Ubiquitylomics: An Emerging Approach for Profiling Protein Ubiquitylation in Skeletal Muscle.

Skeletal muscle is a highly adaptable tissue, finely tuned by various physiological and pathological factors. Whilst the pivotal role of skeletal muscle in overall health is widely acknowledged, unravelling the underlying molecular mechanisms poses ongoing challenges. Protein ubiquitylation, a crucial post-translational modification, is involved in regulating most biological processes. This widespread impact is achieved through a diverse set of enzymes capable of generating structurally and functionally distinct ubiquitin modifications on proteins. The complexity of protein ubiquitylation has presented significant challenges in not only identifying ubiquitylated proteins but also characterising their functional significance. Mass spectrometry enables in-depth analysis of proteins and their post-translational modification status, offering a powerful tool for studying protein ubiquitylation and its biological diversity: an approach termed ubiquitylomics. Ubiquitylomics has been employed to tackle different perspectives of ubiquitylation, including but not limited to global quantification of substrates and ubiquitin linkages, ubiquitin site recognition and crosstalk with other post-translational modifications. As the field of mass spectrometry continues to evolve, the usage of ubiquitylomics has unravelled novel insights into the regulatory mechanisms of protein ubiquitylation governing biology. However, ubiquitylomics research has predominantly been conducted in cellular models, limiting our understanding of ubiquitin signalling events driving skeletal muscle biology. By integrating the intricate landscape of protein ubiquitylation with dynamic shifts in muscle physiology, ubiquitylomics promises to not only deepen our understanding of skeletal muscle biology but also lay the foundation for developing transformative muscle-related therapeutics. This review aims to articulate how ubiquitylomics can be utilised by researchers to address different aspects of ubiquitylation signalling in skeletal muscle. We explore methods used in ubiquitylomics experiments, highlight relevant literature employing ubiquitylomics in the context of skeletal muscle and outline considerations for experimental design.

Identifying heterogeneous subgroups of systemic autoimmune diseases by applying a joint dimension reduction and clustering approach to immunomarkers.

BACKGROUND: The high complexity of systemic autoimmune diseases (SADs) has hindered precise management. This study aims to investigate heterogeneity in SADs. METHODS: We applied a joint cluster analysis, which jointed multiple correspondence analysis and k-means, to immunomarkers and measured the heterogeneity of clusters by examining differences in immunomarkers and clinical manifestations. The electronic health records of patients who received an antinuclear antibody test and were diagnosed with SADs, namely systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), were retrieved between 2001 and 2016 from hospitals in Taiwan. RESULTS: With distinctive patterns of immunomarkers, a total of 11,923 patients with the three SADs were grouped into six clusters. None of the clusters was composed only of a single SAD, and these clusters demonstrated considerable differences in clinical manifestation. Both patients with SLE and SS had a more dispersed distribution in the six clusters. Among patients with SLE, the occurrence of renal compromise was higher in Clusters 3 and 6 (52% and 51%) than in the other clusters (p < 0.001). Cluster 3 also had a high proportion of patients with discoid lupus (60%) than did Cluster 6 (39%; p < 0.001). Patients with SS in Cluster 3 were the most distinctive because of the high occurrence of immunity disorders (63%) and other and unspecified benign neoplasm (58%) with statistical significance compared with the other clusters (all p < 0.05). CONCLUSIONS: The immunomarker-driven clustering method could recognise more clinically relevant subgroups of the SADs and would provide a more precise diagnosis basis.

Comparison of Multiple Carbapenemase Tests Based on an Unbiased Colony-Selection Method.

Carbapenemase-producing organisms (CPOs) present a major threat to public health, demanding precise diagnostic techniques for their detection. Discrepancies among the CPO tests have raised concerns, partly due to limitations in detecting bacterial diversity within host specimens. We explored the impact of an unbiased colony selection on carbapenemase testing and assessed its relevance to various tests. Using the FirstAll method for unbiased colony selection to reduce bias, we compared the results from different methods, namely the modified carbapenem inactivation method/EDTA-modified carbapenem inactivation method (mCIM/eCIM), the Carba5, the CPO panel, and the multiplex PCR (MPCR). We compared the FirstAll method to the conventional colony selection for MPCR with seven CPO species. In addition, we evaluated the test performance on seven CPO species using MPCR as a reference and the FirstAll method as the colony-selection method. The results revealed that the selections from the FirstAll method have improved rates of carbapenemase detection, in comparison to approximately 11.2% of the CPO isolates that were noted to be false negatives in the conventional colony-selection methods. Both the Carba5 test and the CPO panel showed suboptimal performance (sensitivity/specificity: Carba5 74.6%/89.5%, CPO panel 77.2%/74.4%) in comparison to the FirstAll method. The Carba5 test provided specific carbapenemase class assignments, but the CPO panel failed in 18.7% of the cases. The Carba5 test and the CPO panel results correlated well with ceftazidime-avibactam minimal inhibitory concentrations (MICs). The concordance for Class A/D with MICs was 94.7% for Carba5 and 92.7% for the CPO panel; whereas for Class B, it was 86.5% for Carba5 and 75.9% for the CPO panel. In conclusion, FirstAll, as the unbiased colony-selection method, was shown to impact carbapenemase testing. With FirstAll, the diagnostic performance of both the Carba5 and the CPO panel was found to be lower. Furthermore, the utilization of ceftazidime-avibactam guided by either the CPO panel or Carba5 was appropriate.

Red Yeast Rice and Statin Therapy in Patients with Hypercholesterolemia and the Comorbidities: A Retrospective Cohort Study on Lipid-Lowering Effects and Cardiovascular Outcomes.

Red yeast rice (RYR) is known for its lipid-lowering effects in patients with hypercholesterolemia; however, its comparative efficacy with statins and risk reduction remains uncertain. This retrospective study analyzed data from 337,104 patients with hyperlipidemia in the Chang Gung Research Database cohort, spanning from January 2016 to December 2021. Exclusion criteria were applied to ensure data completeness and compliance, including an age limit of [Formula: see text] years, absence of RYR or statin treatment, and a treatment duration of [Formula: see text] days. Propensity score matching was employed to minimize bias based on baseline factors, with one patient matching with four patients in the comparison group. The study encompassed a total of 5,984 adult hyperlipidemic patients, with 1,197 in the RYR group and 4,787 in the statin group. The patients were also stratified into statin ([Formula: see text]) or combined use ([Formula: see text]) groups for further comparison. Following one year of treatment, both the RYR and statin groups exhibited reductions in total cholesterol and triglyceride levels. Most biochemical parameters showed no significant differences, except for elevated glutamic oxaloacetic transaminase levels in the RYR group ([Formula: see text]) and increased glycohemoglobin levels in the statin group at the three-month mark ([Formula: see text]). In patients with comorbid diabetes, hypertension, kidney, or liver diseases, RYR and statins demonstrated comparable risks for emergency room (ER) visits, stroke, and myocardial infarction (MI). However, the combination of RYR and statins was associated with reduced stroke-related hospitalizations in patients with diabetes, hypertension, and kidney disease, as well as decreased MI-related hospitalizations in patients with hypertension and kidney disease (all [Formula: see text]). In conclusion, both RYR and statins effectively lower blood lipid levels and mitigate related complications. Combining these therapies may lead to fewer ER visits, reduced stroke frequency, and fewer MI hospitalizations in hypertensive and kidney disease patients, and they decreased all-cause mortality in the kidney disease population. Further research on combined therapy is warranted.

Uncovering the mechanisms of MuRF1-induced ubiquitylation and revealing similarities with MuRF2 and MuRF3.

MuRF1 (Muscle-specific RING finger protein 1; gene name TRIM63) is a ubiquitin E3 ligase, associated with the progression of muscle atrophy. As a RING (Really Interesting New Gene) type E3 ligase, its unique activity of ubiquitylation is driven by a specific interaction with a UBE2 (ubiquitin conjugating enzyme). Our understanding of MuRF1 function remains unclear as candidate UBE2s have not been fully elucidated. In the present study, we screened human ubiquitin dependent UBE2s in vitro and found that MuRF1 engages in ubiquitylation with UBE2D, UBE2E, UBE2N/V families and UBE2W. MuRF1 can cause mono-ubiquitylation, K48- and K63-linked polyubiquitin chains in a UBE2 dependent manner. Moreover, we identified a two-step UBE2 dependent mechanism whereby MuRF1 is monoubiquitylated by UBE2W which acts as an anchor for UBE2N/V to generate polyubiquitin chains. With the in vitro ubiquitylation assay, we also found that MuRF2 and MuRF3 not only share the same UBE2 partners as MuRF1 but can also directly ubiquitylate the same substrates: Titin (A168-A170), Desmin, and MYLPF (Myosin Light Chain, Phosphorylatable, Fast Skeletal Muscle; also called Myosin Light Regulatory Chain 2). In summary, our work presents new insights into the mechanisms that underpin MuRF1 activity and reveals overlap in MuRF-induced ubiquitylation which could explain their partial redundancy in vivo.

The Clinical Characteristics and Manifestation of Anxious Depression Among Patients With Major Depressive Disorders-Results From a Taiwan Multicenter Study

Objective@#Anxious depression is a prevalent characteristic observed in Asian psychiatric patients diagnosed with major depressive disorder (MDD). This study aims to investigate the prevalence and clinical presentation of anxious depression in Taiwanese individuals diagnosed with MDD. @*Methods@#We recruited psychiatric outpatients aged over 18 who had been diagnosed with MDD through clinical interviews. This recruitment took place at five hospitals located in northern Taiwan. We gathered baseline clinical and demographic information from the participants. Anxious depression was identified using a threshold of an anxiety/somatization factor score ≥7 on the 21-item Hamilton Rating Scale for Depression (HAM-D). @*Results@#In our study of 399 patients (84.21% female), 64.16% met the criteria for anxious depression. They tended to be older, married, less educated, with more children, and an older age of onset. Anxious depression patients had higher HAM-D and Clinical Global Impression–Severity scale score, more panic disorder (without agoraphobia), and exhibited symptoms like agitation, irritability, concentration difficulties, psychological and somatic anxiety, somatic complaints, hypochondriasis, weight loss, and increased insight. Surprisingly, their suicide rates did not significantly differ from non-anxious depression patients. This highlights the importance of recognizing and addressing these unique characteristics. @*Conclusion@#Our study findings unveiled that the prevalence of anxious depression among Taiwanese outpatients diagnosed with MDD was lower compared to inpatients but substantially higher than the reported rates in European countries and the United States. Furthermore, patients with anxious depression exhibited a greater occurrence of somatic symptoms.

Introduction of a Chiral Biphenanthrene-Diol Unit to Achieve Circularly Polarized Thermally Activated Delayed Fluorescence.

Circularly polarized luminescence (CPL) materials are promising candidates for future display technology. However, such highly efficient emitters suffer from the issues of difficult chiral separation and low photoluminescence quantum yield (PLQY). In this work, the chiral 4,4'-biphenanthrene-3,3'-diol (BIPOL) unit was introduced into a thermally activated delayed fluorescence (TADF) framework for the first time. We presented two series of enantiomers, R/S-o-DCzBPNCN and R/S-p-DCzBPNCN, and the synthesis of enantiopure BIPOL can be prepared via normal column chromatography. Notably, o-DCzBPNCN showed narrow singlet-triplet gap of 0.05 eV, efficient TADF, and high PLQYs of 82 % in doped films. In addition, R/S-o-DCzBPNCN exhibited high luminescence dissymmetry factor (gPL ) values of -1.94×10-2 /+1.91×10-2 in doped films. The strategy of BIPOL introduction offers a new approach to organic emitters with stereospecific synthesis, TADF, and chiroptical properties.

Prescription characteristics of Xue-Fu-Zhu-Yu-Tang in pain management: a population-based study using the National Health Insurance Research Database in Taiwan.

Objective: To explore the prevalence and distinctive features of Xue-Fu-Zhu-Yu-Tang (XFZYT) prescriptions by analyzing the National Health Insurance Research Database (NHIRD) to identify the specific medical problems for which XFZYT is prescribed. Methods: This nationwide, population-based, cross-sectional study included 109,073 XFZYT users and 532,848 XFZYT non-users among Chinese herbal product (CHP) users in NHIRD. Chi-squared tests were used to analyze disparities between the XFZYT user and XFZYT non-user cohorts, and the mean age was evaluated using the Wilcoxon rank-sum test. Logistic regression was used to compute the odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: XFZYT was frequently used to treat pain. The top five conditions for which the Taiwanese traditional Chinese medicine (TCM) practitioners would prescribe XFZYT were chest pain; headache; myalgia and myositis; lumbago; and neuralgia, neuritis, and radiculitis. Conclusion: This study represents an inaugural comprehensive survey conducted on the utilization of XFZYT prescriptions among patients with diverse diseases. XFZYT is mostly used to treat pain conditions in Taiwan. Combined with the combination use of other CHPs, XFZYT is used to treat symptoms of the chest and respiratory system, soft tissue conditions, menstruation disorders, and joint and back discomfort. These results suggest that further clinical trials are warranted to verify the effects of XFZYT in pain management.

Willow Bark (Salix spp.) Used for Pain Relief in Arthritis: A Meta-Analysis of Randomized Controlled Trials.

This study intends to assess the analgesic effects, physical facilitation, and safety of willow bark use in patients with arthritis. Our study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Scopus, EMBASE, Web of Science, Cochrane, and ClinicalTrials.gov were searched for relative randomized controlled trials (RCTs) describing the efficacy or adverse events of willow bark in patients with arthritis until 12 April 2023. We used Cochrane ROB 2.0 and the Grading of Recommendations, Assessment, Development, and Evaluations system to evaluate the quality of studies and evidence. The meta-analysis was carried out by the fix-effects model. This study included five studies with six RCTs consisting of 329 patients with arthritis. The results showed significant differences in pain relief and improvement in physical status for patients with arthritis between willow bark treatment and placebo groups, and no significant differences in the risk of all adverse events in patients with arthritis between willow bark treatment and placebo. Owing to the potential bias, the certainty and evidence of our findings are still inadequate. Therefore, further RCTs are needed to confirm our results.

Trend of HPV Molecular Epidemiology in the Post-Vaccine Era: A 10-Year Study.

Cervical cancer, a major health concern among women worldwide, is closely linked to human papillomavirus (HPV) infection. This study explores the evolving landscape of HPV molecular epidemiology in Taiwan over a decade (2010-2020), where prophylactic HPV vaccination has been implemented since 2007. Analyzing data from 40,561 vaginal swab samples, with 42.0% testing positive for HPV, we reveal shifting trends in HPV genotype distribution and infection patterns. The 12 high-risk genotypes, in order of decreasing percentage, were HPV 52, 58, 16, 18, 51, 56, 39, 59, 33, 31, 45, and 35. The predominant genotypes were HPV 52, 58, and 16, accounting for over 70% of cases annually. The proportions of high-risk and non-high-risk HPV infections varied across age groups. High-risk infections predominated in sexually active individuals aged 30-50 and were mixed-type infections. The composition of high-risk HPV genotypes was generally stable over time; however, HPV31, 33, 39, and 51 significantly decreased over the decade. Of the strains, HPV31 and 33 are shielded by the nonavalent HPV vaccine. However, no reduction was noted for the other seven genotypes. This study offers valuable insights into the post-vaccine HPV epidemiology. Future investigations should delve into HPV vaccines' effects and their implications for cervical cancer prevention strategies. These findings underscore the need for continued surveillance and research to guide effective public health interventions targeting HPV-associated diseases.

Postexercise muscle glycogen synthesis with glucose, galactose, and combined galactose-glucose ingestion.

Ingested galactose can enhance postexercise liver glycogen repletion when combined with glucose but effects on muscle glycogen synthesis are unknown. In this double-blind randomized study participants [7 men and 2 women; V̇o2max: 51.1 (8.7) mL·kg-1·min-1] completed three trials of exhaustive cycling exercise followed by a 4-h recovery period, during which carbohydrates were ingested at the rate of 1.2 g·kg-1·h-1 comprising glucose (GLU), galactose (GAL) or galactose + glucose (GAL + GLU; 1:2 ratio). The increase in vastus lateralis skeletal-muscle glycogen concentration during recovery was higher with GLU relative to GAL + GLU [contrast: +50 mmol·(kg DM)-1; 95%CL 10, 89; P = 0.021] and GAL [+46 mmol·(kg DM)-1; 95%CL 8, 84; P = 0.024] with no difference between GAL + GLU and GAL [-3 mmol·(kg DM)-1; 95%CL -44, 37; P = 0.843]. Plasma glucose concentration in GLU was not significantly different vs. GAL + GLU (+ 0.41 mmol·L-1; 95%CL 0.13, 0.94) but was significantly lower than GAL (-0.75 mmol·L-1; 95%CL -1.34, -0.17) and also lower in GAL vs. GAL + GLU (-1.16 mmol·-1; 95%CL -1.80, -0.53). Plasma insulin was higher in GLU + GAL and GLU compared with GAL but not different between GLU + GAL and GLU. Plasma galactose concentration was higher in GAL compared with GLU (3.35 mmol·L-1; 95%CL 3.07, 3.63) and GAL + GLU (3.22 mmol·L-1; 95%CL 3.54, 2.90) with no difference between GLU + GAL (0.13 mmol·L-1; 95%CL -0.11, 0.37) and GLU. Compared with galactose or a galactose + glucose blend, glucose feeding was more effective in postexercise muscle glycogen synthesis. Comparable muscle glycogen synthesis was observed with galactose-glucose coingestion and exclusive galactose-only ingestion.NEW & NOTEWORTHY Postexercise galactose-glucose coingestion or exclusive galactose-only ingestion resulted in a lower rate of skeletal-muscle glycogen replenishment compared with exclusive glucose-only ingestion. Comparable muscle glycogen synthesis was observed with galactose-glucose coingestion and exclusive galactose-only ingestion.

Alternate Antimicrobial Therapies and Their Companion Tests.

New antimicrobial approaches are essential to counter antimicrobial resistance. The drug development pipeline is exhausted with the emergence of resistance, resulting in unsuccessful trials. The lack of an effective drug developed from the conventional drug portfolio has mandated the introspection into the list of potentially effective unconventional alternate antimicrobial molecules. Alternate therapies with clinically explicable forms include monoclonal antibodies, antimicrobial peptides, aptamers, and phages. Clinical diagnostics optimize the drug delivery. In the era of diagnostic-based applications, it is logical to draw diagnostic-based treatment for infectious diseases. Selection criteria of alternate therapeutics in infectious diseases include detection, monitoring of response, and resistance mechanism identification. Integrating these diagnostic applications is disruptive to the traditional therapeutic development. The challenges and mitigation methods need to be noted. Applying the goals of clinical pharmacokinetics that include enhancing efficacy and decreasing toxicity of drug therapy, this review analyses the strong correlation of alternate antimicrobial therapeutics in infectious diseases. The relationship between drug concentration and the resulting effect defined by the pharmacodynamic parameters are also analyzed. This review analyzes the perspectives of aligning diagnostic initiatives with the use of alternate therapeutics, with a particular focus on companion diagnostic applications in infectious diseases.

Long-range hydrogen-bond relay catalyses the excited-state proton transfer reaction.

Solvent (e.g., water)-catalyzed proton transfer (SCPT) via the relay of hydrogen (H)-bonds plays a key role in proton migration. In this study, a new class of 1H-pyrrolo[3,2-g]quinolines (PyrQs) and their derivatives were synthesized, with sufficient separation of the pyrrolic proton donating and pyridinic proton accepting sites to probe excited-state SCPT. There was dual fluorescence for all PyrQs in methanol, i.e., normal (PyrQ) and tautomer 8H-pyrrolo[3,2-g]quinoline (8H-PyrQ) emissions. The fluorescence dynamics unveiled a precursor (PyrQ) and successor (8H-PyrQ) relationship and the correlation of an increasing overall excited-state SCPT rate (kSCPT) upon increasing the N(8)-site basicity. kSCPT can be expressed by the coupling reaction kSCPT = Keq × kPT, where kPT denotes the intrinsic proton tunneling rate in the relay and Keq denotes the pre-equilibrium between randomly and cyclically H-bonded solvated PyrQs. Molecular dynamics (MD) simulation defined the cyclic PyrQs and analyzed the H-bond and molecular arrangement over time, which showed the cyclic PyrQs incorporating ≧3 methanol molecules. These cyclic H-bonded PyrQs are endowed with a relay-like proton transfer rate, kPT. MD simulation estimated an upper-limited Keq value of 0.02-0.03 for all studied PyrQs. When there was little change in Keq, the distinct kSCPT values for PyrQs were at different kPT values, which increased as the N(8) basicity increased, which was induced by the C(3)-substituent. kSCPT was subject to a deuterium isotope effect, where the kSCPT of 1.35 × 1010 s-1 for PyrQ-D in CH3OD was 1.68 times slower than that (2.27 × 1010 s-1) of PyrQ in CH3OH. MD simulation provided a similar Keq for PyrQ and PyrQ-D, leading to different proton tunneling rates (kPT) between PyrQ and PyrQ-D.

Risk Stratification for Herpes Simplex Virus Pneumonia Using Elastic Net Penalized Cox Proportional Hazard Algorithm with Enhanced Explainability.

Herpes simplex virus (HSV) pneumonia is a serious and often fatal respiratory tract infection that occurs in immunocompromised individuals. The early detection of accurate risk stratification is essential in identifying patients who are at high risk of mortality and may benefit from more aggressive treatment. In this study, we developed and validated a risk stratification model for HSV bronchopneumonia using an elastic net penalized Cox proportional hazard algorithm. We analyzed data from a cohort of 104 critically ill patients with HSV bronchopneumonia identified in Chang Gung Memorial Hospital, Linkou, Taiwan: one of the largest tertiary medical centers in the world. A total of 109 predictors, both clinical and laboratory, were identified in this process to develop a risk stratification model that could accurately predict mortality in patients with HSV bronchopneumonia. This model was able to differentiate the risk of death and predict mortality in patients with HSV bronchopneumonia compared to the APACHE II score in the early stage of ICU admissions. Both hazard ratio coefficient and selection frequency were used as the metrics to enhance the explainability of the informative predictors. Our findings suggest that the elastic net penalized Cox proportional hazard algorithm is a promising tool for risk stratification in patients with HSV bronchopneumonia and could be useful in identifying those at high risk of mortality.

Engineering the Strain and Interlayer Excitons of 2D Materials via Lithographically Engraved Hexagonal Boron Nitride.

Strain engineering has quickly emerged as a viable option to modify the electronic, optical, and magnetic properties of 2D materials. However, it remains challenging to arbitrarily control the strain. Here we show that, by creating atomically flat surface nanostructures in hexagonal boron nitride, we achieve an arbitrary on-chip control of both the strain distribution and magnitude on high-quality molybdenum disulfide. The phonon and exciton emissions are shown to vary in accordance with our strain field designs, enabling us to write and draw any photoluminescence color image in a single chip. Moreover, our strain engineering offers a powerful means to significantly and controllably alter the strengths and energies of interlayer excitons at room temperature. This method can be easily extended to other material systems and offers promise for functional excitonic devices.

Chiral Binaphthalene Building Blocks for Self-Assembled Nanoscale CPL Emitters.

The introduction of biuret hydrogen-bonding sites onto chiral binaphthalene-based chromophores was investigated as a route to sub-micron-sized, vesicle-like aggregates endowed with chiroptical properties. The synthesis was conducted from the corresponding chiral 4,4'-dibromo-1,1'-bis(2-naphthol) via Suzuki-Miyaura coupling to afford luminescent chromophores whose emission spectrum could be tuned from blue to yellow-green through extension of the conjugation. For all compounds, the spontaneous formation of hollow spheres with a diameter of ca. 200-800 nm was evidenced by scanning electron microscopy, along with strong asymmetry in the circularly polarized absorption spectra. For some compounds, the emission also displayed circular polarization with values of glum = ca. 10-3 which could be increased upon aggregation.

Describe, Spot and Explain: Interpretable Representation Learning for Discriminative Visual Reasoning.

Despite the recent success achieved by deep neural networks (DNNs), it remains challenging to disclose/explain the decision-making process from the numerous parameters and complex non-linear functions. To address the problem, explainable AI (XAI) aims to provide explanations corresponding to the learning and prediction processes for deep learning models. In this paper, we propose a novel representation learning framework of Describe, Spot and eXplain (DSX). Based on the architecture of Transformer, our proposed DSX framework is composed of two learning stages, descriptive prototype learning and discriminative prototype discovery. Given an input image, the former stage is designed to derive a set of descriptive representations, while the latter stage further identifies a discriminative subset, offering semantic interpretability for the corresponding classification tasks. While our DSX does not require any ground truth attribute supervision during training, the derived visual representations can be practically associated with physical attributes provided by domain experts. Extensive experiments on fine-grained classification and person re-identification tasks qualitatively and quantitatively verify the use our DSX model for offering semantically practical interpretability with satisfactory recognition performances.

Visit to Visit Hemoglobin A1c Variation and Long-term Risk of Major Adverse Limb Events in Patients With Type 2 Diabetes.

CONTEXT: Glycemic variation had been demonstrated to be associated with several complications of diabetes. OBJECTIVE: Investigation of the association between visit to visit hemoglobin A1c (HbA1c) variation and the long-term risk of major adverse limb events (MALEs). METHODS: Retrospective database study. Average real variability was used to represent glycemic variations with all the HbA1c measurements during the 4 following years after the initial diagnosis of type 2 diabetes. Participants were followed from the beginning of the fifth year until death or the end of the follow-up. The association between HbA1c variations and MALEs was evaluated after adjusting for mean HbA1c and baseline characteristics. Included were 56 872 patients at the referral center with a first diagnosis of type 2 diabetes, no lower extremity arterial disease, and at least 1 HbA1c measurement in each of the 4 following years were identified from a multicenter database. The main outcome measure was incidence of a MALE, which was defined as the composite of revascularization, foot ulcers, and lower limb amputations. RESULTS: The average number of HbA1c measurements was 12.6. The mean follow-up time was 6.1 years. The cumulative incidence of MALEs was 9.25 per 1000 person-years. Visit to visit HbA1c variations were significantly associated with MALEs and lower limb amputation after multivariate adjustment. People in the highest quartile of variations had increased risks for MALEs (HR 1.25, 95% CI 1.10-1.41) and lower limb amputation (HR 3.05, 95% CI 1.97-4.74). CONCLUSION: HbA1c variation was independently associated with a long-term risk of MALEs and lower limb amputations in patients with type 2 diabetes.