 95% confidence interval 1.06-2.26) was found to be associated with an increased risk of poor sleep quality in elderly patients with diabetes mellitus, hypertension and hyperlipidaemia. Nocturia, a prevalent problem in the Asian elderly population, has been found to be associated with poor sleep quality in our study. Hence, it is imperative to identify and treat patients with nocturia to improve sleep quality among them.

Clinical features and seasonality of parechovirus infection in an Asian subtropical city, Hong Kong.

BACKGROUND: The epidemiology of human parechovirus (HPeV) in Asia remains obscure. We elucidated the prevalence, seasonality, type distribution and clinical presentation of HPeV among children in Hong Kong. METHODS: A 24-month prospective study to detect HPeV in children ≤36 months hospitalized for acute viral illnesses. RESULTS: 2.3% of the 3911 children examined had HPeV infection, with most (87.5%) concentrated in September-January (autumn-winter). 81.3% were HPeV1 and 12.5% were HPeV4, while HPeV3 was rare (2.5%). HPeV was a probable cause of the disease in 47.7% (42/88), mostly self-limiting including acute gastroenteritis, upper respiratory tract infection and maculopapular rash. A neonate developed severe sepsis-like illness with HPeV3 as the only pathogen detected. A high proportion (60.0%) of children coinfected with HPeV and other respiratory virus(es) had acute bronchiolitis or pneumonia. Six children with HPeV coinfections developed convulsion / pallid attack. Most rash illnesses exhibited a generalized maculopapular pattern involving the trunk and limbs, and were more likely associated with HPeV4 compared to other syndrome groups (36.4% vs. 3.1%, p = 0.011). CONCLUSIONS: In Hong Kong, HPeV exhibits a clear seasonality (autumn-winter) and was found in a small proportion (2.3%) of young children (≤36 months) admitted with features of acute viral illnesses. The clinical presentation ranged from mild gastroenteritis, upper respiratory tract infection and febrile rash to convulsion and severe sepsis-like illness. HPeV3, which is reported to associate with more severe disease in neonates, is rare in Hong Kong. HPeV coinfection might associate with convulsion and aggravate other respiratory tract infections.

Perforin gene mutation in familial haemophagocytic lymphohistiocytosis: the first reported case from Hong Kong.

Familial haemophagocytic lymphohistiocytosis is a rare but invariably fatal disease without haematopoietic stem cell transplantation. Genetic defect identification is useful for confirming a clinical diagnosis, predicting the risk of future recurrence, and defining haemophagocytic lymphohistiocytosis predisposition in asymptomatic family members. Notably, familial haemophagocytic lymphohistiocytosis type 2 associates with mutations in the perforin gene (PRF1) which is the most frequent subtype of familial haemophagocytic lymphohistiocytosis. Although perforin gene mutations have been described in Asians, they are largely reported from Japan. The case reported here is the first familial haemophagocytic lymphohistiocytosis type 2 patient in Hong Kong with an identified perforin gene mutation.

Inherited metabolic diseases in the Southern Chinese population: spectrum of diseases and estimated incidence from recurrent mutations.

Inherited metabolic diseases (IMDs) are a large group of rare genetic diseases. The spectrum and incidences of IMDs differ among populations, which has been well characterised in Caucasians but much less so in Chinese. In a setting of a University Hospital Metabolic Clinic in Hong Kong, over 100 patients with IMDs have been seen during a period of 13 years (from 1997 to 2010). The data were used to define the spectrum of diseases in the Southern Chinese population. Comparison with other populations revealed a unique spectrum of common IMDs. Furthermore, the incidence of the common IMDs was estimated by using population carrier frequencies of known recurrent mutations. Locally common diseases (their estimated incidence) include (1) glutaric aciduria type 1 (∼1/60,000), (2) multiple carboxylase deficiency (∼1/60,000), (3) primary carnitine deficiency (∼1/60,000), (4) carnitine-acylcarnitine translocase deficiency (∼1/60,000), (5) glutaric aciduria type 2 (∼1/22,500), (6) citrin deficiency (∼1/17,000), (7) tetrahydrobiopterin-deficient hyperphenylalaninaemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency (∼1/60,000), (8) glycogen storage disease type 1 (∼1/150,000). In addition, ornithine carbamoyltransferase deficiency and X-linked adrenoleukodystrophy are common X-linked diseases. Findings of the disease spectrum and treatment outcome are summarised here which may be useful for clinical practice. In addition, data will also be useful for policy makers in planning of newborn screening programs and resource allocation.

Rotavirus incidence in hospitalised Hong Kong children: 1 July 1997 to 31 March 2011.

Sentinel laboratory surveillance from one hospital and passive discharge diagnosis (Clinical Management System, CMS) data from all public Hospital Authority (HA) hospitals were used to estimate disease burden and incidence of rotavirus in hospitalised Hong Kong children over 14 rotavirus seasons (1 July 1997 to 31 March 2011). A primary diagnosis of a gastroenteritis-related disorder was noted in 9.8% of children aged below 5 years, and a primary or secondary diagnosis in 11.8%. Any CMS diagnosis of rotavirus (ICD 008.61) was initially used to derive incidence estimates of rotavirus by age group. Rotavirus was recorded as any primary or any secondary diagnosis in 1.6% of children below 5 years of age. The unadjusted incidence rates per 100,000 person-years based on any CMS diagnosis of rotavirus were: 249 (0 to <1m); 612 (1 to <2m); 1066 (2 to <6m); 1383 (6 to <11m); 959 (1 to <2y); 406 (2 to <3y); 233 (3 to <4y); 124 (4 to <5y). Overall the rotavirus incidence was 1071 in children below 2 years and 542 in children below 5 years of age, with the incidence rates trending up during the time period (p=0.001). A similar but less marked upward trend (p=0.046) was noted for the incidence of all-cause gastroenteritis. Laboratory results from a single surveillance hospital (1 July 2000 to 31 March 2011) were then linked to these CMS codes to derive adjustment factors for possible over- and under-diagnosis of rotavirus based on CMS codes alone. This analysis suggested that a CMS diagnosis of rotavirus alone likely under-reported true incidence by a factor of between 1.59 and 2.02 in children below 5 years of age. Despite the availability of rotavirus vaccines in the private sector since 2006, no reduction in the incidence of hospitalisation for either rotavirus or all-cause gastroenteritis was noted in Hong Kong children below 5 years of age over 14 rotavirus seasons (1997-2011).

Isolated persistent elevation of alanine transaminase for early diagnosis of pre-symptomatic Wilson's disease in Chinese children.

BACKGROUND: Recent studies presented a contradictory approach for the investigation of pediatric patients with an isolated increase in alanine transaminase. While classical teaching advised for a thorough investigation, recent studies suggested the yield on further investigation was low and thus not necessary. Yet the approach to the same clinical problem may need to be different due to variable disease prevalence rates among different ethnic populations. For the population with a higher prevalence rate of genetic liver diseases like Wilson's disease, an abnormal liver function may be the first presenting feature for some patients. METHODS: We reviewed 10 Chinese children with Wilson's disease who were diagnosed at a presymptomatic stage because of an isolated persistent elevation of alanine transaminase. RESULTS: All 10 patients did not have overt symptoms of liver impairment or neurological deficit. They were picked up incidentally with an abnormal liver function test. All patients were started on treatment shortly after diagnosis, and they remained well and symptom-free on the latest follow-up. CONCLUSIONS: This case series illustrated that an isolated persistent elevation of alanine transaminase is an important clue to the early diagnosis of pre-symptomatic Wilson's disease. It is particularly relevant in the Asian population where the disease is more prevalent.

The SF-36v2 and SF-12v2 health surveys in New Zealand: norms, scoring coefficients and cross-country comparisons.

OBJECTIVE: To provide New Zealand population norms for version 2 of the SF-36 and SF-12 health surveys and report scoring coefficients that enable the construction of Physical and Mental Component Summary scores from New Zealand SF-36v2 and SF-12v2 data. APPROACH: Norms for the SF-36v2 and scoring coefficients for the Physical and Mental Component Summary scores are estimated using 2006/07 New Zealand Health Survey data, which included 12,488 adults (aged 15 years and over). Norms for the SF-12v2 are derived from 2008 New Zealand General Social Survey data, including 8,721 adults. Comparisons are made between New Zealand norms for versions 1 and 2 of the SF-36 instrument. In addition, New Zealand SF-36v2 and SF-12v2 norms and the scoring coefficients are compared with those for the United States and South Australia. CONCLUSION: Differences between: 1) New Zealand population norms for the SF-36 versions 1 and 2; and 2) SF-36v2 and SF-12v2 population norms for New Zealand and those for the United States and South Australia highlight the importance of using version-specific and country-specific population norms. IMPLICATIONS: The analysis reported here allows for the appropriate use of the SF-36v2 and SF-12v2 instruments in New Zealand.