Alterations in the Choroidal Sublayers in Relationship to Severity and Progression of Diabetic Retinopathy: A Swept-Source OCT Study.

Purpose: To examine the association of baseline choroidal sublayers metrics with the risk of diabetic retinopathy (DR) progression over 2 years, with adjustment for confounding factors that affect choroidal measurements. Design: Prospective, observational cohort study. Participants: One hundred three eyes from 62 patients with diabetes mellitus (DM). Methods: Patients were followed up at 6-month intervals for at least 2 years. Choroidal metrics including choroidal area, choroidal thickness (CT), and choroidal vascularity index were measured for both (1) the choriocapillaris plus Sattler's layer and (2) the Haller's layer within the subfoveal and parafoveal region. Cox proportional models were constructed to estimate the relationship between baseline choroidal metrics and DR progression, adjusted for intereye correlation, established risk factors (i.e., duration of DM, glycated hemoglobin [HbA1c] level, body mass index [BMI], use of insulin, and mean arterial blood pressure [MABP]) and confounding factors of choroidal measurements (i.e., age and axial length). Additional predictive value of choroidal metrics was assessed using the C-statistic. Main Outcome Measures: Hazard ratios (HRs) calculated by Cox proportional hazards model to demonstrate the associations between baseline choroidal metrics and DR progression. Results: After adjusting for age, axial length, and intereye correlation, choroidal metrics in Haller's layer at baseline that were associated with a higher risk of DR progression included increases in subfoveal choroidal area (HR, 2.033; 95% confidence interval [CI], 1.179-3.505; P = 0.011), subfoveal plus parafoveal choroidal area (HR, 1.909; 95% CI, 1.096-3.326; P = 0.022), subfoveal CT (HR, 2.032; 95% CI, 1.181-3.498; P = 0.010), and subfoveal plus parafoveal CT (HR, 1.908; 95% CI, 1.097-3.319; P = 0.022). These associations remained statistically significant after additionally adjusting for duration of DM, HbA1c level, BMI, use of insulin, and MABP. Addition of these choroidal metrics significantly improved the discrimination for DR progression when compared with established risk factors alone (e.g., duration of DM and HbA1c; increase in C-statistic ranged from 8.08% to 9.67% [P < 0.05]). Conclusions: Eyes with a larger choroidal area and CT in Haller's layer at baseline were associated with a higher risk of DR progression over 2 years.

Total knee replacement in osteoarthritis patients on reducing the risk of major adverse cardiac events: a 18-year retrospective cohort study.

OBJECTIVES: Osteoarthritis (OA) is a common degenerative joint disease, and total knee replacement (TKR) is a successful surgical intervention for knee OA treatment. However, the risks of mortality and major cardiovascular events (MACEs) in patients receiving TKR remain unclear. This study investigated the risks of mortality and MACEs in knee OA patients who received TKR. METHODS: For this population-based cohort study, the Longitudinal Health Insurance Database 2000 was used. Two million individuals with knee OA defined by ICD-9-CM codes who received physical therapy between 1999 and 2017 were selected. For propensity score matching (PSM), we considered the year of knee OA diagnosis, demographics, comorbidities, co-medications, and knee OA-related hyaluronic acid or physical therapy at baseline. After PSM, regression analyses were performed to assess the association of mortality or MACEs with TKR and non-TKR individuals. RESULTS: We identified patients (n = 189,708) with a new diagnosis of knee OA between 2000 and 2017. In total, 10,314 propensity-score-paired TKR and non-TKR individuals were selected. The PSM cohort algorithm revealed that the risk of mortality or MACEs was lower in the TKR group (adjusted hazard ratio: 0.791; 95% confidence interval: 0.755-0.830) than in the non-TKR group. CONCLUSIONS: Patients with knee OA who received TKR had decreased risks of mortality and MACEs than those who did not receive TKR. Moreover, the TKR group received a reduced dosage of nonsteroidal anti-inflammatory drugs at the 1-year follow-up.

Frailty Assessment in Community-Dwelling Older Adults: A Comparison of 3 Diagnostic Instruments.

OBJECTIVES: Compare the diagnostic performance of FRAIL against Fried Phenotype and Frailty Index (FI), and identify clinical factors associated with pre-frailty/frailty. DESIGN: Cross-sectional analysis. SETTING: Community-based screenings in Senior Activity Centres, Residents' Corners and Community Centres in northeast Singapore. PARTICIPANTS: 517 community dwelling participants aged >55 years and ambulant independently (with/ without walking aids) were included in this study. Residents of sheltered or nursing homes, and seniors unable to ambulate at least four meters independently were excluded. MEASUREMENTS: The multidomain geriatric screen included assessments for social vulnerability, mood, cognition, sarcopenia and nutrition. Participants completed a battery of physical fitness tests for grip strength, gait speed, lower limb strength and power, flexibility, balance and endurance, with overall physical performance represented by Short Physical Performance Battery (SPPB). Frailty status was assigned on FRAIL, Fried and 35-item FI. RESULTS: Prevalence of frailty was 1.3% (FRAIL) to 3.1% (FI). Pre-frailty prevalence ranged from 17.0% (FRAIL) to 51.2% (FI). FRAIL demonstrated poor agreement with FI (kappa=0.171, p<0.0001), and Fried (kappa=0.194, p<0.0001). A lower FRAIL cut-off ≥1 yielded significantly improved AUC of 0.70 (95%CI 0.55 to 0.86, p=0.009) against Fried, and 0.71 (95%CI 0.55 to 0.86, p=0.008) against FI. All 3 frailty measures were diagnostic of impaired physical performance on SPPB, with AUCs ranging from 0.69 on FRAIL to 0.77 on Fried (all p values <0.01). Prevalence of low socio-economic status, depression, malnutrition and sarcopenia increased significantly, while fitness measures of gait speed, balance, and endurance declined progressively across robust, pre-frail and frail on all 3 frailty instruments (p <0.05). CONCLUSIONS: Our results suggest that different frailty instruments may capture over-lapping albeit distinct constructs, and thus may not be used interchangeably. FRAIL has utility for quick screening, and any positive response should trigger further assessment, including evaluation for depression, social vulnerability and malnutrition.

Centre for Youth Research and Practice: Social Impact Assessment Results.

Purpose: This article outlines the objective and structure of the Center for Youth Research and Practice (CYRP), its contributions toward youth research and practices, importance of the linkages that the CYRP has cultivated between research and practice, the facilitation of knowledge exchange with local and global institutions and professionals, and its role in future endeavors.Method: A social impact assessment has been implemented to address the intervention and the outcome based on the contributions of the CYRP to youth research and practices.Results: From this, the work of the CYRP on youth research and practices is concluded to have significant social impacts at the individual, social, organizational, and global levels. The work has found that the quality of life, self-esteem, involvement in society, empowerment through social capacity building, organizational development, and providing an international hub are crucial for youth development and wellbeing.Discussion: Hitherto, the CYRP has published over a hundred journal articles and held nearly 200 events including training courses, workshops, seminars and a conference. Over 6000 participants have taken part in these events and more than 60 institutions have collaborated with the CYRP to exchange knowledge on youth research and practices. The work of the CYRP as a whole has facilitated the participation of different individuals and organizations. In essence, the work of the CYRP has provided important grounds to initiate its role as an international hub as the CYRP is now considered as a center of significance in youth research and practices for Chinese societies in the East Asia region.

The many facets of neuropathic arthropathy.

Neuropathic arthropathy, also known as Charcot arthropathy, refers to progressive and occasionally rapid joint destruction that results from underlying disorders of the nervous system. This pictorial essay aims to illustrate various radiologic findings in neuropathic arthropathy using various examples in the upper and lower limbs and in the spine. Pearls for radiologic diagnosis, clinical differential considerations and possible complications are discussed individually for each joint. MR imaging techniques for differentiating infection and neuropathic arthropathy are explained with examples. Management issues are outlined.

Lower Relative Contribution of Positive Family History to Colorectal Cancer Risk with Increasing Age: A Systematic Review and Meta-Analysis of 9.28 Million Individuals.

OBJECTIVES: Existing algorithms predicting the risk of colorectal cancer (CRC) assign a fixed score for family history of CRC. Whether the increased CRC risk attributed to family history of CRC was higher in younger patients remains inconclusive. We examined the risk of CRC associated with family history of CRC in first-degree relative (FDR) according to the age of index subjects (<40 vs. ≥40; <50 vs. ≥50; and <60 vs. ≥60 years). METHODS: Ovid Medline, EMBASE, and gray literature from the reference lists of all identified studies were searched from their inception to March 2017. We included case-control/cohort studies that investigated the relationship between family history of CRC in FDR and prevalence of CRC. Two reviewers independently selected articles according to the PRISMA guideline. A random effects meta-analysis pooled relative risks (RR). RESULTS: We analyzed 9.28 million subjects from 63 studies. A family history of CRC in FDR confers a higher risk of CRC (RR = 1.76, 95% CI = 1.57-1.97, p < 0.001). This increased risk was higher in younger individuals (RR = 3.29, 95% CI = 1.67-6.49 for <40 years versus RR = 1.42, 95% CI = 1.24-1.62 for ≥40 years, p = 0.017; RR = 2.81, 95% CI = 1.94-4.07 for <50 years versus RR = 1.47, 95% CI = 1.28-1.69 for ≥50 years, p = 0.001). No publication bias was identified, and the findings are robust in subgroup analyses. CONCLUSIONS: The increase in relative risk of CRC attributed to family history was found to be higher in younger individuals. Family history of CRC could be assigned a higher score for younger subjects in CRC risk prediction algorithms. Future studies should examine if such approach may improve their predictive capability.

How does dose impact on the severity of food-induced allergic reactions, and can this improve risk assessment for allergenic foods?: Report from an ILSI Europe Food Allergy Task Force Expert Group and Workshop.

Quantitative risk assessment (QRA) for food allergens has made considerable progress in recent years, yet acceptability of its outcomes remains stymied because of the limited extent to which it has been possible to incorporate severity as a variable. Reaction severity, particularly following accidental exposure, depends on multiple factors, related to the allergen, the host and any treatments, which might be administered. Some of these factors are plausibly still unknown. Quantitative risk assessment shows that limiting exposure through control of dose reduces the rates of reactions in allergic populations, but its impact on the relative frequency of severe reactions at different doses is unclear. Food challenge studies suggest that the relationship between dose of allergenic food and reaction severity is complex even under relatively controlled conditions. Because of these complexities, epidemiological studies provide very limited insight into this aspect of the dose-response relationship. Emerging data from single-dose challenges suggest that graded food challenges may overestimate the rate of severe reactions. It may be necessary to generate new data (such as those from single-dose challenges) to reliably identify the effect of dose on severity for use in QRA. Success will reduce uncertainty in the susceptible population and improve consumer choice.

Macroscopically constrained Wang-Landau method for systems with multiple order parameters and its application to drawing complex phase diagrams.

A generalized approach to Wang-Landau simulations, macroscopically constrained Wang-Landau, is proposed to simulate the density of states of a system with multiple macroscopic order parameters. The method breaks a multidimensional random-walk process in phase space into many separate, one-dimensional random-walk processes in well-defined subspaces. Each of these random walks is constrained to a different set of values of the macroscopic order parameters. When the multivariable density of states is obtained for one set of values of fieldlike model parameters, the density of states for any other values of these parameters can be obtained by a simple transformation of the total system energy. All thermodynamic quantities of the system can then be rapidly calculated at any point in the phase diagram. We demonstrate how to use the multivariable density of states to draw the phase diagram, as well as order-parameter probability distributions at specific phase points, for a model spin-crossover material: an antiferromagnetic Ising model with ferromagnetic long-range interactions. The fieldlike parameters in this model are an effective magnetic field and the strength of the long-range interaction.

A microfabricated low-profile wideband antenna array for terahertz communications.

While terahertz communications are considered to be the future solutions for the increasing demands on bandwidth, terahertz equivalents of radio frequency front-end components have not been realized. It remains challenging to achieve wideband, low profile antenna arrays with highly directive beams of radiation. Here, based on the complementary antenna approach, a wideband 2 × 2 cavity-backed slot antenna array with a corrugated surface is proposed. The approach is based on a unidirectional antenna with a cardiac radiation pattern and stable frequency characteristics that is achieved by integrating a series-resonant electric dipole with a parallel-resonant magnetic dipole. In this design, the slots work as magnetic dipoles while the corrugated surface radiates as an array of electric dipoles. The proposed antenna is realized at 1 THz operating frequency by stacking multiple metallized layers using the microfabrication technology. S-parameter measurements of this terahertz low-profile metallic antenna array demonstrate high efficiency at terahertz frequencies. Fractional bandwidth and gain are measured to be 26% and 14 dBi which are consistent with the simulated results. The proposed antenna can be used as the building block for larger antenna arrays with more directive beams, paving the way to develop high gain low-profile antennas for future communication needs.

Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist.

Castration-resistant prostate cancer (CRPC) remains a major clinical challenge because of the lack of effective targeted therapy for its treatment. The mechanism underlying how CRPC gains resistance toward hormone depletion and other forms of chemotherapy is poorly understood. Research on understanding the factors that drive these processes is desperately needed to generate new therapies to cure the disease. Here, we discovered a fundamental role of S-phase protein kinase 2 (Skp2) in the formation and progression of CRPC. In transgenic adenocarcinoma mouse prostate model, Skp2 depletion leads to a profound repression of prostate tumor growth and distal metastasis and substantially prolonged overall survival. We revealed that Skp2 regulates CRPC through Twist-mediated oncogenic functions including epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) acquisitions. Mechanistically, Skp2 interacted with Twist and promoted the non-degradative ubiquitination of Twist. Consequently, Skp2 stabilized Twist protein expression by preventing proteasomal degradation of Twist by ß-TrCP. We found that Twist overexpression augments CSC self-renewal and population and that Skp2 inhibition reverts Twist's effects on CSC regulation. Furthermore, genetically depleting or pharmacologically inactivating Skp2 synergistically re-sensitized CRPC cells toward chemotherapies such as paclitaxel or doxorubicin. Together, this study uncovering Skp2-mediated Twist stabilization and oncogenic functions in CRPC offers new knowledge on how CRPC progresses and acquires chemoresistance during tumor progression. It provides proof of principle that Skp2 targeting is a promising approach to combat metastatic CRPC by targeting Twist and CSCs.

Can we identify patients at risk of life-threatening allergic reactions to food?

Anaphylaxis has been defined as a 'severe, life-threatening generalized or systemic hypersensitivity reaction'. However, data indicate that the vast majority of food-triggered anaphylactic reactions are not life-threatening. Nonetheless, severe life-threatening reactions do occur and are unpredictable. We discuss the concepts surrounding perceptions of severe, life-threatening allergic reactions to food by different stakeholders, with particular reference to the inclusion of clinical severity as a factor in allergy and allergen risk management. We review the evidence regarding factors that might be used to identify those at most risk of severe allergic reactions to food, and the consequences of misinformation in this regard. For example, a significant proportion of food-allergic children also have asthma, yet almost none will experience a fatal food-allergic reaction; asthma is not, in itself, a strong predictor for fatal anaphylaxis. The relationship between dose of allergen exposure and symptom severity is unclear. While dose appears to be a risk factor in at least a subgroup of patients, studies report that individuals with prior anaphylaxis do not have a lower eliciting dose than those reporting previous mild reactions. It is therefore important to consider severity and sensitivity as separate factors, as a highly sensitive individual will not necessarily experience severe symptoms during an allergic reaction. We identify the knowledge gaps that need to be addressed to improve our ability to better identify those most at risk of severe food-induced allergic reactions.

Angiographic factors associated with haemorrhagic presentation of brain arteriovenous malformation in a Chinese paediatric population.

OBJECTIVE: To identify specific angiographic factors associated with haemorrhagic presentation of brain arteriovenous malformation in Chinese paediatric patients. DESIGN: Retrospective cross-sectional observational study. SETTING: Four locoregional tertiary neurosurgical centres in Hong Kong: Queen Elizabeth Hospital, Tuen Mun Hospital, Kwong Wah Hospital, and Pamela Youde Nethersole Eastern Hospital. PATIENTS: Patients aged 18 years or younger who underwent pretreatment digital subtraction angiography for brain arteriovenous malformation between 1 January 2005 and 31 July 2013 were included. Patients were divided into haemorrhagic and non-haemorrhagic groups based on the initial presentation. Pretreatment digital subtraction angiographies were independently reviewed by two experienced neuroradiologists. MAIN OUTCOME MEASURES: The following parameters were evaluated for their association with haemorrhagic presentation by univariate and multivariate analyses: nidus location, nidus size, nidus morphology (diffuse or compact); origin and number of arterial feeders; venous drainage; number of draining veins; presence of aneurysms, venous varices, and venous stenosis. RESULTS: A total of 67 children and adolescents (28 male, 39 female) with a mean age of 12 years were included. Of them, 52 (78%) presented with haemorrhage. Arteriovenous malformation size (P=0.004) and morphology (P=0.05) were found to be associated with haemorrhagic presentation by univariate analysis. Small arteriovenous malformation nidus size and diffuse nidal morphology were identified as independent risk factors for haemorrhage by multivariate analysis. CONCLUSION: Smaller arteriovenous malformation size and diffuse nidal morphology are angiographic factors independently associated with haemorrhagic presentation. Bleeding risk is important in determining the therapeutic approach (aggressive vs conservative) and timeframe, particularly in paediatric patients.

Precautionary allergen labelling: perspectives from key stakeholder groups.

Precautionary allergen labelling (PAL) was introduced by the food industry to help manage and communicate the possibility of reaction from the unintended presence of allergens in foods. However, in its current form, PAL is counterproductive for consumers with food allergies. This review aims to summarize the perspectives of all the key stakeholders (including clinicians, patients, food industry and regulators), with the aim of defining common health protection and risk minimization goals. The lack of agreed reference doses has resulted in inconsistent application of PAL by the food industry and in levels of contamination that prompt withdrawal action by enforcement officers. So there is a poor relationship between the presence or absence of PAL and actual reaction risk. This has led to a loss of trust in PAL, reducing the ability of consumers with food allergies to make informed choices. The result has been reduced avoidance, reduced quality of life and increased risk-taking by consumers who often ignore PAL. All contributing stakeholders agree that PAL must reflect actual risk. PAL should be transparent and consistent with rules underpinning decision-making process being communicated clearly to all stakeholders. The use of PAL should indicate the possible, unintended presence of an allergen in a consumed portion of a food product at or above any proposed action level. This will require combined work by all stakeholders to ensure everyone understands the approach and its limitations. Consumers with food allergy then need to be educated to undertake individualized risk assessments in relation to any PAL present.

Monte Carlo simulations of the critical properties of a Ziff-Gulari-Barshad model of catalytic CO oxidation with long-range reactivity.

The Ziff-Gulari-Barshad (ZGB) model, a simplified description of the oxidation of carbon monoxide (CO) on a catalyst surface, is widely used to study properties of nonequilibrium phase transitions. In particular, it exhibits a nonequilibrium, discontinuous transition between a reactive and a CO poisoned phase. If one allows a nonzero rate of CO desorption (k), the line of phase transitions terminates at a critical point (k(c)). In this work, instead of restricting the CO and atomic oxygen (O) to react to form carbon dioxide (CO(2)) only when they are adsorbed in close proximity, we consider a modified model that includes an adjustable probability for adsorbed CO and O atoms located far apart on the lattice to react. We employ large-scale Monte Carlo simulations for system sizes up to 240×240 lattice sites, using the crossing of fourth-order cumulants to study the critical properties of this system. We find that the nonequilibrium critical point changes from the two-dimensional Ising universality class to the mean-field universality class upon introducing even a weak long-range reactivity mechanism. This conclusion is supported by measurements of cumulant fixed-point values, cluster percolation probabilities, correlation-length finite-size scaling properties, and the critical exponent ratio ß/ν. The observed behavior is consistent with that of the equilibrium Ising ferromagnet with additional weak long-range interactions [T. Nakada, P. A. Rikvold, T. Mori, M. Nishino, and S. Miyashita, Phys. Rev. B 84, 054433 (2011)]. The large system sizes and the use of fourth-order cumulants also enable determination with improved accuracy of the critical point of the original ZGB model with CO desorption.