Comparative analysis of breast and lung cancer survival rates and clinical trial enrollments among rural and urban patients in Georgia

Objectives:Rural patients have poor cancer outcomes and clinical trial(CT)enrollment compared to urban patients due to attitudinal,awareness,and healthcare access differential.Knowledge of cancer survival disparities and CT enrollment is important for designing interventions and innovative approaches to address the stated barriers.The study explores the potential disparities in cancer survival rates and clinical trial enrollments in rural and urban breast and lung cancer patients.Our hypotheses are that for both cancer types,urban cancer patients will have longer 5-year survival rates and higher enrollment rates in clinical trials than those in rural counties.Methods:We compared breast and lung cancer patients’survival rates and enrollment ratios in clinical trials between rural(RUCC 4-9)and urban counties in Georgia at a Comprehensive Cancer Center(CCC).To assess these differences,we carried out a series of independent samples t-tests and Chi-Square tests.Results:The outcomes indicate comparable 5-year survival rates across rural and urban counties for breast and lung cancer patients,failing to substantiate our hypothesis.While clinical trial enrollment rates demonstrated a significant difference between breast and lung cancer patients at CCC,no significant variation was observed based on rural or urban classification.Conclusion:These findings underscore the need for further research into the representation of rural patients with diverse cancer types at CCC and other cancer centers.Further,the findings have considerable implications for the initiation of positive social change to improve CT participation and reduce cancer survival disparities.

Nanomedicine in the application of uveal melanoma

Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment. Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the in vivo control release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore, certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment.

Contrast-enhanced ultrasound improved performance of breast imaging reporting and data system evaluation of critical breast lesions

AIM: To determine whether contrast-enhanced ultrasound(CEUS) can improve the precision of breast imaging reporting and data system(BI-RADS) categorization. METHODS: A total of 230 patients with 235 solid breast lesions classified as BI-RADS 4 on conventional ultrasound were evaluated. CEUS was performed within one week before core needle biopsy or surgical resection and a revised BI-RADS classification was assigned based on 10 CEUS imaging characteristics. Receiver operating characteristic curve analysis was then conducted to evaluate the diagnostic performance of CEUS-based BI-RADS assignment with pathological examination as reference criteria. RESULTS: The CEUS-based BI-RADS evaluation classified 116/235(49.36%) lesions into category 3, 20(8.51%), 13(5.53%) and 12(5.11%) lesions into categories 4A, 4B and 4C, respectively, and 74(31.49%) into category 5. Selecting CEUS-based BI-RADS category 4A as an appropriate cut-off gave sensitivity and specificity values of 85.4% and 87.8%, respectively, for the diagnosisof malignant disease. The cancer-to-biopsy yield was 73.11% with CEUS-based BI-RADS 4A selected as the biopsy threshold compared with 40.85% otherwise, while the biopsy rate was only 42.13% compared with 100% otherwise. Overall, only 4.68% of invasive cancers were misdiagnosed.CONCLUSION: This pilot study suggests that evaluation of BI-RADS 4 breast lesions with CEUS results in reduced biopsy rates and increased cancer-to-biopsy yields.

Predictive model for contrast-enhanced ultrasound of the breast: Is it feasible in malignant risk assessment of breast imaging reporting and data system 4 lesions?

AIM: To build and evaluate predictive models for contrast-enhanced ultrasound(CEUS) of the breast to distinguish between benign and malignant lesions. METHODS: A total of 235 breast imaging reporting and data system(BI-RADS) 4 solid breast lesions were imaged via CEUS before core needle biopsy or surgical resection. CEUS results were analyzed on 10 enhancing patterns to evaluate diagnostic performance of three benign and three malignant CEUS models, with pathological results used as the gold standard. A logistic regression model was developed basing on the CEUS results, and then evaluated with receiver operating curve(ROC). RESULTS: Except in cases of enhanced homogeneity, the rest of the 9 enhancement appearances were statistically significant(P < 0.05). These 9 enhancement patterns were selected in the final step of the logistic regression analysis, with diagnostic sensitivity and specificity of 84.4% and 82.7%, respectively, and the area under the ROC curve of 0.911. Diagnostic sensitivity, specificity, and accuracy of the malignant vs benign CEUS models were 84.38%, 87.77%, 86.38% and 86.46%, 81.29% and 83.40%, respectively. CONCLUSION: The breast CEUS models can predict risk of malignant breast lesions more accurately, decrease false-positive biopsy, and provide accurate BIRADS classification.

Awareness of and attitudes towards infertility and its treatment： a cross-sectional survey of men in a United States primary care population

Previous studies have described racial and socioeconomic disparities in the treatment of infertility. Patient factors such as attitudes and awareness may be contributing factors. Since primary care is often the setting that serves as an entry into other areas of medicine, we sought to evaluate men＇s attitudes and awareness of male infertility in the primary care setting. To do this, we performed a cross-sectional survey of men＇s attitudes toward men＇s health issues in 210 men from two primary care clinic waiting rooms in Atlanta, Georgia. The survey was self-administered with closed-ended question items and was approximately 20 min in length. Of the 310 men approached, 210 agreed to participate and returned completed surveys. Overall, 52% of men said they were ＂very＂ or ＂somewhat＂ familiar with infertility and 25% were familiar with treatments for infertility. Some men had heard of surgery （21%） and medication （35%） as treatments for male infertility. Awareness and familiarity with the condition was greater in high socioeconomic status men （i.e. college graduates or those with income 〉$100 k per year） but did not differ by race on multivariate analysis. Attitudes toward infertility varied by race with non-Caucasian men being more likely to indicate that infertility is a serious condition, to be concerned about infertility, and to believe it decreases a man＇s quality-of-life. Therefore, a lack of awareness, but not negative attitudes, may contribute to previously-described disparities in the treatment of infertility.

Quantitative Autoradiographic Study on Receptor Regulation in the Basal Ganglia in Rat Model of Levodopa-induced Motor Complications

In order to study neurotransmitter receptor regulation in the basal ganglia involved in the functional changes underlying levodopa-induced motor complications, quantitative autoradiography was used to observe receptor bindings of dopamine D1 and D2, N-methyl-D-aspartate （NMDA）, amino-3-hydroxy-5-methylisoxazole propionic acid （AMPA） and amino butyric acid （GABA） in the basal ganglia of rats that had unilateral nigrostriatal lesions and had been chronically treated with levodopa until motor complications developed. The rats were randomly assigned to three groups： normal, denervated and treatment-complicated groups. The results showed that response duration to levodopa became progressively shorter and abnormal involuntary movement （AIM） score was progressively increased during the course of levodopa treatment. Chronic treatment augmented D1 receptors more than denervation, and reduced D2 receptors that were also increased by dopamine denervation. Striatal NMDA receptors were substantially up-regulated in the treatment-complicated group. Levodopa treatment did not change receptors of nigral AMPA, pallidal GABA, and subthalamic GABA, which remained the same as that in denervation group. However, chronic treatment reversed the increase of nigral GABA receptors caused by the lesion. It was concluded that a shortening of response duration and AIM mimicked levodopa-induced motor complications of Parkinson＇s patients. These data suggested that up-regulation of dopamine D1 and NMDA receptors in the striatum leads to an imbalance of stimulation through the striatal output pathways, which is associated with levodopa-induced motor complications.

Genetically modified foods:A critical review of their promise and problems

The term“genetic modified organisms(GMO)”has become a controversial topic as its benefits for both food producers and consumers are companied by potential biomedical risks and environmental side effects.Increasing concerns from the public about GMO,particularly in the form of genetic modified(GM)foods,are aimed at the short-and long-lasting health problems that may result from this advanced biotechnology.Complex studies are being carried out around the world independently to evaluate the advantages and disadvantages of GM foods.In this paper,we attempt to summarize up-to-date knowledge about the benefits and potential problems of GM food.We also introduce some recent technological developments in GM foods and their impact in the field.

The clinical characteristics of three subgroups of non-functioning pituitary adenomas

Introduction: Despite the fact that non-functioning pituitary adenomas do not overproduce hormones, many will stain positive for a particular pituitary hormone, which can be used to differentiate these adenomas into subgroups. If these different sub-groups behave differently in terms of post surgical progression of disease (PSPD) rates or other clinical variables, then better treatment and prognosis could be predicted. Methods: This was a retrospective cohort study. Patients who have undergone surgery for removal of a non-functioning pituitary adenoma at Emory University Hospital served as the source for all data used in this study (n = 184). Data were collected from a database of electronic medical records (EMRs) for these patients in 2010 documenting clinical and demographic variables including treatment and PSPD. Results: Risk for PSPD did not differ by adenoma subtypes: follicle-stimulating hormone (FSH+), luteinizing hormone (LH+), or those that do not stain positive for any hormone (non-functioning, or NF?) (p = 0.971). There were two clinical characteristics statistically related to adenoma subtype: altered mental status and the anterior-posterior (AP) dimension of pre-operative adenomas. PSPD was related to several clinical characteristics, including gender, previous adenoma, post-operative residual, and follow-up time.

Incidence and Related Risk Factors of Junctional Ectopic Tachycardia in Infants after Cardiac Surgery for Congenital Heart Disease

Objective:Junctional ectopic tachycardia is common after cardiac surgery for congenital heart disease.However,its incidence and related risk factors in infants after cardiac surgery are not well known.The objective of this study was to determine the overall incidence and related risk factors for junctional ectopic tachycardia in neonates and infants.Methods:We enrolled a total of 271 patients aged<1 year who underwent open cardiac surgery at Severance Cardiovascular Hospital from January 2018 to December 2020.Exclusion criteria were immediate postoperative mortality,other arrhythmias detected in the perioperative period,and prematurity.Result:The overall incidence of junctional ectopic tachycardia was 12.9%.The logistic regression analysis revealed that longer cardiopulmonary bypass time,surgery involving atrioventricular node stretching,and the presence of early repolarization on preoperative electrocardiography increased the risk of junctional ectopic tachycardia.Patients with junctional ectopic tachycardia had longer intubation time and intensive care unit stay.Conclusion:Junctional ectopic tachycardia is a common arrhythmia after cardiac surgery for congenital heart disease in infants.Occasionally,infants developing junctional ectopic tachycardia after cardiac surgery have specific preoperative electrocardiography findings.The risk factors for junctional ectopic tachycardia were associated not only with surgical procedural factors but also with preoperative electrocardiographic parameters.

Gas-propelled nanomotors alleviate colitis through the regulation of intestinal immunoenvironment-hematopexis-microbiota circuits

The progression of ulcerative colitis(UC)is associated with immunologic derangement,intestinal hemorrhage,and microbiota imbalance.While traditional medications mainly focus on mitigating inflammation,it remains challenging to address multiple symptoms.Here,a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO_(2) nanospheres with Cu_(2)O nanoblocks.The resulting CaO_(2)–Cu_(2)O possessed a desirable diameter(291.3 nm)and a uniform size distribution.It could be efficiently internalized by colonic epithelial cells and macrophages,scavenge intracellular reactive oxygen/nitrogen species,and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype.This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles.Rectal administration of CaO_(2)–Cu_(2)O could stanch the bleeding,repair the disrupted colonic epithelial layer,and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation,anti-oxidation,wound healing,and anti-inflammation.Impressively,it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria(e.g.,Odoribacter and Bifidobacterium)and decreasing the abundances of harmful bacteria(e.g.,Prevotellaceae and Helicobacter).Our gas-driven CaO_(2)–Cu_(2)O offers a promising therapeutic platform for robust treatment of UC via the rectal route.

P53亚细胞定位变化对POLD1基因启动子活性的影响

POLD1基因编码DNA聚合酶δ(pol δ)的催化亚基．体外实验表明p53能够抑制POLD1 基因启动子活性．文中探讨p53是否在细胞内直接与POLD1启动子结合调节POLD1基因表达．在瞬时转染pEGFP-p53重组质粒的人乳腺癌MCF7细胞中,p53表达增强;RT-PCR结果显示 POLD1基因mRNA表达受到抑制．染色体免疫共沉淀和荧光素酶报告基因实验证明p53在细胞内与POLD1启动子直接结合抑制其启动子活性．荧光显微镜观察发现EGFP-p53在G1期进入细胞核而在S期和G2期则被转运至细胞质．在稳定表达的pEGFP-p53细胞系中,细胞周期同步化后POLD1启动子活性在细胞周期各时相均处于较低水平．证明了细胞内p53高表达后通过直接与 POLD1启动子结合而抑制POLD1基因表达,且这种抑制作用不受细胞周期进程的影响．

脑卒中后白质完整性与上肢运动功能的关系

目的应用扩散张量成像技术测量偏瘫患者内囊后肢的各向异性(FA)值,分析皮质脊髓束完整性与患侧上肢运动功能的关系。方法选择17例亚急性期脑卒中后偏瘫患者,测量患侧及健侧内囊后肢FA值,并计算FA非对称比值,临床检测包括上肢运动功能指标(WMFT)及运动功能、平衡、感觉及关节功能综合评价指标(FM),利用线性相关分析FA非对称比值与患手FM评分、WMFT非对称比值及log WMFT之间的相关关系。结果患手运动功能评分与内囊后肢FA非对称比值显著相关,FA非对称性比值与患手FM(R2=0.655,P<0.002)呈线性负相关,与WMFT非对称性比值(R2=0.649,P<0.002)、lgWMFT(R2=0.636,P=0.002)以及握力非对称性比值(R2=0.414,P=0.02)均呈线性正相关。结论偏瘫患者亚急性期皮质脊髓束完整性与上肢运动功能显著相关;利用扩散张量成像技术可早期监测皮质脊髓束的完整性。

三七总皂甙对大鼠离体灌流肝的影响

三七总皂甙对四氯化碳损伤的大鼠离体灌流肝具有保护作用,可使肝脏灌流量增加,降低灌流液中的GPT,减轻肝脏的病理损伤。

机械力诱导MHC-Ⅰ构象变化增强TCR抗原识别及T细胞活化

CD8+T细胞主要通过T细胞表面受体(T cell recep tor,TCR)识别并与Ⅰ型主要组织性复合物提呈的抗原(pMHC-Ⅰ)相互作用[1]。TCR对刺激型抗原的识别在CD8+T细胞毒性和适应性免疫中发挥着关键作用。许多证据表明机械力可以延长TCR与刺激性pMHC作用的键合时间(bond lifetime)形成抗原特异性逆锁键(catch bond)[2],并且这种逆锁键对抗原识别非常重要。然而,机械力调控TCR抗原识别的具体结构机制仍不清楚。通过分子动力学模拟、单分子生物膜力学探针、磁镊、T细胞活化实验和动物模型对此问题展开了系统的研究[4]。发现作用在TCR-pMHC-Ⅰ复合体上的拉力可以作用在TCR-pMHC-Ⅰ复合体上的拉力可以打破MHC-I分子内部α1-α2和β2结构域间的相互作用,导致α1-α2结构域旋转并发生构象变化。力诱导的MHC-I构象变化可以进一步别构地调节TCR与刺激性抗原肽及α1-α2结构域的构象及相互作用,诱导产生新的氢键,增强TCR-pMHC-Ⅰ之间的键合时间,但并不能增强TCR与抑制性pMHC-Ⅰ之间的作用。当用点突变阻断这些新形成的氢键,或者α1-α2和β2结构域被二硫键锁住时,最佳力诱导的TCR-pMHC-Ⅰ作用的键合时间明显缩短并且T细胞的活化受到抑制。另外,在人TCR和HLA-A2相互作用中发现了类似机制,并且与肿瘤相关的HLA-A2点突变[3]可以通过限制HLA-A2α1--α2和β2结构域之间的构象打开减弱TCR对肿瘤抗原的识别及T细胞的功能。研究结果表明,机械力诱导的MHC-I构象变化对TCR抗原识别和T细胞活化非常重要,进一步地阐明了机械力调控TCR抗原识别机制,为临床肿瘤的免疫治疗和药物设计提供了新思路和新靶点。

Action-oriented obesity counseling attains weight stabilization and improves liver enzymes among overweight and obese children and adolescents

Introduction: Pediatricians are encouraged to promote behavior modification to reduce childhood obesity and its co-morbidities, yet the effectiveness of office counseling is unclear. We aimed to evaluate if a low-intensity intervention (action-oriented counseling) in a clinic setting results in weight stabilization, and if the effect is modified by a diagnosis of non-alcoholic fatty liver disease (NAFLD). We hypothesized that patients with NAFLD would be more motivated to adhere to the lifestyle goals set in clinic, due to the diagnosis of an obesity-related condition;and, would therefore achieve greater weight reduction compared to similarly overweight and obese patients without a diagnosis of NAFLD. Methods: A retrospective chart review was conducted on 73 (35 male, 38 female) overweight and obese patients (BMI ≥ 85th percentile) attending a pediatric GI clinic between January 2006 and October 2011. Analysis was conducted to determine if lifestyle goals discussed with the patient at each clinic visit were associated with improved BMI, BMI z-score, and liver enzymes. Treatment outcomes among NAFLD patients and similarly obese patients without NAFLD were compared using t-tests and chi-square tests. Results: Of the children evaluated, 74.0% achieved a reduction or stabilization in BMI z-score after 3 months of follow-up. Among NAFLD patients, liver enzymes improved in 72% of those who were able to stabilize or reduce their BMI and among 43% of those who gained weight. Treatment outcome did not significantly differ based on having a diagnosis of NAFLD, although there was a trend towards greater improvements. Conclusion: Our study suggests that action oriented counseling including goal-setting in a low intensity, clinic based approach is effective in improving patient BMI, in the presence or absence of an obesity-related co-morbidity, such as NAFLD. Further, we demonstrated that lifestyle modification led to improvement of liver enzymes in NAFLD patients and may result in other clinically relevant improvements. Longer studies will be needed to determine if the improvements are sustained.

#ChronicPain:Automated Building of a Chronic Pain Cohort from Twitter Using Machine Learning

Importance:Drug-likeness of a compound is an overall assessment of its potential to succeed in clinical trials,and is essential for economizing research expenditures by filtering compounds with unfavorable properties and poor development potential.To this end,a robust drug-likeness prediction method is indispensable.Various approaches,including discriminative rules,statistical models,and machine learning models,have been developed to predict drug-likeness based on physiochemical properties and structural features.Notably,recent advancements in novel deep learning techniques have significantly advanced drug-likeness prediction,especially in classification performance.Highlights:In this review,we addressed the evolving landscape of drug-likeness prediction,with emphasis on methods employing novel deep learning techniques,and highlighted the current challenges in drug-likeness prediction,specifically regarding the aspects of generalization and interpretability.Moreover,we explored potential remedies and outlined promising avenues for future research.Conclusion:Despite the hurdles of generalization and interpretability,novel deep learning techniques have great potential in drug-likeness prediction and are worthy of further research efforts.

The discovery of T–B cell lineages:An interview with Professor Max D Cooper

In the early 1960s,despite a general understanding of antibodies and immunoglobulins,their source and their relationship with anti-infection immunity remained largely enigmatic.However,this changed with the groundbreaking discoveries of Dr.Max D Cooper,professor at Emory University School of Medicine.In the 1960s,Dr.Max D Cooper discovered the existence of two different lymphoid lineages,B and T cells,which are now widely recognized as the cornerstone components of the adaptive immune system.B and T cells are responsible for humoral and cellular immunity,respectively.This discovery served as the foundation of modern immunology.Here,Dr.Max D Cooper shares his inspiring journey,from career choice to research experiences,as well as offering sage advice to aspiring immunologists.

Effects of Clarithromycin at Sub-Minimum Inhibitory Concentrations on Early <i>erm</i>B Gene Expression, Metabolic Activity and Growth of an <i>erm</i>(B)-Expressing Macrolide-Resistant Strain of <i>Streptococcus pneumoniae</i>

Aim: To investigate the effects of exposure of a macrolide-resistant [erm (B)-expressing] strain of Streptococcus pneumoniae (strain 2507) to clarithromycin (0.5 and 5 mg/L) added at the outset and 6 hours after initiation of culture on early gene expression, energy metabolism, and growth. Methods: Bacterial growth was determined by turbidometric and colony counting procedures, energy metabolism by measurement of ATP, while analysis of gene expression was performed using reverse transcription-PCR and sequencing. Results: Addition of clarithromycin, at either concentration, at the outset of culture, caused transient suppression of growth of 10 - 12 hours duration, while delayed addition of antibiotic (during the logarithmic phase) resulted in an abrupt halt in growth followed by recovery. These inhibitory effects of clarithromycin on bacterial growth were associated with up-regulation of expression of erm(B), decreased ATP and protein synthesis, and were unaffected by inclusion of either catalase (500 and 1000 kunits/L), or competence-stimulating peptide (CSP-1, 0.5 mg/L). The inhibitory effects could, however, be overcome by pre-exposure of the bacteria to the antibiotic. Moreover, clarithromycin appeared to potentiate the antimicrobial actions of ceftriaxone, at sub-MIC concentrations, for strain 2507. Conclusions: Unlike several other common bacterial pathogens, the full expression of erm(B)-mediated macrolide resistance by the pneumococcus has a slow onset, which is associated with transient susceptibility to macrolides and inhibition of growth.

Regulation of drug metabolism and toxicity by multiple factors of genetics,epigenetics,lncRNAs,gut microbiota,and diseases:a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations(MDO)

Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.

Health consequences of early-onset compared with late-onset type 2 diabetes mellitus

Background:Although cumulating evidence has suggested that early-onset type 2 diabetes mellitus(T2DM)conferred on patients a broader tendency for complications beyond vascular ones,a comprehensive analysis of patterns of complications across all relevant systems is currently lacking.Method:We prospectively studied 1777 early-onset(age at diagnosis≤45 years)and 35889 late-onset(>45 years)T2DM patients with matched unexposed individuals from the UK Biobank.Diabetes-specific and-related complications were examined using phenomewide association analysis,with patterns identified by comorbidity network analysis.We also evaluated the effect of lifestyle modifications and glycemic control on complication development.Results:The median follow-up times for early-onset and late-onset T2DM patients were 17.83 and 9.39 years,respectively.Compared to late-onset T2DM patients,patients with early-onset T2DM faced a significantly higher relative risk of developing subsequent complications that primarily affected sense organs[hazard ratio(HR)3.46 vs.1.72],the endocrine/metabolic system(HR 3.08 vs.2.01),and the neurological system(HR 2.70 vs.1.81).Despite large similarities in comorbidity patterns,a more complex and well-connected network was observed for early-onset T2DM.Furthermore,while patients with early-onset T2DM got fewer benefits(12.67%reduction in pooled HR for all studied complications)through fair glycemic control(median HbA1c≤53 mmol/mol)compared to late-onset T2DM patients(18.01%reduction),they seemed to benefit more from favorable lifestyles,including weight control,healthy diet,and adequate physical activity.Conclusions:Our analyses reveal that early-onset T2DM is an aggressive disease resulting in more complex complication networks than late-onset T2DM.Aggressive glucose-lowering intervention,complemented by lifestyle modifications,are feasible strategies for controlling early-onset T2DM-related complications.