Social Frailty and Executive Function: Association with Geriatric Syndromes, Life Space and Quality of Life in Healthy Community-Dwelling Older Adults.

BACKGROUND: Despite emerging evidence about the association between social frailty and cognitive impairment, little is known about the role of executive function in this interplay, and whether the co-existence of social frailty and cognitive impairment predisposes to adverse health outcomes in healthy community-dwelling older adults. OBJECTIVES: We aim to examine independent associations between social frailty with the MMSE and FAB, and to determine if having both social frailty and cognitive impairment is associated with worse health outcomes than either or neither condition. METHODS: We studied 229 cognitively intact and functionally independent community-dwelling older adults (mean age= 67.2±7.43). Outcome measures comprise physical activity; physical performance and frailty; geriatric syndromes; life space and quality of life. We compared Chinese Mini Mental State Examination (CMMSE) and Chinese Frontal Assessment Battery (FAB) scores across the socially non-frail, socially pre-frail and socially frail. Participants were further recategorized into three subgroups (neither, either or both) based on presence of social frailty and cognitive impairment. Cognitive impairment was defined as a score below the educational adjusted cut-offs in either CMMSE or FAB. We performed logistic regression adjusted for significant covariates and mood to examine association with outcomes across the three subgroups. RESULTS: Compared with CMMSE, Chinese FAB scores significantly decreased across the social frailty spectrum (p<0.001), suggesting strong association between executive function with social frailty. We derived three subgroups relative to relationship with socially frailty and executive dysfunction: (i) Neither, N=140(61.1%), (ii) Either, N=79(34.5%), and (iii) Both, N=10(4.4%). Compared with neither or either subgroups, having both social frailty and executive dysfunction was associated with anorexia (OR=4.79, 95% CI= 1.04-22.02), near falls and falls (OR= 5.23, 95% CI= 1.10-24.90), lower life-space mobility (odds ratio, OR=9.80, 95% CI=2.07-46.31) and poorer quality of life (OR= 13.2, 95% CI= 2.38-73.4). CONCLUSION: Our results explicated the association of executive dysfunction with social frailty, and their synergistic relationship independent of mood with geriatric syndromes, decreased life space and poorer quality of life. In light of the current COVID-19 pandemic, the association between social frailty and executive dysfunction merits further study as a possible target for early intervention in relatively healthy older adults.

Disentangling the Relationship between Frailty and Intrinsic Capacity in Healthy Community-Dwelling Older Adults: A Cluster Analysis.

BACKGROUND: Frailty and intrinsic capacity (IC) are distinct but interrelated constructs. Uncertainty remains regarding how they are related and interact to influence health outcomes. We aim to understand the relationship between frailty and IC by identifying subgroups based on frailty criteria and IC domains and studying one-year outcomes. METHODS: We studied 200 independent community-dwelling older adults (mean age 67.9±7.9 years, Modified Barthel Index (MBI) score 99±2.6). Frailty was defined by modified Fried criteria. Scores (range: 0-2) were assigned to individual IC domains (cognition, psychological, locomotion, and vitality) to yield a total IC score of 8. To identify subgroups, two-step cluster analysis was performed with age, frailty and IC domains. Cluster associations with one-year outcomes (frailty, muscle strength (grip strength, repeated chair stand test), physical performance (gait speed, Short Physical Performance Battery), function (MBI) and quality-of-life (EuroQol (EQ)-5D)) were examined using multiple linear regression adjusted for age, gender and education. RESULTS: Three distinct clusters were identified - Cluster 1: High IC/Robust (N=74, 37%); Cluster 2: Intermediate IC/Prefrail (N=73, 36.5%); and Cluster 3: Low IC/Prefrail-Frail (53, 26.5%). Comparing between clusters, IC domains, cognition, depressive symptoms, nutrition, strength and physical performance were least impaired in Cluster 1, intermediate in Cluster 2 and most impaired in Cluster 3. At one year, the proportion transitioning to frailty or remaining frail was highest in Cluster 3 compared to Cluster 2 and Cluster 1 (39% vs 6.9% vs 2.8%, P<0.001). Compared to Cluster 1, Cluster 3 experienced greatest declines in grip strength (ß=-4.1, P<.001), MBI (ß=-1.24, P=0.045) and EQ-5D utility scores (ß=-0.053, P=0.005), with Cluster 2 intermediate between Cluster 1 and Cluster 3. CONCLUSIONS: Amongst independent community-dwelling older adults, IC is complementary to frailty measures through better risk-profiling of one-year outcomes amongst prefrail individuals into intermediate and high-risk groups. The intermediate group merits follow-up to ascertain longer-term prognosis.

An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T).

BACKGROUND: ATM, the protein defective in the human genetic disorder, ataxia-telangiectasia (A-T) plays a central role in response to DNA double-strand breaks (DSBs) and in protecting the cell against oxidative stress. We showed that A-T cells are hypersensitive to metabolic stress which can be accounted for by a failure to exhibit efficient endoplasmic reticulum (ER)-mitochondrial signalling and Ca2+ transfer in response to nutrient deprivation resulting in mitochondrial dysfunction. The objective of the current study is to use an anaplerotic approach using the fatty acid, heptanoate (C7), a metabolic product of the triglyceride, triheptanoin to correct the defect in ER-mitochondrial signalling and enhance cell survival of A-T cells in response to metabolic stress. METHODS: We treated control cells and A-T cells with the anaplerotic agent, heptanoate to determine their sensitivity to metabolic stress induced by inhibition of glycolysis with 2- deoxyglucose (2DG) using live-cell imaging to monitor cell survival for 72 h using the Incucyte system. We examined ER-mitochondrial signalling in A-T cells exposed to metabolic stress using a suite of techniques including immunofluorescence staining of Grp75, ER-mitochondrial Ca2+ channel, the VAPB-PTPIP51 ER-mitochondrial tether complexes as well as proximity ligation assays between Grp75-IP3R1 and VAPB1-PTPIP51 to establish a functional interaction between ER and mitochondria. Finally, we also performed metabolomic analysis using LC-MS/MS assay to determine altered levels of TCA intermediates A-T cells compared to healthy control cells. RESULTS: We demonstrate that heptanoate corrects all aspects of the defective ER-mitochondrial signalling observed in A-T cells. Heptanoate enhances ER-mitochondrial contacts; increases the flow of calcium from the ER to the mitochondrion; restores normal mitochondrial function and mitophagy and increases the resistance of ATM-deficient cells and cells from A-T patients to metabolic stress-induced killing. The defect in mitochondrial function in ATM-deficient cells was accompanied by more reliance on aerobic glycolysis as shown by increased lactate dehydrogenase A (LDHA), accumulation of lactate, and reduced levels of both acetyl CoA and ATP which are all restored by heptanoate. CONCLUSIONS: We conclude that heptanoate corrects metabolic stress in A-T cells by restoring ER-mitochondria signalling and mitochondrial function and suggest that the parent compound, triheptanoin, has immense potential as a novel therapeutic agent for patients with A-T.

A validation framework to assess performance of commercial deformable image registration in lung radiotherapy.

INTRODUCTION: Deformable image registration (DIR) can play an important role in the context of adaptive radiotherapy. The AAPM Task Group 132 (TG-132) has described several quantitative measures for DIR error assessment but they can only be accurately defined when there is a ground-truth present in high-contrast regions. This work aims to set out a framework to obtain optimal results for CT-CT lung DIR in clinical setting for a commercially available system by quantifying the DIR performance in both low- and high-contrast regions. METHODS: Five publicly available thorax datasets were used to assess the DIR quality. A "Ghost fiducial" method was implemented by windowing the contrast in a new feature provided by Varian Velocity v4.1. Target registration error (TRE) of the landmarks and Dice-similarity coefficient of the tumour were calculated at three different contrast settings to assess the algorithm in high- and low-contrast scenarios. RESULTS: For the original unedited dataset, higher resolution DIR methods showed best performance acceptable within the recommended limit according to TG-132, when actual displacements were less than 10 mm. The relation of the actual displacement of the landmarks and TRE shows the limited capacity of the algorithm to deal with movements larger than 10 mm. CONCLUSION: This work found the performance of DIR methods and settings available in Varian Velocity v4.1 to be a function of contrast level as well as extent of motion. This highlights the need for multiple metrics to assess different aspects of DIR performance for various applications related to low-contrast and/or high-contrast regions.

Grip Strength Criterion Matters: Impact of Average Versus Maximum Handgrip Strength on Sarcopenia Prevalence and Predictive Validity for Low Physical Performance.

IMPORTANCE: Muscle strength has been elevated to the forefront of sarcopenia diagnosis, with handgrip strength the preferred measure. Extant handgrip protocols adopt different handgrip strength (HGS) criteria. Paucity of direct comparison studies assessing the impact of HGS criterion on prevalence of sarcopenia and predictive validity on physical performance contributes to the lack of standardisation of HGS criteria in sarcopenia diagnosis. OBJECTIVES: Our study aims to compare the effect of average (HGSave) versus maximum (HGSmax) HGS criterion on: (1) prevalence of low HGS and sarcopenia; and (2) association with physical performance at baseline and at 2 years. METHODS: We recruited 200 community dwelling, cognitively intact, and functionally independent older adults. Muscle strength, physical performance measures, cognitive tests and nutritional assessments were performed. Short Physical Performance Battery (SPPB) was administered at baseline and at 2 years. We compared HGSave and HGSmax to assess the prevalence of low HGS and sarcopenia. Univariate analysis was performed comparing baseline characteristics between low and normal groups for each HGS criterion. Significantly different variables were included in logistic regression analysis to examine association of low HGS and SPPB at baseline. Predictive validity of low HGS for SPPB<10 at 2 years was examined by performing logistic regression analysis for HGSave and HGSmax. RESULTS: The prevalence of low HGS and sarcopenia incorporating HGSave criterion is 40% and 33% respectively, whereas that of HGSmax criterion is 21% and 19.5% respectively. There is moderate agreement between the 2 HGS criteria for sarcopenia diagnosis (kappa=0.604) and poorer agreement for low HGS (kappa=0.570). There was no significant association with baseline SPPB for both HGS criteria. At 2 years, only low HGSmax was significantly associated with low SPPB (adjusted OR 3.91, 95% CI 1.24 - 12.33). CONCLUSION: Our study demonstrates that HGS criteria matters in diagnosis of sarcopenia and we support extant HGS protocols using HGSmax criterion in view of better predictive validity for poor physical performance.

Characterization and in vitro evaluation of a vaginal gel containing Lactobacillus crispatus for the prevention of gonorrhea.

The increasing resistance of Neisseria gonorrhoeae to any current antibiotic treatment and the difficulties associated with the use of prevention means such as condom urge the need for alternative methods to prevent this sexually transmitted infection. In this work, a prevention strategy based on the use of a vaginal gel containing Lactobacilli was assessed in vitro. A Lactobacillus crispatus strain (ATCC 33197) was selected based on the published data on its ability to inhibit Neisseria gonorrhoeae. Its probiotic properties were first characterized. Then, a thermo-sensitive hydrogel containing 21.5% of poloxamer 407, 1% of sodium alginate and 9log10 CFU of Lactobacillus crispatus per gel sample (5 g) was developed. The gelation temperature and the rheological characteristics of this formulation appeared suitable for a vaginal administration. Lactobacillus crispatus was viable in the gel for six months although a large amount of the bacteria was not culturable. The ability of Lactobacillus crispatus to inhibit Neisseria gonorrhoeae was still observed with the gel. Such system, thus, appeared promising for the prevention of gonorrhea.

Muscle Strength Definitions Matter: Prevalence of Sarcopenia and Predictive Validity for Adverse Outcomes Using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) Criteria.

BACKGROUND: EWGSOP2 criteria for sarcopenia recommends the use of either handgrip strength (GS) or 5-times repeated chair stand test (RCS) as a muscle strength measure. We aim to compare the impact of different muscle strength definitions on sarcopenia prevalence and predictive validity for 2-year outcomes, using the EWGSOP2 clinical algorithm. METHODS: We studied 200 community-dwelling older adults, comparing sarcopenia prevalence using three muscle strength definitions: 1) maximum GS (Asian Working Group cutoffs); 2) RCS-1 (standard cutoff >15s); and 3) RCS-2 (ROC-derived cutoff >12.5s). Two-year outcomes include: 1) Incident frailty (modified Fried criteria); 2) Physical performance [Short Physical Performance Battery (SPPB) score <10]; and 3) Quality of life [EuroQol-5 dimension (EQ-5D) <25th percentile]. We performed logistic regression on 2-year outcomes adjusted for age, gender, cognition and mood. RESULTS: Prevalence of confirmed sarcopenia was 14.5%, 4% and 9% for GS, RCS-1 and RCS-2 respectively. For 2-year outcomes (N=183), RCS-2 predicted incident frailty (OR: 5.7, 95% CI 1.4-22.8, p=0.013), low SPPB (OR: 4.4, 95% CI 1.4-13.1, p=0.009), and trended towards predicting low QOL (OR: 2.1, 95% CI 0.9-4.9, p=0.095). In contrast, GS and RCS-1 did not predict frailty nor low QOL, but predicted low SPPB only (GS: OR 3.8, 95% CI 1.3-10.6, p=0.01; RCS-1: OR: 8.8, 95% CI 2.2-35.0, p=0.002). CONCLUSIONS: Sarcopenia prevalence varies with muscle strength definitions, with GS being significantly higher vis-à-vis RCS definitions. Our results also support the use of population-specific over standard cutoffs for RCS to obtain intermediate estimates of sarcopenia prevalence and the best predictive validity for two-year outcomes.

Obesity Definitions in Sarcopenic Obesity: Differences in Prevalence, Agreement and Association with Muscle Function.

BACKGROUND: Sarcopenic obesity (SO) is associated with poorer physical performance in the elderly and will increase in relevance with population ageing and the obesity epidemic. The lack of a consensus definition for SO has resulted in variability in its reported prevalence, poor inter-definitional agreement, and disagreement on its impact on physical performance, impeding further development in the field. While sarcopenia definitions have been compared, the impact of obesity definitions in SO has been less well-studied. OBJECTIVES: To compare 3 widely-adopted definitions of obesity in terms of SO prevalence, inter-definitional agreement, and association with muscle function. DESIGN: Cross-sectional. SETTING: GERILABS study, Singapore Participants: 200 community-dwelling, functionally-independent older adults. MEASUREMENTS: We utilized three commonly-used definitions of obesity: body mass index (BMI), waist circumference (WC) and DXA-derived fat mass percentage (FM%). Sarcopenia was defined using Asian Working Group for Sarcopenia criteria. For muscle function, we assessed handgrip strength, gait speed and Short Physical Performance Battery (SPPB). Subjects were classified into 4 body composition phenotypes (normal, obese, sarcopenic and SO), and outcomes were compared between groups. RESULTS: The prevalence rate for SO was lowest for BMI (0.5%) compared to FM% (10.0%) and WC (10.5%). Inter-definitional agreement was lowest between BMI and WC (κ=0.364), and at best moderate between FM% and WC (κ=0.583). SO performed the worst amongst body composition phenotypes in handgrip strength, gait speed and SPPB (all p<0.01) only when defined using WC. In regression analyses, SO was associated with decreased SPPB scores (ß=-0.261, p=0.001) only for the WC definition. CONCLUSION: There is large variation in the prevalence of SO across different obesity definitions, with low-to-moderate agreement between them. Our results corroborate recent evidence that WC, and thus central obesity, is best associated with poorer muscle function in SO. Thus, WC should be further explored in defining obesity for accurate and early characterization of SO among older adults in Asian populations.

Roadmap Out of COVID-19.

The recent coronavirus disease (COVID-19) was declared as a public health emergency by the World Health Organisation on 30th January 2020, and has now affected more than 100 countries. Healthcare institutions and governments worldwide have raced to contain the disease, albeit to varying degrees of success. Containment strategies adopted range from complete lockdowns to remaining open with public advisories regarding social distancing. However, general principles adopted by most countries remain the same, mainly to avoid gatherings in large numbers and limit social interactions to curb the spread of disease. In Singapore, this disease had a very different progression. The first wave of the disease started with the confirmation of the first COVID-19 positive patient in Singapore on 23rd January 2020. Initially, the daily number of confirmed cases were low and manageable. With a rise in unlinked cases, the Disease Outbreak Response System Condition (DORSCON) status was raised from yellow to orange. New cluster outbreaks in foreign worker dormitories led to the rampant spread of disease, with daily spikes of COVID-19 cases. As of 7th June 2020, we have a total of 37,910 confirmed cases of COVID-19 infections, the highest in Southeast Asia, 12,999 active cases and a manageable mortality count of 25 deaths. This details our unique method for dealing with a pandemic, including a brief demographic of trauma patients during this period. We were able to conserve sufficient resources to ensure that our essential services can still continue. Moving on, we have to ensure the continued protection of our population, especially the vulnerable groups such as the elderly and the immunocompromised, as we reopen.

Serum Myostatin and IGF-1 as Gender-Specific Biomarkers of Frailty and Low Muscle Mass in Community-Dwelling Older Adults.

OBJECTIVES: (i) To investigate serum myostatin (absolute and normalized for total body lean mass (TBLM)) and IGF-1 as biomarkers of frailty and low relative appendicular skeletal muscle mass (RASM) in older adults, and; (ii) to examine gender differences in the association of serum myostatin and IGF-1 levels with frailty and low RASM. DESIGN: Cross-sectional study. SETTING: The "Longitudinal Assessment of Biomarkers for characterization of early Sarcopenia and predicting frailty and functional decline in community-dwelling Asian older adults Study" (GERI-LABS) study in Singapore. PARTICIPANTS: 200 subjects aged 50 years and older residing in the community. MEASUREMENTS: Frailty was assessed using the modified Fried criteria. Low RASM was defined using cutoffs for height-adjusted appendicular skeletal muscle mass measured by dual-energy X-ray absorptiometry as recommended by the Asian Working Group for Sarcopenia. Comorbidities, cognitive and functional performance, physical activity and nutritional status were assessed. Blood samples collected included serum myostatin, insulin-like growth factor 1 (IGF-1) and markers of inflammation (total white cell count, CRP, IL-6 and TNFaR1). Subjects were classified into 4 groups: Frail/Prefrail with low RASM (Frail/Low RASM), Frail/Prefrail with normal RASM (Frail/Normal RASM), Robust with low RASM (Robust/Low RASM) and Robust with normal RASM (Robust/Normal RASM). RESULTS: 63 (32%) subjects were classified as Frail/Low RASM, 53 (27%) Frail/Normal RASM, 28 (14%) Robust/Low RASM and 56 (28%) Robust/Normal RASM respectively. Frail/Low RASM subjects were older and had lower BMI compared to Frail/Normal RASM and robust subjects. Mean (SE) normalized myostatin levels were higher in Frail/Low RASM compared to Frail/Normal RASM subjects (1.0 (0.04) versus 0.84 (0.05) ng/ml/kg, P=0.01). Median (IQR) IGF-1 level was lower amongst Frail/Low RASM subjects compared to Frail/Normal RASM subjects (102.3, (77.7, 102.5) vs 119.7 (82.7, 146.0) ng/ml, P=0.046). No differences in myostatin or IGF-1 were observed among robust individuals with or without low muscle mass. In adjusted multinomial logistic regression models with Robust/Normal RASM as the reference group, myostatin (P=0.05) and IGF-1 (P=0.043) were associated with Frail/Low RASM status in the whole cohort. When stratified by gender, myostatin was significantly associated with Frail/Low RASM status in men only (P=0.03). In women, serum IGF-1 was associated with Frail/Low RASM status (P=0.046), but not myostatin (P=0.53). CONCLUSION: Serum myostatin, normalized for TBLM in men and IGF-1 in women are potential biomarkers for frail individuals with low RASM, and may identify a target group for intervention.

Gyroid structures for 3D-printed heterogeneous radiotherapy phantoms.

The extreme customisation and rapid prototyping capabilities of the 3D printing process allows the manufacture of low-cost and patient-specific radiotherapy phantoms for quality assurance purposes. However, the associated printing techniques and materials are experimentally limited and are yet to be quantified in terms of manufacturability. In addition to this, there lacks research in utilising naturally inspired structures, known as triply periodic minimal surfaces (TPMS), as a structural manufacturing basis for these phantoms, enabling material heterogeneity, which is a significant factor in attaining patient-specificity. We propose the use of Gyroid structures for radiotherapy phantom applications to investigate Gyroid-phantom manufacturability, the mathematical definition of Gyroids and their effects on hounsfield units (HU). The printed Gyroid phantoms were assessed for manufacturability using optical microscopy and micro-computed tomography (µCT), and material hounsfield-equivalence using standard medical CT. A mean HU range of -900 to -390 were achieved from the fabricated Gyroid phantoms with varying standard deviation. Compared to traditional printing infills such as grid and slit structures, the Gyroid phantoms were observed to produce isotropic HU and SD at varied scanning orientations, which optimizes CT attenuations in modulating the hounsfield-equivalence of printed structures. This study not only demonstrates the feasibility of manipulating the structural parameters of Gyroids in simulating tissue imaging attenuations but also opens significant research opportunities in fabricating patient-specific phantoms with added pathological features for end-to-end radiotherapy testing.

The challenge of differentiating vaso-occlusive crises from osteomyelitis in children with sickle cell disease and bone pain: A 15-year retrospective review.

PURPOSE: The paediatric sickle cell disease (SCD) osteomyelitis (OM) incidence is 0.3% to 12%. Differentiating vaso-occlusive crises (VOC) from OM is a diagnostic challenge, with limited evidence guiding management. We present a 15-year review of a paediatric sickle cell cohort. We aim to identify OM incidence and provide a management protocol for these children presenting with bone pain. METHODS: A prospective database of children with haemoglobinopathies (2002 to 2017) was analyzed for temperature, C-reactive protein (CRP) and white cell count (WCC) on admission as well as imaging, treatment and cultures. OM diagnosis was supported by imaging and blood cultures. VOC was defined as bone pain that improved without antibiotics. RESULTS: Over 15 years, 96 children with SCD presented 358 times to hospital. Empirical antibiotics were given in 308 presentations. There were five cases of OM (1.4%); two acute and three chronic. In all, 50 presentations of VOC were identified. No significant differences in age were noted between the OM and VOC group. Temperature and CRP were significantly elevated in the OM group with no significant difference in WCC. Cultures were only positive in the chronic OM admissions. There were no cases of septic arthritis. No surgical intervention was required. CONCLUSION: In children with SCD presenting with persistent bone pain, fever, elevated CRP and WCC, OM should be suspected and prompt antibiotic treatment started. Our treatment pathway was successful avoiding OM in 98.6% and septic arthritis in 100%. Further research on novel biological markers distinguishing OM from VOC should be investigated. LEVEL OF EVIDENCE: III.

BOS is associated with decreased HDAC2 from steroid resistant lymphocytes in the small airways.

Immunosuppression therapies including corticosteroids fail to prevent bronchiolitis obliterans syndrome (BOS), primarily a disease of the small airways, following lung transplantation. We reported increases in steroid-resistant proinflammatory lymphocytes and their loss of histone deacetylase 2 (HDAC2), an important mediator of steroid action, in the blood of stable lung transplant recipients. We noted similar increases in the steroid-resistant lymphocytes in both the blood and small airways in BOS compared with the large airways. We hypothesized that these small airway cells would also exhibit a loss of HDAC2, and that these changes could be reversed by treatment with theophylline (HDAC2 activator). Blood, bronchoalveolar lavage and large and small airway brushings were collected from lung transplant patients with BOS (n = 12) or stable lung function (n = 18) and healthy aged-matched controls (n = 13). Intracellular proinflammatory cytokines [interferon (IFN-γ) and tumour necrosis factor (TNF)-α and HDAC2 were measured in CD8+ T, natural killer (NK) T-like and NK cells from cultured small airway brushings ± 5 mg/l theophylline ± 1 µM prednisolone using flow cytometry. Increased small airway CD8 T, NK T-like and NK cells were identified in BOS versus stable transplant and controls. In BOS, these cells exhibited increased IFN-γ/TNF-α and a loss of HDAC2. HDAC2 expression by small airway CD8+ T cells correlated with forced expiratory volume in 1 s (FEV1 ) (R = 0·880, P = 0·031). Theophylline and prednisolone synergistically up-regulated HDAC2 in CD8+ T cells. BOS is associated with loss of HDAC2 from steroid-resistant proinflammatory CD8+ T, NK T-like and NK cells in the small airways. Therapeutically increasing HDAC2 in these lymphocytes may reduce steroid resistance and improve graft survival.

Clavicle fracture nonunion in the paediatric population: a systematic review of the literature.

AIMS: Clavicle fracture nonunions are extremely rare in children. The aim of this systematic review was to assess what factors may predispose children to form clavicle fracture nonunions and evaluate the treatment methods and outcomes. METHODS: We performed a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, aiming to find papers reporting clavicle fracture nonunion in children under the age of 18 years. Data was collected on patient demographics, fracture type, mechanism of injury (MOI), surgical intervention and reported outcome. Two independent reviewers evaluated all the data. RESULTS: A total of 13 articles reporting 21 cases of clavicle fracture nonunion were identified. The mean age at time of injury was 11.4 years (4 to 17). Falls were the most common MOI. The majority of nonunions occurred after displaced fractures on the right side. Six were refractures. Mean time of presentation following injury was 13.5 months (4 to 60). In all, 16 were treated surgically. Radiographic union was eventually achieved in 12 cases, with functional outcome satisfactory in all cases. CONCLUSION: Clavicle nonunion is an extremely rare but possible complication in children. The majority occur after displaced right-sided fractures or refractures and present around one year after injury. Surgical fixation provides good radiographic healing and functional outcomes. LEVEL OF EVIDENCE: IV.

Bronchiolitis obliterans syndrome is associated with increased p-glycoprotein expression and loss of glucocorticoid receptor from steroid-resistant proinflammatory CD8+ T cells.

Immunosuppressive therapy fails to suppress the production of proinflammatory cytokines, particularly by CD8+ T cells, in stable lung transplant recipients and those undergoing chronic rejection, suggesting that some patients may become relatively resistant to immunosuppressants such as glucocorticoids (GC). We have shown loss of GC receptor (GCR) from the CD8+ cells, and we hypothesized that the drug membrane efflux pump, p-glycoprotein-1 (Pgp), may also be involved in lymphocyte steroid resistance following lung transplant. Pgp/GCR expression and interferon (IFN)-γ/tumour necrosis factor (TNF)-α proinflammatory cytokine production was measured in blood lymphocytes from 15 stable lung transplant patients, 10 patients with bronchiolitis obliterans syndrome (BOS) and 10 healthy aged-matched controls (± prednisolone ± Pgp inhibitor, cyclosporin A ± GCR activator, Compound A) using flow cytometry. Both Pgp+ and Pgp- lymphocyte subsets from all subjects produced IFN-γ/TNF-α proinflammatory cytokines. Pgp expression was increased in CD8+ Pgp+ T cells and correlated with IFN-γ/TNF-α expression and BOS grade. Reduced GCR was observed in CD8+ Pgp- T, natural killer (NK) T-like and NK cells from stable patients compared with controls, and reduced further in CD8+ Pgp- T cells in BOS. The addition of 2·5 ng/ml cyclosporin A and 1 µM prednisolone inhibit IFN-γ/TNF-α production significantly by CD8+ Pgp+ T cells from BOS patients. The addition of 10 µM Compound A and 1 µM prednisolone inhibit IFN-γ/TNF-α production significantly by CD8+ Pgp- T cells from BOS patients. BOS is associated with increased Pgp expression and loss of GCR from steroid-resistant proinflammatory CD8+ T cells. Treatments that inhibit Pgp and up-regulate GCR in CD8+ T cells may improve graft survival.

A clinical audit to assess the efficacy of the Coolsense® Pain Numbing Applicator for intravenous cannulation in children.

The Coolsense® device is a topical applicator that is used to anaesthetise the skin before a painful procedure. It is a handheld device with a temperature-controlled head that acts on application, without chemicals, to cool and anaesthetise the site of injection. This prospective observational audit of 100 children and adolescents aged six to 18 years studied the analgesic efficacy and patient and carer satisfaction rating of the device during intravenous cannulation and complications arising from its use. The audit demonstrated effective skin analgesia for intravenous cannulation in children and adolescents. Ninety-four percent of patients rated the pain during cannulation as less than or equal to three on a numerical pain rating scale of zero to ten. Patient and carer satisfaction with the device and cannulation success rates were high; 66% of patients and 82% of carers 'really liked' the device and 28% of patients and 12% of carers 'liked' it. Ninety-five percent of patients were cannulated on the first attempt. The incidence of complications using the device was low. The Coolsense device appears to be a useful tool that provides effective analgesia for intravenous cannulation in children with minimal complications. Comparative studies with topical local anaesthesia creams are warranted.

Validity of estimating muscle and fat volume from a single MRI section in older adults with sarcopenia and sarcopenic obesity.

AIM: To determine if there is a correlation between the cross-sectional areas (CSAs) in a single section and the volumes of muscles and fat in the thigh of sarcopenic and sarcopenic obesity (SO) populations using magnetic resonance imaging (MRI), and to assess the correlation between thigh MRI data and patient health status, i.e., normal, obese, sarcopenia, and SO. MATERIALS AND METHODS: One hundred and ninety community-dwelling older adults were recruited and categorised into four subgroups based on Asian established criteria: normal, obese, sarcopenia, and SO. MRI images were acquired and muscles, subcutaneous fat (SF), and intermuscular fat (IMF) were automatically segmented in the thighs. Volumes of muscles and fat were calculated for the middle third of the thigh, while CSAs were assessed using a single section at 50% femur length. RESULTS: Correlation between CSA and volume were significantly high (p<0.001) for all components of muscle (0.907), SF (0.963), and IMF (0.939). Thigh CSA and volume both correlated significantly with a clinical diagnosis of normal, obesity, sarcopenia, and SO (p<0.03). CONCLUSIONS: A single CSA at 50% of femur length yields good estimation of muscle and fat volume in the thighs of older adults and correlates closely with the clinical criteria for sarcopenia and SO. This has the potential to greatly reduce costs, scan time, and post-processing time in clinical practice for the prediction of these conditions.

Lacrimal gland-derived IL-22 regulates IL-17-mediated ocular mucosal inflammation.

Inflammatory damage of mucosal surface of the eye is a hallmark of dry eye disease (DED) and, in severe cases, can lead to significant discomfort, visual impairment, and blindness. DED is a multifactorial autoimmune disorder with a largely unknown pathogenesis. Using a cross-sectional patient study and a well-characterized murine model of DED, herein we investigated the immunoregulatory function of interleukin-22 (IL-22) in the pathogenesis of DED. We found that IL-22 levels were elevated in lacrimal fluids of DED patients and inversely correlated with severity of disease. Acinar cells of the lacrimal glands (LGs), not inflammatory immune cells, are the primary source of IL-22, which suppresses inflammation in ocular surface epithelial cells upon desiccating stress. Moreover, loss of function analyses using IL-22 knockout mice demonstrated that IL-22 is essential for suppression of ocular surface infiltration of Th17 cells and inhibition of DED induction. Our novel findings elucidate immunoregulatory function of LG-derived IL-22 in inhibiting IL-17-mediated ocular surface epitheliopathy in DED thus making IL-22 a new relevant therapeutic target.

Enhancement of bifidobacteria survival by Williopsis saturnus var. saturnus in milk.

The viability of three strains of probiotic Bifidobacterium lactis that were inoculated into UHT milk was examined with and without the presence of the yeast, Williopsis saturnus var. saturnus NCYC 22, in polypropylene tubes at 30 °C. The B. lactis viable cell count for strains HN019 and BB-12 remained above 6.0 Log cfu/ml, while strain B94 had 5.7 Log cfu/ml after six weeks of incubation in the presence of the co-inoculated yeast. Incubating the bifidus milk without added yeast under anaerobic condition did not improve the survival of B. lactis HN019, indicating that oxygen removal may not be responsible for W. saturnus NCYC 22's viability enhancing property. The addition of yeast supernatant or non-viable yeast also did not show any stabilising effects, suggesting that physical contact and/or interaction between viable W. saturnus and B. lactis plays an important role in sustaining the viability of the probiotic. W. saturnus NCYC 22 could increase the survival of B. lactis in bifidus milk under ambient temperature regardless of the initial concentration of yeast cells inoculated due to yeast growth. This study demonstrated the viability enhancing effect of viable W. saturnus NCYC 22 on B. lactis HN019, which could help towards extending the shelf-life of dairy beverages containing probiotic bifidobacteria.