Objectives: Type 2 diabetes mellitus(T2DM) can accelerate the clinical process of atherosclerosis(AS). Dipeptidyl peptidase-4 inhibitors(DPP-4Is) have potential anti-AS effects. And, we completed a meta-analysis of the changes in carotid intima-media thickness(CIMT), flow-mediated dilation(FMD), and pulse wave velocity(PWV) of DPP-4Is to research the effect of DPP-4Is in the progression of AS in T2DM patients. Materials and methods: We included RCTs that evaluated the impact of DPP-4Is on CIMT, FMD, and PWV compared to other treatments from PubMed, Cochrane trials, and Embase database before October 31, 2020. We selected the random-effect model and calculated the weighted mean difference(WMD) to evaluate the effect of CIMT, FMD, and PWV in T2DM patients. Results：Through the meta-analysis, we found that DPP-4Is can significantly reduce CIMT in T2DM patients(WMD =-0.036, 95% CI:-0.055 to-0.017; p≤0.001). Based on the subgroup analysis, we found that CIMT was significantly decreased in patients with greater than 12 months of intervention and without cardiovascular diseases. Besides, we also found that DPP-4Is had a not significant efficacy on the improvement of FMD in T2DM patients(WMD=0.635, 95% CI: -0.112 to 1.383, p= 0.097). Our subgroup analysis showed that for T2DM patients who have cardiovascular diseases, DPP-4Is can significantly increase their FMD. In addition, we also found that DPP-4Is had an insignificant influence on PWV in T2DM patients(WMD= 0.424, 95% CI: -0.198 to 1.046, p= 0.18). but SGLT2 inhibitors may reduce the PWV of T2DM patients. Conclusions: DPP-4Is can alleviate the development of AS in T2DM patients to a certain extent by reducing CIMT. And, we believe that long-term use of DPP-4Is may be more helpful to alleviate the atherosclerotic development of T2DM without obvious cardiovascular history.

Background: Infection after cardiovascular surgery is multifactorial. We sought to determine whether the anthropometric profile influence the occurrence of infection after isolated coronary artery bypass grafting (CABG). Methods: Between January 2011 and June 2016, 1,777 consecutive adult patients were submitted to isolated coronary artery bypass grafting. Mean age was 61.7 ± 9.8 years and 1,193 (67.1%) were males. Patients were divided into four groups according to the Body Mass Index (BMI) classification: underweight (BMI<18.5 kg/m2: N=17, 0.9%), normal range (BMI 18.5 – 24.99 kg/m2: N=522, 29.4%), overweight (BMI 25 – 29.99 kg/m2: N=796, 44.8%) and obese (>30 kg/m2: N=430, 24.2%). In-hospital outcomes were compared and independent predictors of infection were obtained through multiple Poisson regression with robust variation. Results: Independent predictors of any infection morbidity were female sex (RR 1.47, P=0.002), age > 60 years (RR 1.85, P<0.0001), cardiopulmonary bypass > 120 minutes (RR 1.89, P=0.0007), preoperative myocardial infarction < 30 days (RR 1.37, P=0.01), diabetes mellitus (RR 1.59, P=0.0003), ejection fraction < 48% (RR 2.12, P<0.0001) and blood transfusion (RR 1.55, P=0.0008). Among other variables, obesity, as well as diabetes mellitus, were independent predictors of superficial and deep sternal wound infection. Conclusions: Other factors rather than the anthropometric profile are more important in determining the occurrence of any infection after CABG. However, surgical site infection has occurred more frequently in obese patients. Appropriate patient selection, control of modifiable factors and application of surgical bundles would minimize this important complication.

Disulfide bond reduction has been a challenging issue in antibody manufacturing, as it leads to reduced product purity, failed product specifications and more importantly, impacting drug safety and efficacy. Scientists across industry have been examining the root causes and developing mitigation strategies to address the challenge. In recent years, with the development of high-titer mammalian cell culture processes to meet the rapidly growing demand for antibody biopharmaceuticals, disulfide bond reduction has been observed more frequently. Thus, it is necessary to continue evolving the disulfide reduction mitigation strategy and development of novel approaches to achieve high product quality. Additionally, in recent years as more complex molecules emerge such as bispecific and trispecific antibodies, the molecular heterogeneity due to incomplete formation of the interchain disulfide bonds becomes a more imperative issue. Given the disulfide reduction challenges that our industry are facing, in this review, we provide a comprehensive contemporary scientific insight into the root cause analysis of disulfide reduction during process development of antibody therapeutics, mitigation strategies and recovery based on our expertise in commercial and clinical manufacturing of biologics. First, this paper intended to highlight different aspects of the root cause for disulfide reduction. Secondly, to provide a broader understanding of the disulfide bond reduction in downstream process, this paper discussed disulfide bond reduction impact to product stability and process performance, analytical methods for detection and characterization, process control strategies and their manufacturing implementation. In addition, brief perspectives on development of future mitigation strategies will also be reviewed, including platform alignment, mitigation strategy application for bi- and tri-specific antibodies and using machine learning to identify molecule susceptibility of disulfide bond reduction. The data in this review are originated from both the published papers and our internal development work.

Background and Purpose: The development of effective therapeutic strategies against Alzheimer’s disease (AD) remains a challenge. I2 Imidazoline receptors (I2-IR) ligands have a neuroprotective role in AD. While co-treatment of acetylcholinesterase inhibitors with neuroprotective agents have shown better effects on the prevention of dementia. Here, we assessed the potential therapeutic effect of the I2-IR ligand LSL60101, donepezil and their combination in 5XFAD mice. Experimental Approach: 5XFAD female mice were treated with low doses of LSL60101 (1mg/kg/day), donepezil (1mg/kg/day), and donepezil plus LSL60101 (1+1mg/kg/day), during 4 weeks per os. Novel object recognition, Morris water maze, open field, elevated plus maze and three-chamber tests were employed to evaluate the cognitive and behavioural status of the mice after treatment. The effects of the treatments on AD-like pathology were assessed with immunohistochemistry, Western blot and qPCR. Key results: Chronic low-dose treatment with LSL60101 and donepezil reversed cognitive deficits and impaired social behaviour. LSL60101 treatment did not affect anxiety-like behaviour in contrast to donepezil. In the 5XFAD brains, LSL60101 and donepezil/LSL60101 treatments decreased Aβ-pathology and Tau hyperphosphorylation, and these alterations were accompanied by decreased microglia marker Iba-1 levels and increased Trem2 gene expression. LSL60601 and donepezil decreased glial fibrillary acidic protein (GFAP) astrocytic marker reactivity. However, only LSL60601 treatment significantly increased the levels of the synaptic markers post-density 95 (PSD95) and synaptophysin (SYN). Conclusion and implications: Our results suggest that chronic low dose treatment with selective I2-IR ligands can be an effective treatment for AD and provide insights into combination treatments of symptomatic and disease-modifying drugs

Title: Misleading Title and Communication.Regarding Brief Communication: First clinical use of real-time remote programming in cardiac implantable electronic devices.  Dr. Toshimasa Okabe et al. J Cardiovascular Electrophysiol. 2020;31:2759-2761. DOI:10.1111/jce.14698Author: Dr. Esteban Martin Kloosterman

Objective: The aim of this study is to evaluate the outcome of ablation therapy in our clinic for the treatment of patients with small renal mass Materials and Methods: We retrospectively evaluated the technic and follow-up data of 30 patients with 36 tumors who underwent Radiofrequency Ablation (RFA) and Microwave Ablation (MWA) in our clinic. Demographic data, ablation type, tumor characteristics, peroperative and postoperative complications and treatment success of the patients were evaluated. Results: A total of 36 tumors who underwent ablation treatments, 23 were treated with RFA, 13 with MWA. The mean tumor size was 28.9 ± 6.92 mm in RFA and 29.3 ± 7.70 mm in MWA. 12 (52.1%) of the RFA procedures were applied to the right kidney while 11 (47.8%) were applied to the left kidney. 6 (46.1%) of the MWA procedures were performed on the right kidney and 7 (53.8%) on the left kidney. Of the 36 tumors, 4 (11.1%) were located central and 32 (88.8%) were peripheral. Complications occurred in 2 patients. In one of these patients, acute renal failure and urea creatinine were found to be elevated. In the other patient, local pain was found in the ablation side and minor bleeding was detected at the ablation site in USG. The mean follow-up period was 49.6 ± 24.7 months in patients with RFA and mean follow-up was 16 ± 8,05 months in MWA treatments. The overall success in MWA administration was calculated as 76.9%, while the overall success in RFA was 80%. Conclusion: Long-term oncologic efficacy of RFA appears to be successful in the treatment of T1a renal carcinomas. Further studies can be conducted to elucidate the influence of MWA on long-term oncological outcomes.

Aim: In this study, we aimed to evaluate the anxiety and depression status of prostate cancer (PCa) patients whose planned operations in the urology clinic of our hospital, which is serving as a pandemic hospital in Turkey have been postponed due to the coronavirus disease 2019 pandemic. Methods: This survey study was conducted at urology clinic of Ankara City Hospital between March 1 and June 1, 2020 and included 24 male patients who agreed to answer the questionnaires (State-Trait Anxiety Inventory [STAI] I and II and Beck Depression Inventory [BDI]). Demographical and clinical data (age, time since diagnosis, total serum prostate specific antigen (PSA) levels, risk groups according to the D’Amico classification system, smoking, alcohol habitus, major surgical history, and comorbidities) of the patients were collected from hospital software. Results: The mean STAI-I score of the patients (46.7 ± 1.4 [44–49]) was significantly higher than their STAI-II score (41.7 ± 2.4 [39–47]) (p < 0.001). The negative correlation between the decrease in age and STAI-I score was found to be statistically significant (r = 0.439, p < 0.05). The mean BDI score of the patients was 4.3 ± 3.2 (0–13), which was compatible with mild depression. There was no statistically significant difference between the time elapsed from diagnosis, PSA levels, smoking and alcohol habitus, major surgical history and comorbidity status, and STAI-I, STAI-II, and BDI scores (p > 0.05). Conclusion: Prostate cancer patients with postponed operations should be guided properly in order to manage their anxiety status especially young patients.

Background COVID‐19 is usually mild, but patients can present with pneumonia, acute respiratory distress syndrome (ARDS) and circulatory shock. Although the symptoms of the disease are predominantly respiratory, involvement of the cardiovascular system is common. Patients with heart failure (HF) are particularly vulnerable when suffering from COVID‐19. Aim of the Review To examine the challenges faced by healthcare organisations, and mechanical circulatory support management strategies available to patients with heart failure, during the COVID-19 pandemic. Results Extracorporeal membrane oxygenation (ECMO) can be lifesaving in patients with severe forms of ARDS, or refractory cardio-circulatory compromise. The Impella RP can provide right ventricular circulatory support for patients who develop right side ventricular failure or decompensation caused by COVID-19 complications, including pulmonary embolus. HT are reserved for only those patients with a high short-term mortality. LVAD as a bridge to transplant may be a viable strategy to get at-risk patients home quickly. Elective LVAD implantations have been reduced and only patients classified as INTERMACS profile 1 and 2 are being considered for LVAD implantation. Delayed recognition of LVAD‐related complications, misdiagnosis of COVID‐19, and impaired social and psychological well‐being for patients and families may ensue. Remote patient care with virtual or telephone contacts is becoming the norm. Conclusions HF incidence, prevalence, and undertreatment will grow as a result of new COVID-19-related heart disease. ECMO should be reserved for highly selected cases of COVID-19 with a reasonable probability of recovery. Special considerations are needed for patients with advanced HF, including those supported by durable LVADs.

Objective: Although elderly patients undergoing surgery for acute type A aortic dissection (ATAAD) is increasing, their physical activities are not fully understood. We report the physical activities and surgical outcomes in the elderly patients who underwent ATAAD. Methods: From 2009 to 2019, 103 consecutive patients underwent surgery for ATAAD at our institution. Surgical outcomes along with pre- and postoperative physical activities in 52 elderly patients (≥70 years old) were compared with those in 51 younger patients (<70 years old). Postoperative walking difficulty was defined as taking ≥30 days to regain the ability to walk 200 m postoperatively or as the inability to walk at discharge. Results: It took longer for elderly patients to regain the ability to walk 100 or 200 m postoperatively. ROC analysis revealed the AUC of the duration for walking 200 m postoperatively as a prognostic indicator for late deaths was 0.878, with the highest accuracy at 30 days (sensitivity = 83.3%, specificity = 91.8%). Hospital mortality within 30 days was 3.8%, and 1-, 3-, and 5-years survival rates were 92%, 84.7%, 84.7%, respectively, for elderly patients, with no significant differences between groups. Cox proportional hazard analysis showed postoperative walking difficulty was an independent risk factor for late mortality in all cohorts (P = 0.017). Conclusions: Elderly patients undergoing surgical ATAAD repair showed acceptable surgical outcomes. However, they were more likely to decrease their physical activities postoperatively. Postoperative difficulty in walking was an independent risk factor for the late mortality in patients with ATAAD.

Type A aortic dissection most often requires emergent surgery to prevent malperfusion, stroke, and/or rupture of aorta. The conduct of the surgery is mostly targeted at restoring true lumen flow. In this regard, institution of cardiopulmonary bypass and circulation management is key to allow adequate systemic flow, perfusion of brain and visceral organs and comprehensive systemic cooling to achieve circulatory arrest when needed. Different strategies have been used with varying success rates, with the most common being femoral cannulation. More recently axillary and central cannulation strategies have shown satisfactory results with the promise of antegrade flow. Cannulation approach should, therefore, depend on individual patient characteristics, presentation and true lumen anatomy.

Rationale, aims and objectives: Consistent data demonstrates negative psychological effects of caregiving on front-line health professionals. Evidence that psychological resilience factors can help minimise distress and the potential for low-cost interventions have created interest in resilience-based development programmes; yet evidence of perceived value amongst health professionals is lacking. This study explored health professionals’ experiences and perceptions of a novel, resilience-based intervention designed to pro-actively prepare staff for coping with error; to investigate their perceptions of what resilience meant to them, the relevance of the intervention, and impact of participation on ability to cope with error. Method: Semi-structured interviews 4-6 weeks post intervention with 23 randomly selected participants from seven cohorts (midwives, paediatricians, obstetrians/gynaecologists, paramedics) and trainees (physician associates, mammographers, sonographers). Thematic analysis of interview data. Findings: Participants reported various interpretations of, and a shift in perception regarding what the concept of psychological resilience meant to them and their practice. These included for example, resilience as a positive or negative concept and their awareness and response to a range of personal, organisational and system factors influencing personal resilience. They valued the prophylactic, clinically relevant, interactive and applied nature of the intervention; having developed and applied valuable skills beyond the context of involvement in error, noting that individuals needed to be willing to explore their own coping mechanisms and human fallibility to gain maximum benefit. There was also consensus that whilst proactively developing individual level psychological resilience is important, so too is addressing the organisational and system factors that affect staff resilience which are outside individual staff control. Conclusion: Enhancing resilience appears to be considered useful in supporting staff to prepare for coping with error and the wider emotional burden of clinical work, but such interventions require integration into wider system approaches to reduce the burden of clinical work for health professionals.

This work concerns the typical conformational behaviors for di-substituted cyclohexanes that inherently depend on spatial orientations of side chains in flexible cyclic ring. The 1,3-dimethylcyclohexane and 1,4-dimethylcyclohexane in both cis- and trans-configurations were focused here to unravel their conformational inversion-topomerization mechanisms. Full geometry optimizations were performed at B3LYP/6-311++G(d,p) level of theory to explicitly identify all distinguishable molecular structures, and thus explore potential energy surfaces (PES) of the complete interconversion routes for two stereoisomers of 1,3-dimethylcyclohexane and 1,4-dimethylcyclohexane. Additional quantum calculations were carried out by separately applying MP2/6-311++G(d,p), G4, and CCSD(T)/6-311++G(d,p) methods to further refine all PES’ stationary points. With respect to quantum results, the conformational analysis was conducted to gain insight into the determination, thermodynamic stabilities, and relative energies of distinct molecular geometric structures. On base of highly biased conformational equilibria, the temperature-dependent populations of stable local minima for four studied dimethylcyclohexanes were obtained by utilizing Boltzmann distribution within 300-2500 K. Moreover, two unique interconversion processes for them, including inversion and topomerization, were fully investigated, and their potential energy surfaces were illustrated with the rigorous descriptions in two or three-dimensional schemes for clarify.

Aims Serum biomarkers have a potential role in the risk stratification of patients with heart valve disease and may help determine the optimal timing of intervention. Much of the published literature relates to biomarker sampling in a resting state, but the relationship of exercise biomarkers is less well described. We performed a systematic review to examine the significance of exercise natriuretic peptides on echocardiographic variables and cardiovascular events, in valvular heart disease. Methods A search for studies that assessed exercise biomarkers in patients with moderate to severe valve lesions was performed. We examined the relationship between rest and exercise BNP and also the endpoints of symptoms, haemodynamic or echocardiographic variables and clinical outcomes. Results 11 prospective studies were identified (844 participants). 61% were male and the mean age was 55.2 ± 9.6 years. The majority of the blood samples were taken at baseline and within 3 minutes of stopping exercise. There was a significant increase in exercise BNP compared with rest, in patients with aortic stenosis, mitral regurgitation and mitral stenosis. Elevated exercise BNP levels correlated with mean gradient and left atrial area, and there was a relationship between a higher exercise BNP and a blunted blood pressure response, in aortic stenosis. Furthermore, exercise BNP was independently associated with cardiac events, over and above resting values, in patients with mitral regurgitation and aortic stenosis. Conclusions The results suggesting that exercise natriuretic peptide levels may have additive prognostic importance over resting levels, as well as demographic and echocardiographic data.

We present a patient with 3 separate primary cancers over the course of 11 years: Follicular Lymphoma, Abdominal mesothelioma and Rectal Adenocarcinoma respectively Multiple primary malignancies are exceedingly rare but they may occur sequentially in a patient. Peritoneal mesothelioma known as a fatal malignancy may completely regress with chemotherapy.

The clinical presentation of cardiac sarcoidosis is variable. We report two cases of cardiac sarcoidosis to highlight the varied clinical presentations and diagnostic challenges in our setting and encourage the consideration of sarcoidosis as a differential in unexplained arrhythmias and heart failure.

In this article we report a case of SCC in an untreated 45-year-old male patient of psoriasis. The patient referred to the dermatology department manifesting erythrodermic psoriasis. After taking multiple biopsies from scalp lesions, the result was reported to be SCC with sebaceous differentiation.

Bariatric or weight-loss surgery is a popular option for weight reduction. Depending on the surgical procedure, gastric changes like decreased transit time and volume and increased pH, decreased absorption surface in the small intestine, decreased exposure to bile acids and enterohepatic circulation, and decreased gastrointestinal transit time may be expected. In the years after bariatric surgery, patients will also substantially lose weight. As a result of these changes, the absorption, distribution, metabolism, and/or elimination of drugs may be altered. The purpose of this article is to report the general influence of bariatric surgery on oral drug absorption, and to provide guidance for dosing of commonly used or high-risk drugs in this special population. Upon oral drug administration, the time to maximum concentration is often earlier and this concentration may be higher with less consistent effects on trough concentrations and exposure. Additionally, prescription of liquid formulations to bariatric patients is supported by some reports, even though the high sugar load of these suspensions may be of concern. Studies on extended release medications result in an unaltered exposure for a substantial number of drugs. Also, studies evaluating the influence of timing after surgery show dynamic absorption profiles. Although for this group a specific advice can be proposed for many drugs, we conclude that there is insufficient evidence for general advices for oral drug therapy after bariatric surgery implying that a risk assessment on a case-by-case basis is required for each drug.

The impact of treatment on the risk of lymphoma in patients with rheumatoid arthritis (RA) is unclear. Here, we aimed to assess if the risk of lymphoma differs according to the type of Tumor Necrosis factor inhibitor (TNFi), comparing monoclonal anti-TNF antibodies (Ab) to the soluble TNF receptor. We used BAFF-transgenic (Tg) mice as a model of autoimmunity-associated lymphoma. Six-month aged BAFF-Tg mice were treated with TNFi for 12 months. Histological examination of the spleen, assessment of the cellular composition of the spleen by flow cytometry and assessment of B cell clonality were performed at sacrifice. Crude mortality and incidence of lymphoma were significantly higher in mice treated with monoclonal anti-TNF Ab compared to both controls and mice treated with the soluble TNF receptor, even at high dose. Flow cytometry analysis revealed decreased splenic macrophage infiltration in mice treated with monoclonal anti-TNF Ab. Overall, this study demonstrates, for the first time, that a very prolonged treatment with monoclonal anti-TNF Ab increase the risk of lymphoma in B cell-driven autoimmunity. This data suggests a closer monitoring for lymphoma development in patients suffering from B cell-driven autoimmune disease with long-term exposure to monoclonal anti-TNF Ab.