Search

Backgruound: The aim was to investigate if autonomic symptoms questionnaire Composite Autonomic Symptom Score (COMPASS) 31 has different association with cardiovascular autonomic neuropathy (CAN) and diagnostic performance between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)., Methods: Seventy-nine participants with T1DM and 140 with T2DM completed COMPASS 31 before cardiovascular reflex tests (CARTs) for CAN, and assessment of symptoms, signs, vibration, and thermal perception thresholds for diabetic polyneuropathy (DPN) diagnosis., Results: COMPASS 31 total weighted score (TWS) was similar in the two groups, but significantly associated with confirmed CAN only in T1DM (P=0.0056) and not T2DM group (P=0.1768) and correlated with CARTs score more strongly in T1DM (rho=0.356, P=0.0016) than in T2DM group (rho=0.084, P=0.3218) (P=0.016). Only in T1DM and not T2DM group, the area under the receiver operating characteristic curve (AUC) reached a fair diagnostic accuracy (>0.7) for confirmed CAN (0.73±0.07 vs. 0.61±0.08) and DPN (0.75±0.06 vs. 0.68±0.05), although without a significant difference. COMPASS 31 TWS (cut-off 16.44) reached acceptable diagnostic performance in T1DM, with sensitivity for confirmed CAN 81.2% and sensitivity and specificity for DPN 76.3% and 78%, compared to T2DM group (all <70%). AUC for DPN of orthostatic intolerance domain was higher in T1DM compared to T2DM group (0.73±0.05 vs. 0.58±0.04, P=0.027)., Conclusion: COMPASS 31 is more weakly related to CAN in T2DM than in T1DM, with a fair diagnostic accuracy for confirmed CAN only in T1DM. This difference supports a multifactorial origin of symptoms and should be considered when using COMPASS 31.

Objectives: To evaluate the determinants of orthostatic hypotension (OH) in type 2 diabetes (T2D) and the usefulness of Δheart rate (HR)/Δsystolic blood pressure (SBP), index of cardiac baroreflex function, in identifying neurogenic OH., Methods: In 208 participants with T2D, we diagnosed early cardiovascular autonomic neuropathy (CAN) and confirmed CAN according to 1 and 2 HR-based cardiovascular reflex tests (HR-CARTs). Through OH test we defined OH as SBP falls of ≥20 and ≥30 mm Hg with supine SBPs of <140 and ≥140 mm Hg, respectively. In participants with OH, we used the lying-to-standing and OH test and its diagnostic accuracy for neurogenic OH (as OH plus confirmed HR-CAN)., Results: OH was present in 25 participants and associated with lower HR-CART scores, higher glycosylated hemoglobin level, the presence of CAN, retinopathy, and peripheral vascular disease, the absence of hypertension, and physical activity (all, P < .05) but not with interfering drugs and β-blockers. In a multiple logistic regression, HR-CAN was the main determinant of OH (odds ratio, 4.74) with physical activity and hypertension (odds ratios, 0.16 and 0.23; R 2  = 0.22). ΔHR/ΔSBP had a good diagnostic accuracy for neurogenic OH (area under the receiver operating characteristic curve, 0.816 ± 0.087) and, at the cutoff of 0.5 bpm/mm Hg, a sensitivity of 100% and specificity of 63.2%., Conclusion: CAN remains the primary determinant of OH in T2D but does not explain all its variance. The index ΔHR/ΔSBP may represent a useful clinical tool to identify neurogenic OH., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Introduction: Apheresis practices in the United States (US) have not been comprehensively characterized to date. This study aimed to address this gap by evaluating apheresis therapy through a national survey., Methods: A multi-institutional survey was conducted between April and July 2023. The survey, comprising 54 questions, focused on institutional demographics, procedures, equipment, staffing, training, and impacts of the Coronavirus Disease 2019 (COVID-19) pandemic. Responses from 22 institutions, primarily academic medical centers, were analyzed., Results: Therapeutic plasma exchange (TPE) was the most common procedure, followed by hematopoietic progenitor cell collection (HPC-A) and red blood cell exchange (RCE). CAR-T cell collections were widespread, with some institutions supporting over 30 protocols concurrently. Most sites used the Spectra Optia Apheresis System, were managed by a transfusion medicine service, and employed internal apheresis providers. Insufficient staffing levels, exacerbated by the COVID-19 pandemic, were common and most often addressed using overtime., Discussion: The survey highlighted the ubiquity of TPE, expanding cellular collections and staffing challenges. The role of apheresis in supporting cellular therapy, particularly in newly developing cell and gene therapies and clinical trials, was evident. Staffing issues during the pandemic emphasized the need for innovative recruitment strategies., Conclusion: This nationwide survey provides the most comprehensive analysis to date of apheresis practices in large US academic centers., (© 2024 The Author(s). Journal of Clinical Apheresis published by Wiley Periodicals LLC.)

Introduction: Kallmann syndrome (KS) is a genetically heterogeneous developmental disorder that most often manifests hypogonadotropic hypogonadism (HH) and hypo-/anosmia due to early embryonic impairment in the migration of gonadotropin-releasing hormone neurons. SOX10 (SRY-Box 10; MIM*602229), a key transcriptional activator involved in the development of neural crest cells, has been associated with KS and is identified as one of the causative genes of Waardenburg syndrome (WS)., Case Presentation: A 28-year-old female patient, who was clinically diagnosed with KS in her childhood, presented with HH and anosmia, mild bilateral sensorineural hearing loss (SNHL), and pigmentation abnormalities. Next-generation sequencing analysis detected a missense heterozygous SOX10 pathogenic variant (NM&#95;006941.4:c.506C>T) in the proposita and in her mother, whose phenotype included exclusively anosmia and hypopigmented skin patches. The same variant has been described by Pingault et al. [Clin Genet. 2015;88(4):352-9] in a patient with apparently isolated bilateral severe SNHL., Conclusion: Our finding substantiates the extreme phenotypic variability of SOX10 -related disorders, which range from classical KS and/or WS to contracted endophenotypes that could share a common pathway in the development of neural crest cells and highlights the need for careful evaluation and long-term follow-up of SOX10 patients, with special focus on atypical/additional and/or late-onset phenotypic traits., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The aim of the current study was to evaluate the outcomes of patients with diabetic foot osteomyelitis (DFO), comparing subjects with and without peripheral arterial disease (PAD). The study is a prospective study including a population of patients affected by a DFO located in the forefoot. All patients were managed by a surgical conservative approach defined by the removal of the infected bone, in association with the antibiotic therapy. Patients were divided into two groups: those with PAD (neuro-ischaemic DFO) and those without (neuropathic DFO). After 1 year of follow-up, the following outcome were evaluated and compared between groups: healing, healing time, minor amputation, major amputation, hospitalization, need for surgical re-intervention. Overall, 166 patients were included, 87(52.4%) of them had neuro-ischaemic DFO and 79 (47.6%) neuropathic DFO. Patients with neuro-ischaemic DFO in comparison to neuropathic DFO were older (72.5 ± 9 vs 64.1 ± 15.5 years, P  < .0001), had longer diabetes duration (21.8 ± 5.6 vs 16.4 ± 7.6 years, P  < .0001), higher rate of dialysis (13.8 vs 1.3%, P  = .001) and ischaemic heart disease (79.3 vs 12.7%, P  < .0001). Outcomes for neuro-ischaemic DFO and neuropathic DFO were: healing (96.5 vs 97.5%, P  = .7), healing time (7.8 ± 6.2 vs 5.7 ± 3.7 weeks, P  = .01), minor amputation (16.1 vs 3.8%, P  = .006), major amputation (0 vs 0%, ns), hospitalization (90.8 vs 51.9%, P  < .0001), surgical re-intervention (14.9 vs 8.8%, P  = .004) respectively. In addition, PAD resulted in an independent predictor of minor amputation, hospitalization, and surgical re-intervention. DFO in patients with PAD was characterized by longer healing time, more cases of minor amputation, hospitalization, and surgical re-intervention. PAD independently predicted the risk of minor amputation, hospitalization, and surgical re-intervention, while it was not associated with the healing rate., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Nanomedicine could improve the treatment of diabetes by exploiting various therapeutic mechanisms through the use of suitable nanoformulations. For example, glucose-sensitive nanoparticles can release insulin in response to high glucose levels, mimicking the physiological release of insulin. Oral nanoformulations for insulin uptake via the gut represent a long-sought alternative to subcutaneous injections, which cause pain, discomfort, and possible local infection. Nanoparticles containing oligonucleotides can be used in gene therapy and cell therapy to stimulate insulin production in β-cells or β-like cells and modulate the responses of T1DM-associated immune cells. In contrast, viral vectors do not induce immunogenicity. Finally, in diabetic wound healing, local delivery of nanoformulations containing regenerative molecules can stimulate tissue repair and thus provide a valuable tool to treat this diabetic complication. Here, we describe these different approaches to diabetes treatment with nanoformulations and their potential for clinical application.

Background: If unrecognized, Charcot neuro-osteoarthropathy (CNO) can be a devastating complication of diabetes. Methods: The aim of this retrospective study was to evaluate the outcomes in a cohort of diabetic patients diagnosed with active CNO managed in a tertiary level diabetic foot clinic (DFC). We included consecutive patients with active CNO, stage 0-1, according to the Eichenholtz-Shibata classification, who were referred from 1 January 2019 to 27 September 2022. Diagnosis of CNO was based on clinical signs and imaging (X-rays and magnetic resonance). All patients were completely offloaded by a total-contact cast (TCC) or removable knee-high device. Each patient was closely monitored monthly until CNO remission or another outcome. At 12 months of follow-up, the following outcomes were analyzed: remission, time to remission, major amputations (any above the ankle), and surgical indication. Results: Forty-three patients were included. The mean age was 57.6 ± 10.8 years; 65% were males and 88.4% had type 2 diabetes, with a mean duration of 20.6 ± 9.9 years. At baseline, 32.6% was affected by peripheral artery disease. Complete remission was recorded in 40/43 patients (93%), with a mean time to remission of 5.6 ± 1.5 months; major amputation and surgical indication occurred, respectively in 1/43 patients (2.3%) and 3/43 patients (7%). Conclusions: Early treatment of active Stage 0/1 CNO leads to high rates of remission and limb salvage.

Background: Space travel has always been one of mankind's greatest dreams. Thanks to technological innovation, this dream is becoming more of a reality. Soon, humans (not only astronauts) will travel, live, and work in space. However, a microgravity environment can induce several pathological alterations that should be, at least in part, controlled and alleviated. Among those, glucose homeostasis impairment and insulin resistance occur, which can lead to reduced muscle mass and liver dysfunctions. Thus, it is relevant to shed light on the mechanism underlaying these pathological conditions, also considering a nutritional approach that can mitigate these effects., Methods: To achieve this goal, we used Prdx6 -/- mice exposed to Hindlimb Unloading (HU), a well-established experimental protocol to simulate microgravity, fed with a chow diet or an omega-3-enriched diet., Results: Our results innovatively demonstrated that HU-induced metabolic alterations, mainly related to glucose metabolism, may be mitigated by the administration of omega-3-enriched diet. Specifically, a significant improvement in insulin resistance has been reported., Conclusions: Although preliminary, our results highlight the importance of specific nutritional approaches that can alleviate microgravity-induced harmful effects. These findings should be considered soon by those planning trips around the earth.

Chronic obstructive pulmonary disease (COPD) may coexist with type 2 diabetes mellitus (T2DM). Patients with COPD have an increased risk of developing T2DM compared with a control but, on the other side, hyperglycaemia and DM have been associated with reduced predicted levels of lung function. The mechanistic relationships between these two diseases are complicated, multifaceted, and little understood, yet they can impact treatment strategy. The potential risks and benefits for patients with T2DM treated with pulmonary drugs and the potential pulmonary risks and benefits for patients with COPD when taking antidiabetic drugs should always be considered. The interaction between the presence and/or treatment of COPD, risk of infection, presence and/or treatment of T2DM and risk of acute exacerbations of COPD (AECOPDs) can be represented as a vicious circle; however, several strategies may help to break this circle. The most effective approach to simultaneously treating T2DM and COPD is to interfere with the shared inflammatory substrate, thus targeting both lung inflammation (COPD) and vascular inflammation (DM). In any case, it is always crucial to establish glycaemic management since the reduction in lung function found in people with diabetes might decrease the threshold for clinical manifestations of COPD. In this article, we examine possible connections between COPD and T2DM as well as pharmacological strategies that could focus on these connections.

The aim of the current study was to evaluate the rate of readmission in patients affected by diabetes and foot ulcers (DFUs), and causes and outcomes of patients requiring a new hospitalization. The current study is a retrospective observational study including patients who have required hospitalization since January 2019 to September 2022 due to a DFU. Once patients were discharged, they were regularly followed as outpatients. Within 6 months of follow-up, the rate of hospital readmission for a diabetic foot problem was recorded. According to the readmission or not, patients were divided into 2 groups, readmitted and not readmitted patients, respectively. Hence, all patients were followed for 6 months more and outcomes of the 2 groups were analyzed and compared. Overall, 310 patients were included. The mean age was 68  ±  12 years, the majority of patients reported type 2 diabetes (>90%), and the mean diabetes duration was approximately 20 years. Sixty-eight (21.9%) patients were readmitted. The main reason for hospital readmission was the presence of critical limb ischemia (CLI) in the contralateral limb (6.1%), the recurrence of CLI in the previous treated limb (4.5%), and the onset of new infected DFU in the contralateral foot (4.5%). Readmitted patients reported lower rate of healing (51.5% vs 89.2%, P  < .0001) and higher rate of major amputation (10.3% vs 4.5%, P   =  .2) in comparison to not readmitted patients. Critical limb ischemia resulted in the only independent predictor of hospital readmission. Hospital readmission is a frequent issue among patients with DFUs, and readmitted patients showed a lower chance of wound healing. Critical limb ischemia resulted in the main cause of new hospitalization., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims and Data Synthesis: Glucose variability (GV) is increasingly considered an additional index of glycemic control. Growing evidence indicates that GV is associated with diabetic vascular complications, thus being a relevant point to address in diabetes management. GV can be measured using various parameters, but to date, a gold standard has not been identified. This underscores the need for further studies in this field also to identify the optimal treatment., Conclusions: We reviewed the definition of GV, the pathogenetic mechanisms of atherosclerosis, and its relationship with diabetic complications., (© 2023. The Author(s).)

Aims: The current study aims to evaluate the effectiveness of a multidisciplinary diabetic foot team (MDFT) in the management of in-patients affected by diabetic foot problems., Materials and Methods: The study was a retrospective observational study. Consecutive patients with a diabetic foot problem requiring hospitalisation were included. All patients were managed by a MDFT led by diabetologists according to the guidance. The rate of in-hospital complications (IHCs), major amputation, and survival were recorded at the end of patient's hospitalisation. IHC was defined as any new infection different from wound infection, cardiovascular events, acute renal injury, severe anaemia requiring blood transfusion, and any other clinical problem not present at the assessment., Results: Overall, 350 patients were included. The mean age was 67.9 ± 12.6 years, 254 (72.6%) were males, 323 (92, 3%) showed Type 2 diabetes with a mean duration of 20.2 ± 9.6 years; 224 (64%) had ischaemic diabetic foot ulcers (DFUs) and 299 (85.4%) had infected DFUs. IHCs were recorded in 30/350 (8.6%) patients. The main reasons for IHCs were anaemia requiring blood transfusion (2.8%), pneumonia (1.7%), acute kidney failure (1.1%). Patients with IHCs showed a higher rate of major amputation (13.3 vs. 3.1%, p = 0.02) and mortality (16.7 vs. 0.6%, p < 0.0001) in comparison to those without. Ischaemic heart disease (IHD) and wound duration at the assessment (>1 month) were independent predictors of IHC, whereas IHCs, heart failure, and dialysis were independent predictors of in-hospital mortality., Conclusions: The multidisciplinary management of diabetic foot problems leads to an IHC rate of 8%. The risk of IHCs is higher in patients with IHD and long wound duration., (© 2023 John Wiley & Sons Ltd.)

The current study aimed to evaluate the effectiveness of peripheral blood mononuclear cell (PB-MNC) therapy as adjuvant treatment for patients with diabetic foot ulcers (DFUs) and no-option critical limb ischaemia (NO-CLI). The study is a prospective, noncontrolled, observational study including patients with neuro-ischaemic DFUs and NO-CLI who had unsuccessful revascularization below the ankle (BTA) and persistence of foot ischaemia defined by TcPO2 values less than 30 mmHg. All patients received three cycles of PB-MNC therapy administered through a " below-the-ankle approach " in the affected foot along the wound-related artery according to the angiosome theory. The primary outcome measures were healing, major amputation, and survival after 1 year of follow-up. The secondary outcome measures were the evaluation of tissue perfusion by TcPO2 and foot pain defined by the numerical rating scale (NRS). Fifty-five patients were included. They were aged >70 years old and the majority were male and affected by type 2 diabetes with a long diabetes duration (>20 years); the majority of DFUs were infected and nearly 90% were assessed as gangrene. Overall, 69.1% of patients healed and survived, 3.6% healed and deceased, 10.9% did not heal and deceased, and 16.4% had a major amputation. At baseline and after PB-MNC therapy, the TcPO2 values were 17 ± 11 and 41 ± 12 mmHg, respectively ( p < 0.0001), while the pain values (NRS) were 6.8 ± 1.7 vs. 2.8 ± 1.7, respectively ( p < 0.0001). Any adverse event was recorded during the PB-MNC therapy. Adjuvant PB-MNC therapy seems to promote good outcomes in patients with NO-CLI and neuro-ischaemic DFUs.

Aims: After the acute phase of SARS-CoV-2 infection, the onset of glycemic impairment and diabetes have been reported. Nevertheless, the exact burden of glycemic impairment and diabetes after COVID-19 has not been clearly described., Materials and Methods: Electronic search was run in Pubmed (MEDLINE), Web of Science, Scopus, and ClinicalTrial.org for reports published from database inception to September 2022. We included observational studies reporting quantitative data on diabetes prevalence or its onset in subjects with a history of SARS-CoV-2 infection from at least 60 days. Risk of bias was assessed by the JBI's critical appraisal checklist. Random effect model was used to calculate pooled data. The review protocol was registered on PROSPERO (CRD42022310722)., Results: Among 1,630 records screened, 20 studies were included in the analysis. The mean or median age of participants ranged from ~ 35 to 64 years, with a percentage of males ranging from 28% to 80%. Only two studies were considered at low risk of bias. The estimate of diabetes prevalence, calculated on a total of 320,948 participants pooled with 38,731 cases, was 16% (95%CI: 11-22%). The estimate of proportion of incident cases of diabetes was 1.6% (95%CI: 0.8-2.7%). Subgroup analysis showed that previous hospitalization increased the prevalence of diabetes and the proportion of incident cases., Conclusion: Diabetes is common in individuals who have experienced SARS-CoV-2 infection, especially if they required hospitalization. This data may be helpful to screen for diabetes and manage its complications in individuals who experienced COVID-19., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display&#95;record.php?ID=CRD42022310722, identifier CRD42022310722., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bellia, Andreadi, D’Ippolito, Scola, Barraco, Meloni, Lauro and Bellia.)

Hyperandrogenism during menopause is often underestimated by clinicians and attributed to the natural aging process. Hyperandrogenism can be associated with some metabolic abnormalities linked together in a vicious circle by insulin resistance. We present the case of an elderly woman affected with type 2 diabetes and obesity who reported the occurrence of clinical hirsutism after physiological menopause at the age of 47 years. At presentation, physical examination and Ferriman-Gallwey score revealed a condition of moderate hirsutism, with markedly increased levels of plasma testosterone and delta-4-androstenedione, obesity (body mass index 31.9), and inadequate glycemic control (glycated hemoglobin 65 mmol/mol). The patient underwent a thorough differential diagnosis by a multidisciplinary team approach, including the various causes of hyperandrogenism during menopause. After choosing surgical option as the appropriate treatment, clinical resolution of hirsutism was observed alongside patient satisfaction and marked improvement of the glucometabolic profile., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

The study aimed to evaluate the clinical and microbiological characteristics of diabetic foot infections (DFIs) in patients referring to a specialized diabetic foot service (DFS). The study is a retrospective observational study conducted in a single center, including patients who were referred for a new DFI. All patients were managed through a limb salvage protocol according to international guidelines. The following items were recorded: type of bacteria, presence of single or polymicrobial infection, and the antibiotic resistance. Overall, 268 patients were included. The mean age was 68.9  ±  10.9 years, 75% were male, and 97.2% had type 2 diabetes with a mean diabetes duration of 16  ±  9 years. One hundred thirty-nine (51.9%) DFU were ischemic, 120 (44.7%) patients had osteomyelitis, 107 (39.9%) had gangrene, 37 (13.9%) had phlegmon/abscess/cellulitis and 4 (1.5%) had necrotizing fasciitis. Among 370 bacteria isolated, gram positive were found in 207 (55.9%) cases, and gram negative in 163 (44.1%) cases. The higher rates of isolates were Staphylococcus aureus (32.9%), Pseudomonas aeruginosa (10.8%), and Enterococcus faecalis (8.9%). Polymicrobial infection was reported in 33.6% of cases and antibiotic resistance was recorded in 16.5% of isolates. Among them, 10.3% were methicillin-resistant S. aureus (MRSA). Antibiotic resistance was detected in 40.9% of cases in association with gangrene and osteomyelitis. The current study shows as polymicrobial infections and antibiotic resistance is frequently reported in DFIs, and antibiotic resistance was more associated with gangrene and osteomyelitis. Among bacteria reporting antimicrobial resistance, the highest rate was found for MRSA.

Background: The prevalence of coronary artery disease (CAD) considerably varies by ethnicity. High-risk populations include patients from Eastern Europe (EEP), the Middle East and North Africa (MENAP) and South Asia (SAP)., Methods: This retrospective study aims to highlight cardiovascular risk factors and specific coronary findings in high-risk immigrant groups. We examined the medical records and coronary angiographies of 220 patients from the above-mentioned high-risk ethnic groups referred for Acute Coronary Syndrome (ACS) and compared them with 90 Italian patients (IP) from 2016 to 2021. In the context of high-risk immigrant populations, this retrospective study aims to shed light on cardiovascular risk factors and particular coronary findings. We analyzed the medical records of 220 patients from the high-risk ethnic groups described above referred for ACS and compared them with 90 IPs between 2016 and 2021. In addition, we assessed coronary angiographies with a focus on the culprit lesion, mainly evaluating multi-vessel and left main disease., Results: The mean age at the first event was 65.4 ± 10.2 years for IP, 49.8 ± 8.5 years for SAP (Relative Reduction (ReR) 30.7%), 51.9 ± 10.2 years for EEP (ReR 26%) and 56.7 ± 11.4 years for MENAP (ReR 15.3%); p < 0.0001. The IP group had a significantly higher prevalence of hypertension. EEP and MENAP had a lower prevalence of diabetes. EEP and MENAP had a higher prevalence of STEMI events; SAP showed a significant prevalence of left main artery disease ( p = 0.026) and left anterior descending artery disease ( p = 0.033) compared with other groups. In SAP, we detected a higher prevalence of three-vessel coronary artery disease in the age group 40-50., Conclusions: Our data suggest the existence of a potential coronary phenotype in several ethnicities, especially SAP, and understate the frequency of CV risk factors in other high-risk groups, supporting the role of a genetic influence in these communities.

Purpose: Calcium ions are involved in the regulation of several cellular processes and may also influence viral replication. Hypocalcemia has been frequently reported during infectious diseases and in critically ill patients, including also COVID-19 patients, significantly related with the pro-inflammatory state and mortality. The aim of this study is to investigate the prevalence of hypocalcemia at admission in patients hospitalized for COVID-19 (Coronavirus disease 2019) and to evaluate association of hypocalcemia with in-hospital COVID-19 outcomes., Methods: Retrospective analysis on 118 consecutive patients, hospitalized for COVID-19 between March and May 2020. Clinical characteristics, inflammation markers, biochemical routine and mineral metabolism parameters at admission were collected. Hypocalcemia was defined as total serum calcium <2.2 mmol/L. Population was stratified by tertiles of total serum calcium. Primary outcome was the composite of in-hospital death or admission to intensive care unit (ICU). Secondary outcomes included in-hospital death, admission to ICU and need for non-invasive ventilation as separate events. Associations were tested by logistic regression and Cox-regression analysis with survival curves., Results: Overall prevalence of hypocalcemia was 76.6%, with just 6.7% of patients reporting levels of 25-(OH)-vitamin D > 30 ng/ml. Total serum calcium was inversely related with selected inflammatory biomarkers (p < 0.05) and poorer outcome of COVID-19 during hospitalization. Lower tertile of total calcium (≤2.02 mmol/L) had increased risk of in-hospital mortality (HR 2.77; 1.28-6.03, p = 0.01) compared with other groups., Conclusion: Total serum calcium detected on admission is inversely related with proinflammatory biomarkers of severe COVID-19 and is useful to better define risk stratification for adverse in-hospital outcome., (© 2022. The Author(s).)

Background : Obesity is a pandemic disease characterized by excessive severe body comorbidities. Reduction in fat accumulation represents a mechanism of prevention, and the replacement of white adipose tissue (WAT) with brown adipose tissue (BAT) has been proposed as one promising strategy against obesity. In the present study, we sought to investigate the ability of a natural mixture of polyphenols and micronutrients (A5 + ) to counteract white adipogenesis by promoting WAT browning. Methods : For this study, we employed a murine 3T3-L1 fibroblast cell line treated with A5 + , or DMSO as control, during the differentiation in mature adipocytes for 10 days. Cell cycle analysis was performed using propidium iodide staining and cytofluorimetric analysis. Intracellular lipid contents were detected by Oil Red O staining. Inflammation Array, along with qRT-PCR and Western Blot analyses, served to measure the expression of the analyzed markers, such as pro-inflammatory cytokines. Results : A5 + administration significantly reduced lipids' accumulation in adipocytes when compared to control cells ( p < 0.005). Similarly, A5 + inhibited cellular proliferation during the mitotic clonal expansion (MCE), the most relevant stage in adipocytes differentiation ( p < 0.0001). We also found that A5 + significantly reduced the release of pro-inflammatory cytokines, such as IL-6 and Leptin ( p < 0.005), and promoted fat browning and fatty acid oxidation through increasing expression levels of genes related to BAT, such as UCP1 ( p < 0.05). This thermogenic process is mediated via AMPK-ATGL pathway activation. Conclusion : Overall, these results demonstrated that the synergistic effect of compounds contained in A5 + may be able to counteract adipogenesis and then obesity by inducing fat browning.

Diabetes Mellitus is a multifactorial disease with a critical impact worldwide. During prediabetes, the presence of various inflammatory cytokines and oxidative stress will lead to the pathogenesis of type 2 diabetes. Furthermore, insulin resistance and chronic hyperglycemia will lead to micro- and macrovascular complications (cardiovascular disease, heart failure, hypertension, chronic kidney disease, and atherosclerosis). The development through the years of pharmacological options allowed us to reduce the persistence of chronic hyperglycemia and reduce diabetic complications. This review aims to highlight the specific mechanisms with which the new treatments for type 2 diabetes reduce oxidative stress and insulin resistance and improve cardiovascular outcomes.

The association between acne and insulin resistance has not been investigated as thoroughly in males as it has been in women, despite the fact that in adult men, acne prevalence has grown. On the face, sebaceous glands produce and secrete sebum, which lubricates the skin and protects it from friction. Metformin, an insulin-sensitizing medication, may modify the association between acne vulgaris and insulin resistance (IR). Individuals with IR, metabolic syndrome or with impaired glucose tolerance are sometimes treated 'off label' with Metformin. In these conditions, IR may be a leading factor in the pathogenesis of acne, and in men, Metformin treatment may reduce the Global Acne Grading System (GAGS) score by enhancing insulin sensitivity. However, additional clinical studies are required to corroborate these assumptions.

This study was aimed at developing a clinical risk score for cardiovascular autonomic neuropathy (CAN) for type 1 and type 2 diabetes. In a retrospective cross-sectional one-centre study in an unselected population, 115 participants with type 1 diabetes (age 41.1 ± 12.2 years) and 161 with type 2 diabetes (age 63.1 ± 8.9 years), well-characterized for clinical variables, underwent standard cardiovascular reflex tests (CARTs). Strength of associations of confirmed CAN (based on 2 abnormal CARTs) with clinical variables was used to build a CAN risk score. CAN risk score was based on resting heart rate, HbA1c, retinopathy, nephropathy, cardiovascular disease in both type 1 and type 2 diabetes, and on HDL cholesterol, systolic blood pressure, and smoking in type 1 diabetes or insulin treatment and physical activity in type 2 diabetes (range 0-10). In type 1 diabetes, CAN risk score showed an area under the ROC curve (AUC) of 0.890 ± 0.034, and at cut-off of 4 sensitivity of 88%, specificity of 74.4%, and negative predictive value (NPV) of 95.7% for confirmed CAN. In type 2 diabetes, CAN risk score showed an AUC of 0.830 ± 0.051 and at the cut-off of 4 sensitivity and specificity of 78.6% and 73.5%, respectively, and NPV of 97.3% for confirmed CAN. These newly developed CAN risk scores are accessible in clinical practice and, if confirmed in a validation study, they might identify asymptomatic individuals with diabetes at greater risk of CAN to be referred to CARTs, thus limiting the burden of a universal screening., (© 2022 Peripheral Nerve Society.)

The study aimed to evaluate the prevalence, characteristics and outcomes of patients affected by Charcot neuro-arthropathy (CN) and peripheral arterial disease (PAD) compared to CN without PAD. Consecutive patients presenting with an acute CN were included. The sample size was calculated by the power analysis by adopting the two-tailed tests of the null hypothesis with alfa = 0.05 and a value of beta = 0.10 as the second type error and, therefore, a test power equal to 90%. Seventy-six patients were identified. Twenty-four patients (31.6%) had neuro-ischaemic CN; they were older (66 vs. 57yrs), p = 0.03, had a longer diabetes duration (19 vs. 14yrs), p < 0.001, and more cases of end-stage-renal-disease (12.5 vs. 0%), p = 0.04 and ischaemic heart disease (58.3 vs. 15.4%), p < 0.0001 than neuropathic CN. Fifty patients (65.8%) had concomitant foot ulcers, 62.5% and 67.3% (p = 0.3), respectively, in CN with and without PAD. Neuro-ischaemic CN show arterial lesions of 2.9 vessels, and PAD was located predominantly below-the-knee (75%) but not below-the-ankle (16.7%). The outcomes for neuro-ischaemic and neuropathic CN patients were, respectively: wound healing (86.7 vs. 94.3%), p = 0.08; minor amputation (25 vs. 7.7%), p = 0.003; major amputation (8.3 vs. 1.9%), p = 0.001; hospitalization (75 vs. 23%), p = 0.0001. The study showed a frequent association between CN and PAD, leading to a neuro-ischaemic Charcot foot type. Neuro-ischaemic CN leaded to an increased risk of minor and major amputation and hospitalization, compared to neuropathic CN.

Several studies have shown a strong correlation between the different types of diets and gut microbiota composition on glycemia and weight loss. In this direction, low-carbohydrate and ketogenic diets have gained popularity, despite studies published so far leading to controversial results on subjects with diabetes. In this narrative review, firstly, we aimed to analyze the role of very-low-calorie ketogenic diets (VLCKDs) in type 2 diabetes (T2DM) and obesity management. Secondly, in this context, we focused attention on gut microbiota as a function of VLCKD, particularly in T2DM and obesity treatment. Finally, we reported all this evidence to underline the importance of gut microbiota to exalt new nutritional strategies for "tailor-made" management, treatment, and rehabilitation in subjects with T2DM and obesity, even with diabetic complications. In conclusion, this narrative review outlined the beneficial impact of VLCKD on gut microbiota even in subjects with T2DM and obesity, and, despite inner VLCKD short-duration feature allowing no sound-enough provisions for long-term outcomes, witnessed in favor of the short-term safety of VLCKD in those patients.Level of evidence Level V: Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aim: The aim of the current study is to evaluate the association between below-the-ankle (BTA) arterial disease and coronary artery disease (CAD) in patients with diabetic foot ulcers (DFUs)., Methods: The study group was composed of patients with an active neuro-ischaemic DFUs managed in a tertiary care diabetic foot clinic. All patients received a pre-set limb salvage protocol including lower limb revascularization. By a retrospective analysis of individual angiograms, patients were divided in two groups: below-the-ankle (BTA) and above-the-ankle (ATA) arterial disease groups. The rate of CAD at baseline assessment and the new events of acute myocardial ischaemia (AMI) during 1-year of follow-up were evaluated and compared between the two groups., Results: Two hundreds seventy-two (272) patients were included, 120 (44.1%) showed BTA arterial disease while 152 (55.9%) ATA arterial disease. The mean age was 68.9 ± 9.6 years, 198 (72.8%) were male, 246 (90.4%) had type 2 diabetes, the mean diabetes duration was 20.7 ± 11.6 years, the mean HbA1c was 7.8 ± 4.2% (62 ± 22 mmmol/mol). The whole population reported CAD in 172 cases (63.4%), and the rate in the BTA group was significantly higher than in ATA group, respectively, 90 (75.4%) vs 82 (54.1%), p < 0.0001. During the follow-up, BTA group had 5% of new cases of AMI in comparison to 1.3% in ATA group (p < 0.001). At the multivariate analysis BTA resulted an independent marker of CAD [OR 1.9 CI 9 5% (1.3-4.5) p = 0.0001]., Conclusion: The current study shows a significant association between BTA arterial disease and CAD. A close cardiovascular screen should be required in patients with DFUs., (© 2022. Springer-Verlag Italia S.r.l., part of Springer Nature.)

The sodium-glucose transporter 2 inhibitors (SGLT2i) are a relatively new class of medication used in the management of type 2 diabetes. Recent clinical trials and research have demonstrated this class's effectiveness in treating heart failure, since they reduce the risk of cardiovascular events, hospitalization, and mortality. The mechanism by which they do so is unclear; however, SGLT2i inhibit the tubular reabsorption of glucose, lowering the interstitial volume. This mechanism leads to a reduction in blood pressure and an improvement of endothelial function. As a result, improvements in hospitalization and mortality rate have been shown. In this review, we focus on the primary outcome of the clinical trials designed to investigate the effect of SGLT2i in heart failure, regardless of patients' diabetic status. Furthermore, we compare the various SGLT2i regarding their risk reduction to investigate their potential as a treatment option for patients with reduced ejection fraction and preserved ejection fraction.

Background: Peripheral blood stem cells (PBSCs) are the predominant graft source for adult allogeneic hematopoietic stem cell transplantation (HSCT). In poorly mobilized autologous donors, plerixafor improves collection outcomes. We examine plerixafor use in allogeneic donors who mobilize poorly with granulocyte colony-stimulating factor (G-CSF) in those who are healthy and those with pre-existing medical conditions, and determine the optimal threshold to add plerixafor., Study Design/methods: We retrospectively examined all allogeneic PBSC collections from January 2013 to October 2020 at our center. Donors received G-CSF 10 mcg/kg daily for 4 days before undergoing apheresis collection on day 5. Plerixafor was added based on poor CD34+ cell collection yield after the first or second collection day., Results: Of the 1008 allogeneic donors, 41 (4.1%) received one dose of plerixafor in addition to G-CSF due to poor collection yield. After starting plerixafor there was a 0.75- to 7.74-fold (median 2.94) increase in CD34+ yield from the previous day. No donors with G-CSF-only mobilization who collected <2.0 × 10 6 CD34+ cells/kg recipient weight on day one achieved the goal of ≥4.0 × 10 6 CD34+ cells/kg recipient weight total over 2 days but 59.2% of donors who used rescue plerixafor did., Conclusion: Donors both healthy and those with pre-existing disease responded well to plerixafor with minimal side effects. If the first-day collection yield is less than ~63% of the collection goal, addition of plerixafor may be necessary to reach the collection goal and limit the number of collection days in allogeneic donors., (© 2022 The Authors. Journal of Clinical Apheresis published by Wiley Periodicals LLC.)

Metabolic Syndrome (MetS) is a cluster of metabolic alterations mostly related to visceral adiposity, which in turn promotes glucose intolerance and a chronic systemic inflammatory state, characterized by immune cell infiltration. Such immune system activation increases the risk of severe disease subsequent to viral infections. Strong correlations between elevated body mass index (BMI), type-2-diabetes and increased risk of hospitalization after pandemic influenza H1N1 infection have been described. Similarly, a correlation between elevated blood glucose level and SARS-CoV-2 infection severity and mortality has been described, indicating MetS as an important predictor of clinical outcomes in patients with COVID-19. Adipose secretome, including two of the most abundant and well-studied adipokines, leptin and interleukin-6, is involved in the regulation of energy metabolism and obesity-related low-grade inflammation. Similarly, skeletal muscle hormones-called myokines-released in response to physical exercise affect both metabolic homeostasis and immune system function. Of note, several circulating hormones originate from both adipose tissue and skeletal muscle and display different functions, depending on the metabolic context. This review aims to summarize recent data in the field of exercise immunology, investigating the acute and chronic effects of exercise on myokines release and immune system function.

Objective: Spontaneous coronary artery dissection (SCAD) is a spontaneous separation of the coronary artery wall whose etiology appears to be poorly understood. SCAD is a rare cause of acute coronary syndromes, and it is a life-threatening condition., Case Report: We report the case of a young woman who developed SCAD during a thyroid storm (TS)., Results: To the best of our knowledge, this is the first reported case of SCAD during a TS, and it suggests a possible association between high levels of circulating thyroid hormones and SCAD susceptibility., Conclusions: Early identification of SCAD predisposing factors is important to identify high-risk patients. In patients presenting to the emergency department because of chest pain with a history of dysthyroidism, early determination of thyroid hormones and troponin could prevent certain forms of sudden cardiac death.

In pancreatic beta cells, mitochondrial metabolism controls glucose-stimulated insulin secretion (GSIS) by ATP production, redox signaling, and calcium (Ca 2+ ) handling. Previously, we demonstrated that knockout mice for peroxiredoxin 6 ( Prdx6 -/- ), an antioxidant enzyme with both peroxidase and phospholipase A2 activity, develop a mild form of diabetes mellitus with a reduction in GSIS and in peripheral insulin sensitivity. However, whether the defect of GSIS present in these mice is directly modulated by Prdx6 is unknown. Therefore, the main goal of the present study was to evaluate if depletion of Prdx6 affects directly GSIS and pancreatic beta β-cell function. Murine pancreatic β-cell line (βTC6) knockdown for Prdx6 (Prdx6 KD ) was employed, and insulin secretion, ATP, and intracellular Ca 2+ content were assessed in response to glucose stimulation. Mitochondrial morphology and function were also evaluated through electron microscopy, and by testing mitochondrial membrane potential, oxygen consumption, and mitochondrial mass. Prdx6 KD cells showed a significant reduction in GSIS as confirmed by decrease in both ATP release and Ca 2+ influx. GSIS alteration was also demonstrated by a marked impairment of mitochondrial morphology and function. These latest are mainly linked to mitofusin downregulation, which are, in turn, strictly related to mitochondrial homeostasis (by regulating autophagy) and cell fate (by modulating apoptosis). Following a pro-inflammatory stimulus (typical of diabetic subjects), and in agreement with the deregulation of mitofusin steady-state levels, we also observed an enhancement in apoptotic death in Prdx6 KD compared to control cells. We analyzed molecular mechanisms leading to apoptosis, and we further demonstrated that Prdx6 suppression activates both intrinsic and extrinsic apoptotic pathways, ultimately leading to caspase 3 and PARP-1 activation. In conclusion, Prdx6 is the first antioxidant enzyme, in pancreatic β-cells, that by controlling mitochondrial homeostasis plays a pivotal role in GSIS modulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pacifici, Della-Morte, Capuani, Coppola, Scioli, Donadel, Andreadi, Ciccosanti, Fimia, Bellia, Orlandi and Lauro.)

Parkinson's disease (PD) is second-most common disabling neurological disorder worldwide, and unfortunately, there is not yet a definitive way to prevent it. Polyphenols have been widely shown protective efficacy against various PD symptoms. However, data on their effect on physio-pathological mechanisms underlying this disease are still lacking. In the present work, we evaluated the activity of a mixture of polyphenols and micronutrients, named A5 + , in the murine neuroblastoma cell line N1E115 treated with 6-Hydroxydopamine (6-OHDA), an established neurotoxic stimulus used to induce an in vitro PD model. We demonstrate that a pretreatment of these cells with A5 + causes significant reduction of inflammation, resulting in a decrease in pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α, and CXCL1), a reduction in ROS production and activation of extracellular signal-regulated kinases (ERK)1/2, and a decrease in apoptotic mechanisms with the related increase in cell viability. Intriguingly, A5 + treatment promoted cellular differentiation into dopaminergic neurons, as evident by the enhancement in the expression of tyrosine hydroxylase, a well-established dopaminergic neuronal marker. Overall, these results demonstrate the synergic and innovative efficacy of A5 + mixture against PD cellular pathological processes, although further studies are needed to clarify the mechanisms underlying its beneficial effect.

Individuals with diabetes mellitus are at increasing risk for major lower-extremity amputations (LEAs). Poor quality of life and remarkable disabilities are associated with LEAs, determining a high economic burden for the healthcare systems. Reducing LEAs is therefore a primary marker of quality of care of the diabetic foot. At global level, between-countries comparisons of LEAs rates are basically hampered by differences in criteria used for data collection and analysis among studies. Significant variability in amputation rates exists between geographic areas, and also within specific regions of a country. Overall 5-year mortality rate after major amputations is reported to vary substantially across countries, from 50 to 80%. The odds of LEAs are substantially higher for Black, Native American and Hispanic ethnicities compared with White groups, with similar figures observed in the economically disadvantaged areas compared to more developed ones. Such discrepancies may reflect differences in diabetes prevalence as well as in financial resources, health-care system organization and management strategies of patients with diabetic foot ulcers. Looking at the experience of countries with lower rates of hospitalization and LEAs worldwide, a number of initiatives should be introduced to overcome these barriers. These include education and prevention programs for the early detection of diabetic foot at primary care levels, and the multidisciplinary team approach with established expertise in the treatment of the more advanced stage of disease. Such a coordinated system of support for both patients and physicians is highly required to reduce inequalities in the odd of diabetes-related amputations worldwide., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bellia, Meloni, Andreadi, Uccioli and Lauro.)

Type 2 Diabetes Mellitus (T2D) is a chronic disease with a pandemic incidence whose pathogenesis has not yet been clarified. Raising evidence highlighted the role of oxidative stress in inducing insulin resistance, pancreatic beta-cell dysfunction, and leading to cardiovascular disease (CVD). Therefore, understanding the link between oxidative stress, T2D and CVD may help to further understand the pathological processes beyond this association, to personalize the algorithm of the cure, and to find new therapeutic targets. Here, we discussed the role of oxidative stress and the decrease of antioxidant defenses in the pathogenesis of T2D. Furthermore, some aspects of hypoglycemic therapies and their potential role as antioxidant agents were examined, which might be pivotal in preventing CVD in T2D patients., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: The aim of this study was to assess the impact of glucose control, diabetes-related complications and cardiometabolic risk factors on the risk of diabetic foot ulcers (DFUs) and DFU complications in Albanian adult inpatients with T2D., Patients and Methods: We conducted a retrospective case-control study on 482 Albanian adult inpatients with T2D. DFU was defined as a full-thickness skin lesion requiring ≥14 days for healing and was classified at the time of hospital admission. Demographic and biochemical parameters of the study participants, the presence of comorbidities and diabetes-related complications at the time of hospital admission were evaluated through a retrospective chart review., Results: Mean age of study participants was 54.8±10.7 years. Participants (284 males and 198 females) were divided into two groups: DFU (cases; n=104) and non-DFU (controls; n=378). Multivariate analysis (performed by a logistic regression model) revealed that the most relevant independent variables associated with DFU were BMI [OR=0.62; p=0.007], HDL-cholesterol [OR=0.00; p<0.0001], triglycerides [OR=7.48; p=0.0004], cigarette smoking [OR=26.46; p=0.005], duration of diabetes [OR=1.53; p<0.0001], fasting plasma glucose (FPG) [OR=1.06; p<0.0001], systolic blood pressure (SBP) [OR=1.13; p=0.0004] and insulin therapy alone [OR=0.11; p=0.02]. ROC curve analysis showed that FPG (AUC=0.83), glycated hemoglobin (HbA1c) (AUC=0.75), triglycerides (AUC=0.78) and HDL-cholesterol (AUC=0.82) were the most reliable biomarkers able to detect DFU. In the DFU group, the most relevant independent variables associated with previous minor lower-extremity amputations (LEAs) were represented by HbA1c [OR=1.47; p=0.03], age <55 years [OR=0.12; p=0.05] and female sex [OR=4.18; p=0.03]; whereas the most relevant independent variables associated with diabetic peripheral neuropathy (DPN) were HbA1c [OR=1.70; p=0.006], SBP [OR=1.08; p=0.05], BMI [OR=1.20; p=0.03] and lack of cigarette smoking [OR=0.07; p=0.01]. Correlation analysis (performed through the nonparametric Spearman's rank correlation test or through the parametric Pearson test, as appropriate) revealed a significant positive relationship between HbA1c and FPG (r=0.58; p<0.0001), ulcer surface area (r=0.50; p<0.0001), ulcer grade (r=0.23; p=0.02), minor LEAs (r=0.20; p=0.04), DPN (r=0.41; p<0.0001), and metformin therapy alone (r=0.72; p<0.0001). There was a significant inverse correlation between HbA1c and insulin therapy alone (r=-0.31; p=0.01) and combined metformin and insulin therapy (r=-0.60; p<0.0001). Both DFU and non-DFU groups exhibited suboptimal mean LDL-cholesterol levels (>100 mg/dl) and mean HbA1c values >7.5%. Moreover, in DFU group HbA1c values were markedly elevated (≥10%) particularly in patients with a grade 3 ulcer and an ulcer surface area ≥4 cm2, as well as in patients with history of minor LEAs and in patients affected by DPN., Conclusions: The present study suggested that longer duration of diabetes, cigarette smoking, lower HDL-cholesterol levels, poor glucose control, and elevated triglyceride and SBP values may all represent major risk factors for the development of DFU in Albanian patients with T2D. Thus, community interventions and health policies aimed to improve the management of diabetes and related cardiometabolic risk factors should be urgently implemented in Albania, in order to prevent DFUs and other diabetes complications in patients with T2D.

Epidemiologic studies have documented an association between diabetes and increased risk of cognitive decline in the elderly. Based on animal model studies, several mechanisms have been proposed to explain such an association, including central insulin signaling, neurodegeneration, brain amyloidosis, and neuroinflammation. Nevertheless, the exact mechanisms in humans remain poorly defined. It is reasonable, however, that many pathways may be involved in these patients leading to cognitive impairment. A major aim of clinicians is identifying early onset of neurologic signs and symptoms in elderly diabetics to improve quality of life of those with cognitive impairment and reduce costs associated with long-term complications. Several biomarkers have been proposed to identify diabetics at higher risk of developing dementia and diagnose early stage dementia. Although biomarkers of brain amyloidosis, neurodegeneration and synaptic plasticity are commonly used to diagnose dementia, especially Alzheimer disease, their role in diabetes remains unclear. The aim of this review is to explore the molecular mechanisms linking diabetes with cognitive decline and present the most important findings on the clinical use of biomarkers for diagnosing and predicting early cognitive decline in diabetics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: It is known that the highest COVID-19 mortality rates are among patients who develop severe COVID-19 pneumonia. However, despite the high sensitivity of chest CT scans for diagnosing COVID-19 in a screening population, the appearance of a chest CT is thought to have low diagnostic specificity. The aim of this retrospective case-control study is based on evaluation of clinical and radiological characteristics in patients with COVID-19 (n = 41) and no-COVID-19 interstitial pneumonia (n = 48) with mild-to-moderate symptoms., Methods and Results: To this purpose we compared radiological, clinical, biochemical, inflammatory, and metabolic characteristics, as well as clinical outcomes, between the two groups. Notably, we found similar radiological severity of pneumonia, which we quantified using a disease score based on a high-resolution computed tomography scan (COVID-19 = 18.6 ± 14.5 vs n-COVID-19 = 23.2 ± 15.2, p = 0.289), and comparable biochemical and inflammatory characteristics. However, among patients without diabetes, we observed that COVID-19 patients had significantly higher levels of HbA1c than n-COVID-19 patients (COVID-19 = 41.5 ± 2.6 vs n-COVID-19 = 38.4 ± 5.1, p = 0.012). After adjusting for age, sex, and BMI, we found that HbA1c levels were significantly associated with the risk of COVID-19 pneumonia (odds ratio = 1.234 [95%CI = 1.051-1.449], p = 0.010)., Conclusions: In this retrospective case-control study, we found similar radiological and clinical characteristics in patients with COVID-19 and n-COVID-19 pneumonia with mild-to-moderate symptoms. However, among patients without diabetes HbA1c levels were higher in COVID-19 patients than in no-COVID-19 individuals. Future studies should assess whether reducing transient hyperglycemia in individuals without overt diabetes may lower the risk of SARS-CoV-2 infection., Competing Interests: Declaration of competing interest All authors declare that they have no personal or financial conflicts of interest., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The study aims to evaluate the effectiveness of foot revascularization in persons with diabetic foot ulcers (DFUs) and below-the-ankle (BTA) arterial disease. Consecutive patients referred for a new active ischaemic DFU requiring lower limb revascularization were considered. Among those, only patients with a BTA arterial disease were included. Revascularization procedures were retrospectively analysed: in the case of successful foot revascularization (recanalization of pedal artery, or plantar arteries or both) or not, patients were respectively divided in two groups, successful foot perfusion (SFP) and failed foot perfusion (FFP). Healing, minor and major amputation at 12 months of follow-up were evaluated and compared. Eighty patients (80) were included. The mean age was 70.5 ± 10.9 years, 55 (68.7%) were male, 72 (90%) were affected by type 2 diabetes with a mean duration of 22.7 ± 11.3 years. Overall 45 (56.2%) patients healed, 47 (58.7%) had minor amputation and 13 (16.2%) major amputation. Outcomes for SFP and FFP were respectively: healing (89.3 vs. 9.1%, p < 0.0001), minor amputation (44.7 vs. 78.8%, p = 0.0001), major amputation (2.1 vs. 36.3%, p < 0.0001). Failed foot revascularization resulted an independent predictor of non-healing, minor amputation, and major amputation. Foot revascularization is mandatory to achieve healing and avoid major amputation in persons with ischaemic DFU and BTA arterial disease.

Objective: Identifying metabolic factors associated with critical disease can help to improve management of patients hospitalized for coronavirus disease 2019 (COVID-19). High triglycerides and low HDL levels characterize the atherogenic dyslipidemia closely related to insulin resistance and diabetes. We examined associations of atherogenic dyslipidemia detected on admission with outcome of COVID-19 during hospitalization., Research Design and Methods: We retrospectively analyzed clinical reports of 118 consecutive patients hospitalized for COVID-19 in Rome, Italy, between March and May 2020. Clinical characteristics, inflammation markers, and glucose and lipid metabolism parameters at admission were collected. Critical disease was defined as in-hospital death or need for endotracheal intubation. Associations were tested using logistic regression analysis., Results: Patients with critical COVID-19 ( n = 43) were significantly older than those with noncritical disease ( n = 75) and presented higher levels of fasting glucose, triglycerides, C-reactive protein, interleukin-6, procalcitonin, and d-dimer ( P < 0.01 for all), whereas HDL levels were lower ( P = 0.003). Atherogenic dyslipidemia was more frequent in patients with critical COVID-19 (46 vs. 24%, P = 0.011), as well as diabetes (37 vs. 19%, P = 0.026), and significantly associated with death or intubation (odds ratio 2.53 [95% CI 1.16-6.32], P = 0.018). Triglycerides were significantly associated with selected inflammatory biomarkers ( P < 0.05 for all) and poorer outcome of COVID-19 during hospitalization in both the overall population and the subgroup with atherogenic dyslipidemia., Conclusions: Atherogenic dyslipidemia detected on admission can be associated with critical in-hospital course of COVID-19. Further investigations are needed to elucidate the hypothetical role of insulin resistance and related lipid abnormalities in severe acute respiratory syndrome coronavirus 2 pathogenesis. Assessment of lipid profile should be encouraged in patients hospitalized for COVID-19., (© 2021 by the American Diabetes Association.)

The pathophysiology of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and especially of its complications is still not fully understood. In fact, a very high number of patients with COVID-19 die because of thromboembolic causes. A role of plasminogen, as precursor of fibrinolysis, has been hypothesized. In this study, we aimed to investigate the association between plasminogen levels and COVID-19-related outcomes in a population of 55 infected Caucasian patients (mean age: 69.8 ± 14.3, 41.8% female). Low levels of plasminogen were significantly associated with inflammatory markers (CRP, PCT, and IL-6), markers of coagulation (D-dimer, INR, and APTT), and markers of organ dysfunctions (high fasting blood glucose and decrease in the glomerular filtration rate). A multidimensional analysis model, including the correlation of the expression of coagulation with inflammatory parameters, indicated that plasminogen tended to cluster together with IL-6, hence suggesting a common pathway of activation during disease's complication. Moreover, low levels of plasminogen strongly correlated with mortality in COVID-19 patients even after multiple adjustments for presence of confounding. These data suggest that plasminogen may play a pivotal role in controlling the complex mechanisms beyond the COVID-19 complications, and may be useful both as biomarker for prognosis and for therapeutic target against this extremely aggressive infection., (© 2021. The Author(s).)

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1β from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.

A protective effect of vegan diets on health outcomes has been observed in previous studies, but its impact on diabetes is still debated. The aim of this review is to assess the relationship between vegan diets and the risk for type 2 diabetes (T2D) along with its effect on glycemic control and diabetes-related complications. In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, Pubmed and Cochrane library databases were systematically searched for all relevant studies. Seven observational and eight randomized controlled (RCTs) studies were included. The methodological quality of studies was assessed using the National Institutes of Health quality assessment tool for observational cohort and cross-sectional studies and the Cochrane Risk of Bias Tool for RCTs. We found that a vegan diet is associated with lower T2D prevalence or incidence and in T2D patients decreases high glucose values and improves glucose homeostasis, as reported from the majority of included studies. This approach seems to be comparable to other recommended healthful eating models, but as it may have potential adverse effects associated with the long-term exclusion of some nutrients, appropriate nutritional planning and surveillance are recommended, particularly in specific groups of diabetic patients such as frail elderly, adolescents, and pregnant or breastfeeding women.

Ischemic stroke (IS) is still among the leading causes of death and disability worldwide. The pathogenic mechanisms beyond its development are several and are complex and this is the main reason why a functional therapy is still missed. The beneficial effects of natural compounds against cardiovascular diseases and IS have been investigated for a long time. In this article, we reviewed the association between the most studied polyphenols and stroke protection in terms of prevention, effect on acute phase, and rehabilitation. We described experimental and epidemiological studies reporting the role of flavonols, phenolic acid, and stilbens on ischemic mechanisms leading to stroke. We analyzed the principal animal models used to evaluate the impact of these micronutrients to cerebral blood flow and to molecular pathways involved in oxidative stress and inflammation modulation, such as sirtuins. We reported the most significant clinical trials demonstrated as the persistent use of polyphenols is clinically relevant in terms of the reduction of vascular risk factors for IS, such as Atrial Fibrillation. Interestingly, different kinds of polyphenols provide brain protection by activating different pathways and mechanisms, like inducing antithrombotic effect, such as Honokiol. For this reason, we discussed an appropriate integrative use of them as a possible therapeutic alternative against stroke.

In the present review we summarized current knowledge about significant interactions (DIs) of direct oral anticoagulants (DOACs) with other medications frequently prescribed to elderly patients with cardiometabolic diseases. Literature search was performed using PubMed from 1990 to October 2020. Randomized clinical trials (RCTs), subgroup analyses from RCTs, longitudinal studies, case series and case reports were included. Only studies in humans were considered. Elderly was defined as ≥75 years. Assessment of DIs with DOACs is often tricky because of the lack of validated tools to routinely assess magnitude of their anti-coagulation effect. Most of reports in the cardiometabolic area regarded the classes of anti-antiarrhythmic, lipid-lowering and platelet-inhibitors drugs, namely drugs that are widely used to reduce cardiovascular risk in patients with common metabolic diseases. Reports about elderly are limited in general, and it is not known whether certain types of DIs occur more frequently in elderly subjects. DIs were more frequently reported in association with dabigatran, which however has been available for a longer period of time compared with other DOACs. In most cases, no complete information about dosages of medications was available. DIs of DOACs leading to adverse events (both ischemic and bleeding ones) were generally facilitated by older age, polymedication and impaired renal function. Further studies should be carried out to properly investigate DIs of DOACs with cardiometabolic drugs in elderly patients, with particular focus on differences between DOACs and the influence of different dosages., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background : The comorbidities and clinical signs of coronavirus disease 2019 (COVID-19) patients have been reported mainly as descriptive statistics, rather than quantitative analysis even in very large investigations. The aim of this study was to identify specific patients' characteristics that may modulate COVID-19 hospitalization risk. Research design and methods : A pooled analysis was performed on high-quality epidemiological studies to quantify the prevalence (%) of comorbidities and clinical signs in hospitalized COVID-19 patients. Pooled data were used to calculate the relative risk (RR) of specific comorbidities by matching the frequency of comorbidities in hospitalized COVID-19 patients with those of general population. Results : The most frequent comorbidities were hypertension, diabetes mellitus, and cardiovascular and/or cerebrovascular diseases. The RR of COVID-19 hospitalization was significantly (P < 0.05) reduced in patients with asthma (0.86, 0.77-0.97) or chronic obstructive pulmonary disease (COPD) (0.46, 0.40-0.52). The most frequent clinical signs were fever and cough. Conclusion : The clinical signs of hospitalized COVID-19 patients are similar to those of other infective diseases. Patients with asthma or COPD were at lower hospitalization risk. This paradoxical evidence could be related with the protective effect of inhaled corticosteroids that are administered worldwide to most asthmatic and COPD patients.

Tyrosol (TR), a major polyphenol found in extra virgin olive oil (EVOO), exerts several antioxidant effects. However, only scarce evidences are present regarding its activity on adipocytes and obesity. This study evaluated the role of TR in adipogenesis. Murine 3T3-L1 preadipocytes were incubated with TR (300 and 500  μ M), and TR administration inhibited adipogenesis by downregulation of several adipogenic factors (leptin and aP2) and transcription factors (C/EBP α , PPAR γ , SREBP1c, and Glut4) and by modulation of the histone deacetylase sirtuin 1. After complete differentiation, adipocytes treated with 300 and 500  μ M TR showed a reduction of 20% and 30% in lipid droplets, respectively. Intracellular triglycerides were significantly reduced after TR treatment ( p < 0.05). Mature adipocytes treated with TR at 300 and 500  μ M showed a marked decrease in the inflammatory state and oxidative stress as shown by the modulation of specific biomarkers (TNF, IL6, ROS, and SOD2). TR treatment also acted on the early stage of differentiation by reducing cell proliferation (~40%) and inducing cell cycle arrest during Mitotic Expansion Clonal (first 48 h of differentiation), as shown by the increase in both S1 phase and p21 protein expression. We also showed that TR induced lipolysis by activating the AMPK-ATGL-HSL pathway. In conclusion, we provided evidence that TR reduces 3T3-L1 differentiation through downregulation of adipogenic proteins, inflammation, and oxidative stress. Moreover, TR may trigger adipose tissue browning throughout the induction of the AMPK-ATGL-UCP1 pathway and, subsequently, may have promise as a potential therapeutic agent for the treatment and prevention of obesity., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Francesca Pacifici et al.)

Cardiopulmonary arrest (CA) is the leading cause of death and disability in the United States. CA-induced brain injury is influenced by multifactorial processes, including reduced cerebral blood flow (hypoperfusion) and neuroinflammation, which can lead to neuronal cell death and functional deficits. We have identified serum and glucocorticoid-regulated kinase-1 (SGK1) as a new target in brain ischemia previously described in the heart, liver, and kidneys (i.e., diabetes and hypertension). Our data suggest brain SGK1 mRNA and protein expression (i.e., hippocampus), presented with hypoperfusion (low cerebral blood flow) and neuroinflammation, leading to further studies of the potential role of SGK1 in CA-induced brain injury. We used a 6-min asphyxia cardiac arrest (ACA) rat model to induce global cerebral ischemia. Modulation of SGK1 was implemented via GSK650394, a SGK1-specific inhibitor (1.2 μg/kg icv). Accordingly, treatment with GSK650394 attenuated cortical hypoperfusion and neuroinflammation (via Iba1 expression) after ACA, whereas neuronal survival was enhanced in the CA1 region of the hippocampus. Learning/memory deficits were observed 3 days after ACA but ameliorated with GSK650394. In conclusion, SGK1 is a major contributor to ACA-induced brain injury and neurological deficits, while inhibition of SGK1 with GSK650394 provided neuroprotection against CA-induced hypoperfusion, neuroinflammation, neuronal cell death, and learning/memory deficits. Our studies could lead to a novel, therapeutic target for alleviating brain injury following cerebral ischemia. NEW & NOTEWORTHY Upregulation of SGK1 exacerbates brain injury during cerebral ischemia. Inhibition of SGK1 affords neuroprotection against cardiac arrest-induced hypoperfusion, neuroinflammation, neuronal cell death, and neurological deficits.

We investigated early effects of Whole-Body Electromyostimulation added to hypocaloric diet on metabolic syndrome features in sedentary middle-aged individuals. We randomly assigned 25 patients to Whole-Body Electromyostimulation plus caloric restriction or caloric restriction alone for 26 weeks. Anthropometrics, blood pressure, fasting glucose and insulin, HOMA-IR, glycated hemoglobin, lipids, uric acid, creatinphosphokynase, C-reactive protein were assessed. Body composition was evaluated with direct-segmental, multi-frequency Bioelectrical Impedance Analysis. Both groups lost approximately 10% of weight, with similar effects on waist circumference and fat mass. Change in free-fat mass was significantly different between groups (caloric restriction -1.5±0.2 vs. Whole-Body Electromyostimulation plus caloric restriction +1.1±0.4 kg, p=0.03). Whole-Body Electromyostimulation plus caloric restriction group experienced greater percent reductions in insulin (-45.5±4.4 vs. -28.2±3.6%, p=0.002), HOMA-IR (-51.3±3.2 vs. -25.1±1.8%, p=0.001), triglycerides (-22.5±2.9 vs. -4.1±1.6%, p=0.004) and triglycerides/HDL (p=0.028). Subjects trained with Whole-Body Electromyostimulation had also significant improvement in systolic pressure (138±4 vs. 126±7 mmHg, p=0.038). No discontinuations for adverse events occurred. In middle-aged sedentary subjects with the metabolic syndrome, Whole-Body Electromyostimulation with caloric restriction for 26 weeks can improve insulin-resistance and lipid profile compared to diet alone. Further studies are needed to ascertain long-term efficacy and feasibility of this approach in individuals with the metabolic syndrome., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Our aim was to evaluate in a cohort of 125 Italian patients with type 2 diabetes (T2D), who underwent neurological evaluation, the possible differences in the number of mitochondrial DNA copies (mtDNA) comparing positive and negative patients for cardiovascular autonomic neuropathy (CAN) or diabetic peripheral neuropathy (DPN) and comparing them with healthy controls. We also investigated a possible correlation of the number of mtDNA copies with the polymorphism rs3746444 of the MIR499A . T2D patients show a decrease in the number of mtDNA copies compared to healthy controls ( p  = 2 × 10 -10 ). Dividing the T2D subjects by neurological evaluation, we found a significant mtDNA decrease in patients with DPN compared with those without ( p  = 0.02), while no differences were observed between subjects with and without CAN. Furthermore, the homozygous variant genotype for the polymorphism rs3746444 of MIR499A correlates with a decrease in the number of mtDNA copies, particularly in T2D patients ( p  = 0.009). Our data show a decrease in the number of mtDNA copies in subjects with T2D and suggest that this decrease is more evident in patients who develop DPN. Furthermore, the association of the variant allele of MIR499A with the number of mtDNA copies allows us to hypothesize a possible effect of this polymorphism in oxidative stress.

Although vascular and autonomic nervous system have been involved in the regulation of morning surge in blood pressure (MBPS), data on clinical correlates of MBPS in diabetic population are scarce, in particular with regard to diabetic complications. This study was aimed at investigating predictors and correlates of MBPS in diabetes. In a cross-sectional study including 167 patients with diabetes (age 58.5 ± 11.1 years, duration 15.9 ± 12.1 years), clinical variables, diabetic and neuropathic complications, and MBPS (using 24-h ambulatory blood pressure monitoring) were measured. The upper quartile of MBPS (>30.5 mmHg) was associated with higher values of waist circumference (P = 0.027), triglycerides (P = 0.021), and Michigan Diabetic Neuropathy Score (P = 0.042), with lower HDL cholesterol (P = 0.030), and with the presence of cardiovascular autonomic neuropathy (CAN) (P = 0.016) and peripheral vascular disease (PVD) (P < 0.0001). In a logistic regression analysis, PVD (odds ratio: 10.2, P = 0.001), CAN (odds ratio: 6.09, P = 0.016), and diastolic blood pressure (BP) (odds ratio: 1.06, P = 0.022) predicted MBPS upper quartile (r 2  = 0.20, P = 0.0005). In a multiple regression analysis, PVD (P = 0.002) and diastolic BP (P = 0.003) were the only determinants of MBPS (r 2  = 0.20). MBPS upper quartile was associated with BP dipping (systolic BP day-night reduction > 10%) (P = 0.012), and MBPS was positively related to systolic (rho = 0.41, P < 0.0001) and diastolic BP day-night reduction. In conclusion, metabolic syndrome stigmata, diastolic BP, CAN and PVD are the main predictors of MBPS in the diabetic population. Excessive MBPS and nondipping are not concurrent 24-h BP alterations. Autonomic dysfunction might exert an exacerbating effect on MBPS phenomenon.