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Purpose: Our purposes were: 1) to estimate the prediction performance (PP) of cytology in identifying papillary thyroid carcinoma (PTC) subtypes; 2) to explore how the PTC subtypes distribute among the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) categories., Methods: Nodules were included if both the histology with the PTC subtype report and the cytology report with the possible PTC subtype were available. The PP was calculated by making the proportion of True positives/False positives+false negatives., Results: 309 cytologically "suspicious for malignancy" and "malignant" thyroid nodules with PTC histology were evaluated. ACR TI-RADS categorization for classical PTC was significantly different from non-classical PTC (p-value 0.02). For the whole cohort the PP of cytologically classical cases was 0.74, while that of cytologically non classical cases was 0.41. ACR TI-RADS categorization was not significantly different for aggressive vs non-aggressive PTC subtypes (p-value 0.1). When considering only aggressive or non-aggressive PTC subtypes, the PP of cytologically classical cases was respectively 0.86 and 0.87, while that of cytologically non classical cases was respectively 0.27 and 0.22. The PP of cytologically classical cases was 0.73 and 0.79, respectively for macroPTCs and microPTCs, while that of cytologically non classical cases was 0.55 and 0.33, respectively for macroPTCs and microPTCs., Conclusion: Cytology examination reliably performed in predicting classical PTC versus non classical PTC subtypes. ACR TI-RADS categorization was significantly different among classical PTC versus non classical PTC subtypes., (© 2023. The Author(s).)

Purpose: To assess the magnitude and durability of the metabolic benefits by simplification of complex insulin treatments in patients with type 2 diabetes inadequately controlled by a full basal-bolus insulin regimen. Herein we report the results of the scheduled 2-year extension of the BEYOND trial., Methods: Originally, 305 participants with inadequate glycemic control (HbA1c > 7.5%) were randomly assigned to intensification of basal-bolus insulin regimen (n = 101), to a fixed-ratio combination (basal insulin + GLP-1RA, n = 102), or to an association of basal insulin plus an SGLT-2 inhibitor (gliflo-combo, n = 102). The primary efficacy outcome was change from baseline in HbA1c at 24 months assessed by an intention-to-treat analysis. A per-protocol analysis was also performed., Results: Fifty-five percent of patients completed the study in the two comparison arms. Compared with patients randomized to basal-bolus, patients of the other groups experienced non statistically different reductions in HbA1c level according to either an intention-to-treat analysis (-0.8 ± 1.1%, -0.7 ± 1.1%, and -1.3 ± 1.1%, mean ± SD, fixed-ratio, gliflo-combo and basal bolus, respectively) or per-protocol analysis (-1.2 ± 1.0%, -1.2 ± 1.1%, and -1.3 ± 1.0%, respectively). The final HbA1c level (per protocol) was 7.2 ± 0.8%, 7.3 ± 0.9%, and 7.5 ± 0.9%, respectively (P = NS). Treatment satisfaction (DTSQ) increased in both exchange groups, whereas the proportion of patients with hypoglycemia was lower., Conclusion: Simplification of complex insulin regimen may be a durable option in at least one-half of patients with type 2 diabetes., Clinical Trial Registration: Clinical trial registration no. NCT04196231, clinicaltrials.gov., (© 2023. The Author(s).)

Purpose: Continuous Glucose Monitoring (CGM) is a key tool for insulin-treated people with diabetes (PwD). CGM devices include both real-time CGM (rtCGM) and intermittently scanned CGM (isCGM), which are associated with an improvement of glucose control and less hypoglycemia in clinical trials of people with type 1 and type 2 diabetes., Methods: This is an expert position to update a previous algorithm on the most suitable choice of CGM for insulin-treated PwD in light of the recent evidence and clinical practice., Results: We identified six different clinical scenarios, including type 1 diabetes, type 2 diabetes, pregnancy on intensive insulin therapy, regular physical exercise, new onset of diabetes, and frailty. The use of rtCGM or isCGM is suggested, on the basis of the predominant clinical issue, as suboptimal glucose control or disabling hypoglycemia, regardless of baseline HbA 1c or individualized HbA 1c target., Conclusion: The present algorithm may help to select the best CGM device based on patients' clinical characteristics, needs and clinical context, offering a further opportunity of a "tailored" therapy for people with insulin-treated diabetes., (© 2023. The Author(s).)

Context: Patients with adrenal insufficiency (AI) have excess mortality and morbidity, mainly due to cardiovascular (CV) diseases. The mechanisms for this is unclear., Objective: To assess CV structure and function in AI patients on conventional replacement therapy and after switching to once-daily, modified-release hydrocortisone (OD-HC) in comparison with healthy matched controls., Methods: This was a retrospective analysis of 17 adult AI patients (11 with primary AI, 6 with secondary AI) on stable replacement with cortisone acetate [median (minimum, maximum) 33.5 (12.5-50) mg] and, if needed, fludrocortisone [0.1 (0.05-0.2) mg], and 17 healthy matched controls. Ten patients were switched to an equivalent dose of OD-HC. Data from echocardiography, 24 h Holter-ECG and 24 h blood pressure monitoring were collected at baseline and 6 months after the switch to OD-HC., Results: At baseline, AI patients had smaller left ventricular diastolic diameter (47.1 ± 4.2 vs. 51.6 ± 2.3 mm; P = 0.001) and left atrial diameter (34.9 ± 4.7 vs. 38.2 ± 2.6 cm; P = 0.018), and a higher ejection fraction (62.5 ± 6.9% vs. 56.0 ± 4.7%; P = 0.003) than controls. AI patients had lower nocturnal systolic and diastolic blood pressure than controls (108 ± 15 mmHg vs. 117 ± 8 mmHg; P = 0.038 and 65 ± 9 mmHg vs. 73 ± 7 mmHg; P = 0.008, respectively). After the switch to OD-HC, nocturnal diastolic blood pressure normalised. No significant changes were observed in echocardiographic and Holter-ECG parameters following the switch., Conclusions: AI patients on conventional treatment display cardiovascular abnormalities that could be related to hypovolemia. Switch to OD-HC seems to have beneficial effect on blood pressure profile, but no effect on cardiovascular structure and function.

Aim: We performed a meta-analysis of randomized controlled trials (RCTs) that evaluated the effect of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium glucose co-transporter-2 inhibitors (SGLT-2i) on heart failure (HF) risk in patients with type 2 diabetes (T2D)., Methods and Results: The electronic search was carried out until 10 November 2018. RCTs were included if they compared add-on therapy with any DPP-4i, GLP-1 RAs, or SGLT-2i with placebo, and included in the outcome hospitalization for HF, and other outcomes required for cardiovascular safety studies. Risk of HF was the primary outcome for this meta-analysis. We used a random-effect model to calculate hazard ratio (HR) and 95% CI. Twelve trials were identified, involving 120,765 patients. Compared with placebo, HF risk showed a non-significant 10% reduction with the newer anti-hyperglycemic drugs (HR = 0.90, 0.80-1.01); use of DPP-4i and GLP-1 RAs was associated with nonsignificant modifications of the HF risk (+5% and -9%, respectively), while the use of SGLT-2i was associated with a significant 31% reduction of the HF risk (HR = 0.69, 0.61-0.79, P < 0.001), with no heterogeneity (I 2  = 0%, P = 0.741), suggesting a class effect. The meta-regression analysis of all 12 trials showed no association of reductions of hemoglobin A1C with HF risk., Conclusion: In T2D, SGLT-2i can reduce the risk of HF that is unrelated to improved glycemic control; DPP-4i and GLP-1 RAs behave as neutral.

In the past decades, dietary guidelines focused on reducing saturated fat as the primary strategy for cardiovascular disease prevention, neglecting the many other potential effects of diet on health, in particular the harmful effects of sugar. A greater intake of soft drinks (sugar-sweetened beverages), for example, is associated with a 44% increased prevalence of metabolic syndrome, a higher risk of obesity, and a 26% increased risk of developing diabetes mellitus. Carbohydrates comprise around 55% of the typical western diet, ranging from 200 to 350 g/day in relation to a person's overall caloric intake. For long-term weight gain, food rich in refined grains, starches, and sugar appear to be major culprits. Low-carbohydrate diets restrict daily carbohydrates between 20 and 50 g, as in clinical ketogenic diets. The results of controlled trials show that people on ketogenic diets (a diet with no more than 50 g carbohydrates/day) tend to lose more weight than people on low-fat diets. Moreover, there is no good evidence for recommending low-fat diets, as low-carbohydrate diets lead to significantly greater weight loss (1.15 kg) than did low-fat interventions. However, the magnitude of such a benefit is small. As the quality of ingested carbohydrates seems more important than the quantity for health outcomes, people with metabolic disorders should avoid or substantially reduce low-fiber, rapidly digested, refined grains, starches, and added sugars. So, the consumption of the right carbohydrates (high-fiber, slowly digested, and whole grains), in a moderately lower amount (between 40 and 50% of daily energy content), is compatible with a state of good health and may represent a scientifically-based and palatable choice for people with metabolic disorders.

Purpose: To describe gender differences concerning glycemic control, cardiovascular risk factors, diabetic complications, concomitant pathologies, and circulating endothelial progenitor cells (EPCs), in a population of young adults with type 1 diabetes., Methods: We collected data from 300 consecutively patients (168 males and 132 females), aged 18-30 years, among those admitted at Diabetes Unit of University of Campania "Luigi Vanvitelli" (Naples, Italy) from March 2012 to January 2017. Circulating levels of seven EPCs phenotypes were determined by flow cytometry., Results: As compared to men, women with type 1 diabetes had a significantly higher HbA1c levels (%, 8.4 ± 1.3 vs. 8.1 ± 1.3, P = 0.020), body mass index (Kg/m 2 , 24.8 ± 4.2 vs. 23.9 ± 3.9, P = 0.034), HDL-cholesterol (mg/dL, 61.7 ± 13.7 vs. 54.7 ± 13.9, P < 0.001), and a lower count of both CD133+KDR+ and CD34+KDR+CD133+ EPCs (P = 0.022, P < 0.001, respectively). A higher proportion of women had overweight/obesity, and thyroiditis; smoking and sexual dysfunctions were more prevalent in men than in women., Conclusions: Young adults with type 1 diabetes present gender differences with regard to glycemic control, prevalence of some cardiovascular risk factors, sexual dysfunctions and circulating levels of EPCs, most often to the detriment of women.

Despite the availability of many new treatment options for type 2 diabetes, the proportion of patients achieving the HbA1c target < 7.0% remains around 50%. We put forward the hypothesis that the unchanged HbA1c results, observed in the last decade in type 2 diabetes patients, are also a consequence of medication nonadherence and clinical inertia. Poor medication-taking behavior is usually defined as medication nonadherence and is responsible for uncontrolled hemoglobin A1c level in 23% of cases. Medication nonadherence may also affect clinical outcomes, as diabetic patients with good adherence (≥80%) had a significant 10% lower rate of hospitalization events and a significant 28% lower rate of all-cause mortality when compared with patients with poor adherence (<80%). Residual vascular risk may be defined as the risk of macrovascular (major cardiovascular events) and microvascular (retinopathy, nephropathy, neuropathy) complications that remains after intensive and successful glycemic control in type 2 diabetes. For major cardiovascular events, risk reduction following intensive glycemic control is 9% and, therefore, residual vascular risk is 91%. For microvascular complications, as nephropathy, residual vascular risk is as high as 80%. Residual vascular risk remains high in type 2 diabetes despite intensive glycemic control. Medication nonadherence by the diabetic patient and clinical inertia by the clinician may have contributed to the high level of residual vascular risk (both macro and microvascular) of type 2 diabetic patients.

Purpose: Breast cancer patients (BCP) are at risk of female sexual dysfunction (FSD). Our aim was to clarify the effects of treatment strategies, and steroid hormones levels on FSD., Methods: We enrolled 136 BCP (46.9 ± 0.8 years), and 122 completed questionnaires. BCP were divided into four groups: 22 women with advanced breast cancer on neoadjuvant therapy (NAT), 48 on adjuvant therapy (AT), 30 taking hormonal therapy (HT) and 22 with metastatic cancer on first line chemotherapy (FLT). Fifty-eight healthy women (43 ± 2.8 years) were enrolled as controls. FSD was evaluated by FSFI, and sexual distress was assessed with FSDS-R. We have collected demographic data, laboratory values, and LH, FSH, total testosterone (T), and estradiol (E2) levels., Results: BCP showed a prevalence of FSD of 69%, total FSFI score was 17. FSDS-R was 8.3. FSD had a prevalence of 72 % in NAT, 65% in AT, 77% in metastatic BCP under FLT, 67% in HT, compared with a prevalence of 20% in controls. BCP showed lower E2 than normal values, as well as T. LH and FSH were significantly elevated than normal values. Total FSFI score was positively correlated with T in 122 BCP, no significant correlation was found between E2 and FSFI. Significant differences were found between NAT and HT in lubrication, pain domains and total FSDS-R score, AT and HT in pain domain, AT and NAT in lubrication domain., Conclusions: BCP are at high risk of developing FSD both for treatment choice and hormonal status, but they have not sexually related personal distress.

In randomized controlled trials (RCTs), more intensive glucose control in patients with type 2 diabetes leads to a modest (9%) reduction in major cardiovascular events (MACE), associated with a 20% reduction of kidney events and 13% reduction of eye events. The FDA issued guidance in 2008 led to the conduct of numerous cardiovascular outcomes (CVOT) trials to assess cardiovascular safety of new antihyperglycemic therapies in patients with type 2 diabetes. The results of these trials show that insulin glargine, three different dipeptidyl peptidase-4 (DPP-4) inhibitors (saxagliptin, alogliptin, and sitagliptin) and lixisenatide (a glucagon like peptide-1 receptor agonist) produce no significant difference in CVOT when compared with usual care or placebo. Other trials with newer diabetes drugs, including empagliflozin and canagliflozin (two sodium-glucose co-transporter-2 inhibitors), liraglutide and semaglutide (two GLP-1 receptor agonists) succeeded in demonstrating CV benefit in people with type 2 diabetes. In the last two decades, the equation "diabetes equals myocardial infarction" have contributed to the development of preventive therapy for risk factors in diabetes. In both primary and secondary prevention, the diabetic patients with high rates of statin and aspirin treatment have improved CV outcome, as compared with non-users. The drugs used to reduce glucose levels in patients with type 2 diabetes seem important for the ultimate cardiovascular outcome: the combination of intensive glycemic control, when safely attainable, with newer diabetes drugs (empagliflozin, canagliflozin, liraglutide, and semaglutide) may decrease the incidence of MACE, nephropathy and retinopathy. Moreover, depending on the drug used, CV mortality and heart failure may also be reduced.

Exposure to small particulate matter (PM 2.5 ) has become the 5th highest ranking risk factor for death, responsible for 4.2 million deaths worldwide. PM pollution is also associated with cardiovascular disease and type 2 diabetes, and may contribute to deteriorate the already poor cardiometabolic outlook of the diabetic patient. Although most sources of outdoor air pollution are well beyond the control of individuals, there is still room for personal action. Health behaviors (smoking cessation, avoiding obesity, and increasing physical activity) may increase the poor life expectancy of individuals in the lowest income quartile of the Western population; moreover, a favorable lifestyle, (no current smoking, no obesity, physical activity at least once weekly, and a healthy diet pattern), may cut by nearly 50% the risk of coronary heart disease among people at high genetic risk. Things seem not immutable, as individual healthy choices do matter.

Continuous glucose monitoring associated with intensive insulin regimens represents a useful tool to lower HbA1c in selected adults with type 1 diabetes. Recent randomized controlled trials demonstrated greater glycemic benefits in type 1 diabetic patients treated with multiple daily injections of insulin and continuous glucose monitoring over usual care. These positive outcomes, however, are counter-balanced by several limitations that restrict the use of continuous glucose monitoring in the real life, including the apparent lack of benefits in children and pregnant diabetic women, the high cost, the stringent patients' selection, and the presence of a multi-disciplinary team with specific expertise. Pros and Cons of using continuous glucose monitoring in type 1 diabetic patients with multiple daily injections of insulin are here discussed.

Diabetes mellitus and cancer are two growing health problems. They have in common many modifiable risk factors including sex, age, obesity, physical activity, diet, alcohol, and smoking, and have a long latency before overtly manifesting. Patients with diabetes experience a roughly 20-25% higher cancer incidence compared to individuals without diabetes, and it depends on cancer site. Moreover, patients with diabetes who further develop cancer have increased early and late mortality in comparison with cancer patients without diabetes. Prediabetes and metabolic syndrome are also related to an increased risk of developing and die from cancer. Possible mechanisms linking diabetes and prediabetes with cancer include hyperglycemia (endogenous or exogenous), hyperinsulinemia, and alterations of insulin-like growth factor system, chronic subclinical inflammation, abnormalities in sex hormone metabolism, and adipokines. It becomes crucial to define the right orientation of the associations between diabetes and cancer in order to identify the modifiable pathogenic mechanisms. The common soil hypothesis claims that prediabetes and diabetes, as well as metabolic syndrome, may be considered a surrogate sign for dietary risk factors of cancer. The clepsydra of foods may help choose foods associated with healthy benefit while avoiding foods associated with harm, including cancer.

Dietary patterns influence various cardiometabolic risk factors, including body weight, lipoprotein concentrations, and function, blood pressure, glucose-insulin homeostasis, oxidative stress, inflammation, and endothelial health. The Mediterranean diet can be described as a dietary pattern characterized by the high consumption of plant-based foods, olive oil as the main source of fat, low-to-moderate consumption of fish, dairy products and poultry, low consumption of red and processed meat, and low-to-moderate consumption of wine with meals. The American Diabetes Association and the American Heart Association recommend Mediterranean diet for improving glycemic control and cardiovascular risk factors in type 2 diabetes. Prospective studies show that higher adherence to the Mediterranean diet is associated with a 20-23 % reduced risk of developing type 2 diabetes, while the results of randomized controlled trials show that Mediterranean diet reduces glycosylated hemoglobin levels by 0.30-0.47 %, and is also associated with a 28-30 % reduced risk for cardiovascular events. The mechanisms by which Mediterranean diet produces its cardiometabolic benefits in type 2 diabetes are, for the most, anti-inflammatory and antioxidative: increased consumption of high-quality foods may cool down the activation of the innate immune system, by reducing the production of proinflammatory cytokines while increasing that of anti-inflammatory cytokines. This may favor the generation of an anti-inflammatory milieu, which in turn may improve insulin sensitivity in the peripheral tissues and endothelial function at the vascular level and ultimately act as a barrier to the metabolic syndrome, type 2 diabetes and development of atherosclerosis.

Chronic inflammation is supposed to be an important mediator of cardiometabolic dysfunctions seen in type 2 diabetes. In this mini-review, we collected evidence (PubMed) from randomized controlled trials (through March 2016) evaluating the effect of anti-inflammatory drugs on indices of glycemic control and/or cardiovascular events in people with type 2 diabetes. Within the last 25 years, many anti-inflammatory drugs have been tested in type 2 diabetes, including hydroxychloroquine, anti-tumor necrosis factor therapies (etanercept and infliximab), salsalate, interleukin-1 antagonists (anakinra, canakinumab, gevokizumab, LY2189102), and CC-R2 antagonists. Despite being promising, the observed effects on HbA1c or glucose control remain rather modest in most clinical trials, especially with the new drugs. There are many trials underway with anti-inflammatory agents to see whether patients with cardiovascular diseases and/or type 2 diabetes may have clinical benefit from marked reductions in circulating inflammatory markers. Until now, a large trial with losmapimod (a p38 inhibitor) among patients with acute myocardial infarction, including one/third of diabetic patients, showed no reduction in the risk of major ischemic cardiovascular events. Further evidence is warranted in support of the concept that targeting inflammation pathways may ameliorate glycemic control and also reduce cardiovascular complications in type 2 diabetes.

Because of the increasing prevalence of type 2 diabetes, the need to intensify treatment to manage hyperglycemia is expanding. Premixed insulin regimens were designed to maximize patient convenience and reduce the number of daily injections required by providing both rapid-acting and intermediate-acting components in one formulation. Although the basal bolus insulin regimen is considered by many as "the golden standard" in reaching goals of glycemic control, proper use of intensified insulin regimens, such as basal bolus or premixed, will result in similar HbA1c reduction, hypoglycemic events, and weight gain. At the same number of daily insulin injections (2 shots/day), the premixed regimen is associated with a significant 0.2 % HbA1c decrease, as compared with the basal plus regimen (one shot of long-acting plus one shot of short-acting insulin). The choice of insulin regimen should consider the preferences, and resources of the individual and the family for adapting treatment to the patient needs. At last, the process of insulin initiation and intensification in type 2 diabetes must be carried out in the context of patient safety, minimizing the risk of hypoglycemia, weight gain, and injection burden.

Mediterranean-style diets provide cardiovascular benefits and increase insulin sensitivity. There is little evidence that adherence to Mediterranean diet may influence the levels of the inflammatory milieu in type 2 diabetes. The aim of this study was to assess whether Mediterranean diet influences both C-reactive protein (CRP) and adiponectin in newly diagnosed type 2 diabetes, and whether adherence to Mediterranean diet affects their circulating levels. In a two-arm, single-center trial, 215 men and women with newly diagnosed type 2 diabetes were randomized to a Mediterranean diet (n = 108, 54 males and 54 females) or a low-fat diet (n = 107, 52 males and 55 females), with a total follow-up of 8.1 years. At baseline visit and at 1 year, body weight, HOMA index, CRP, and adiponectin and its fractions were assessed. Adherence to the diets was assessed by calculating the Mediterranean-diet score. At 1 year, CPR fell by 37 % and adiponectin rose by 43 % in the Mediterranean diet group, while remaining unchanged in the low-fat diet group. The pattern of adiponectin fractions (high and non-high molecular weight) showed a response similar to that of total adiponectin. Diabetic patients with the highest scores (6-9 points) of adherence to Mediterranean diet had lower circulating CRP level and higher circulating total adiponectin levels than the diabetic patients who scored <3 points on the scale (P = 0.001). The results of this randomized controlled trial demonstrate that Mediterranean diet cools down the inflammatory milieu of type 2 diabetes.

Cancer may impair sexual function in women. We provide an overview of studies that address Female Sexual Dysfunction (FSD) in women with cancer with a meta-analysis of observational studies that used a validated diagnostic tool. Searches included MEDLINE, Scopus, and Google Scholar for studies published from January 2000 to 31 December 2014. Every included study had to involve at least 30 cancer patients, to investigate FSD based on the Female Sexual Function Index (FSFI), and to have been published in peer-review journals. Duplicate independent data extraction and quality assessment were performed. Data were pooled using a random effects model if statistical heterogeneity was present. The main outcomes were FSFI total score and FSD prevalence. FSFI is a 19-item self-report instrument for assessing key dimensions of female sexual function. A value less than 26.55 is consistent with FSD. Thirty-five studies met the inclusion criteria. Among these, 27 reported FSFI scores, and 16 FSD prevalence. Most studies (56 %) had low to moderate quality. The mean value of FSFI was lower than 20 at all cancer sites: 16.25 (pooled random effect, 95 % CI 14.91-17.58, I 2  = 14.5 %) for colorectal cancer, 18.11 (95 % CI 14.45-21.77, I 2  = 97.8 %) for gynecological cancer, and 19.58 (95 % CI 17.64-21.53, I 2  = 90.9 %) for breast cancer. FSD prevalence was higher than 60 % at all cancer sites, with the highest value for gynecological cancer (78.44 %, 95 % CI 68.36-88.52 %, I 2  = 94.1 %). Women with cancer showed low FSFI scores with a high prevalence of FSD.

Diabetes mellitus is a major risk factor for cardiovascular disease. However, the excess risk of death may vary substantially in subgroups of patients with type 2 diabetes, being highest in those younger than 55 years of age. A HbA1c value of 7.0 % or less is recommended for most patients with type 2 diabetes to reduce the incidence of microvascular disease, although individualized approaches that balance the benefits of glycemic control against the harms of hypoglycemia are encouraged. The selection of antidiabetic medications is of paramount importance, as the drug should not aggravate, and ideally even improve cardiovascular risk factors, with the hope to reduce cardiovascular morbidity and mortality. Patients with diabetes mellitus between 40 and 75 years of age with LDL-C between 70 and 189 mg/dL should be treated with a moderate-intensity statin. Implicit in this recommendation is the aim to reduce further LDL-C level in diabetes, in order to improve the cardiovascular outlook. The new PCSK9 inhibitors (evolocumab and arilocumab) are very promising, but, at present, their cost-effectiveness ratios exceed commonly accepted thresholds. For many people with diabetes mellitus and hypertension blood pressure should be <140/90 mmHg, although lower systolic targets (e.g., <130 mmHg) may be appropriate for certain individuals. With the likely exception of LDL-C, it is difficult to define a universal HbA1c and blood pressure target for all patients with type 2 diabetes mellitus. Ultimately, in the face of uncertainty in medicine, the final decision regarding a specific patient is best left to the clinician.

Diurnal salivary and plasma cortisol variations are considered valid expression of circadian cortisol rhythmicity. The aim of this study was to assess the reliability of salivary and plasma cortisol and if glycemia and glycemic oscillations may interfere with their concentration. Forty-seven type 2 diabetic patients and 31 controls were studied for glycemic profile and diurnal salivary and plasma cortisol variations on two contemporary samples taken at 08:00 a.m.-11:00 p.m (Late Night, LN). Glucose variability was evaluated in diabetic patients by considering the standard deviation of blood glucose (BGSD) readings, by calculating the mean amplitude of glycemic excursions (MAGEs) and continuous overlapping net glycemic action (CONGA). A significant correlation between LN serum cortisol and morning fasting glycemia (r = 0.78; p = 0.004) was observed in T2DM group but not in the control group (r = 0.09; p = 0.74). While LN serum cortisol significantly correlated with CONGA in diabetic patients (r = 0.50; p < 0.001), LN salivary cortisol did not correlate with any indices of glucose variability. Moreover, a highly significant correlation between LN salivary and LN serum cortisol concentrations was found in control group (r = 0.80; p < 0.001) but not in diabetic patients (r = 0.07; p = 0.62). This study shows for the first time that LN salivary rather than plasma cortisol may give information on the dynamics of adrenal function of type 2 diabetic patients, as it is not significantly influenced by glycemic variations. However, our preliminary results need to be confirmed by further studies with more complete evaluations including many more patients.

Circulating endothelial progenitor cells (EPCs) are involved in the repairing mechanisms of vascular damage. Glucose variability may contribute to the development of chronic vascular complications of diabetes. We evaluated whether reducing glucose variability with continuous subcutaneous insulin infusion (CSII) would increase circulating levels of EPCs in type 1 diabetes. The study population consisted of 106 type 1 diabetic patients: 41 subjects considered eligible for CSII completed a 6-month follow-up. Sixty-five patients on intensified insulin therapy with multiple daily injections served as control group. Seven EPCs phenotypes were assessed by flow cytometry, and glucose variability by mean amplitude of glycemic excursions (MAGE). Both CD34+KDR+ [difference between groups 32.0, 95 % CI (19.6-44.4) number/10(6) cells, P < 0.001] and CD34+KDR+CD133+ [12.5 (5.5-19.5), P < 0.001)] cell count increased at endpoint in the CSII group, associated with a reduction of MAGE [-1.1 (-2.1 to -0.1), P = 0.026]. No changes occurred in the control group. In multivariate analyses, changes in MAGE were independently associated with changes in both CD34+KDR+ (P = 0.019) and CD34+KDR+CD133+ (P = 0.022) cell count. Reducing glucose variability with CSII in type 1 diabetes increases circulating EPCs levels, suggesting a novel mechanism of vascular damage by oscillating glucose.

The purpose of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the effect of intensified insulin regimens (basal-bolus versus premixed) on glycemic control in patients with type 2 diabetes. We conducted an electronic search until March 2015 on many electronic databases including online registries of ongoing trials. All RCTs comparing basal-bolus with premixed insulin regimens, with a duration of >12 weeks and with >30 patients per arm, were included. Investigators extracted data on study characteristics, outcome measures, and methodological quality. We found thirteen RCTs lasting 16-60 weeks and involving 5255 patients assessed for the primary endpoint (reduction of HbA1c from baseline). Meta-analysis of change in HbA1c level between basal-bolus and premixed insulin regimens resulted in a small and non-significant difference of 0.09% (95% CI -0.03 to 0.21), with substantial heterogeneity between studies (I(2) = 74.4%). There was no statistically significant difference in the event rate for overall hypoglycemia (0.16 episode/patient/year, 95%CI -2.07 to 2.3), weight change (-0.21 kg, -0.164 to 0.185), and daily insulin dose (-0.54 U/day, -2.7 to 1.6). The likelihood for reaching the HbA1c <7% was 8% higher (3-13%, I(2) = 68.8%) with the basal-bolus as compared with the premixed regimen. There is no clinically relevant difference in the efficacy of basal-bolus versus premixed insulin regimens for HbA1c decrease in type 2 diabetic patients. These findings may be helpful to adapt treatment to individual patient needs.

The World Health Organization estimates that worldwide in 2012 around 7 million deaths occurred prematurely due to air pollution, which is now the world's largest single environmental health risk. The higher premature mortality associated with air pollution is due to exposure to small particulate matter of 10 microns (PM10) or less in diameter. Exposure to air pollution has also been suggested as a contributing to diabetes incidence and progression. There are a number of possible biological pathways linking air pollutants to diabetes, including endothelial dysfunction, dysregulation of the visceral adipose tissue through inflammation, hepatic insulin resistance, elevated hemoglobin A1c level, elevated blood pressure, and alterations in autonomic tone, which may increase insulin resistance. The risk of future diabetes associated with exposure to 10 μg/m(3) increase of PM2.5 has been quantified in the range of 10 to 27%; the risk of diabetes mortality associated with PM2.5 appears to be quite lower, around 1% for each increment exposure of 10 μg/m(3) of both PM2.5 and PM10. Limitations of the current epidemiological evidence include the complex mixture of pollutants, the different design of the studies, the limited data available for non Western populations, and the lack of demonstration that improvement of air quality is associated with a decrease incidence of type 2 diabetes. Although the most sources of outdoor air pollution are well beyond the control of individuals, people should be informed that there are means to reduce the burden of air pollutants on diabetes risk, including avoidance of passive smoking, adoption of an healthy diet, and increasing leisure-time physical activity.

Current guidelines specify hemoglobin A1c (HbA1c) targets around or less than 7.0 %, with more (<6.5 %) or less (<8 %) stringent goals being appropriate for selected patients. The difficulty in setting a precise HbA1c target depends, at least in part, on the physician perception of the relative importance of the parameters to be considered when determining the target. Using the "a priori" approach, physicians set the HbA1c target first, then prescribe the appropriate antidiabetic drug in order to cover the distance from the target, i.e., the difference between the current HbA1c value of the patient and the individualized HbA1c target: calculating the distance from the target may also be useful as a predictor of therapeutic success. In the "a posteriori" approach, physicians first prescribe, then decide if the achieved HbA1c is an appropriate level for that patient. Attainment of the HbA1c target ultimately depends on which target the physician set: both approaches ("a priori" and "a posteriori") may be useful for both physicians to make appropriate therapeutic decisions and patients to adhere to the best possible treatment. All this presumably will avoid unnecessary therapeutic inertia.

Circulating endothelial progenitor cells (EPCs) are bone marrow-derived stem cells able to migrate to sites of damaged endothelium and differentiate into endothelial cells, thereby contributing to vascular repair. Recent studies demonstrated a reduction of EPCs in patients with diabetes mellitus or erectile dysfunction (ED). The aim of this study was to evaluate the circulating levels of different EPCs phenotypes and their relation with testosterone levels in young type 1 diabetic patients with ED. We studied 118 consecutively type 1 diabetic patients and 60 age-matched healthy controls. Erectile function was assessed by completing the International Index of Erectile Function (IIEF-5) and EPCs levels by flow cytometry. Testosterone concentrations were evaluated in all the study population. We identified 38 diabetic patients with ED (Group 1) and 80 patients without ED (Group 2). CD34+KDR+CD133+ cells were significantly lower in patients in Group 1 as compared with those in Group 2 [median and interquartile range, n/10(6) events, 12 (6-16) vs. 18 (13-22), P < 0.001)]. In all participants in the study, there was a significant correlation between circulating CD34+KDR+CD133+ cells and testosterone levels (r = 0.410, P < 0.001), which was highest in Group 1, intermediate in Group 2, and lowest in Group 3 (controls). There was a significant correlation between IIEF-5 score and both CD34+KDR+ (r = 0.459, P = 0.003) and CD34+KDR+CD133+ (r = 0.316, P = 0.050) cells among patients of Group 1, as well as between testosterone levels and most of the EPCs phenotypes. Finally, multivariate regression analysis identified levels of circulating CD34+KDR+ cells as an independent risk factor for ED (β-coefficient 0.348, P = 0.007). In conclusion, type 1 diabetic patients with ED show reduced levels of CD34+KDR+CD133+ cells, whose number correlates with IIEF. Further studies are needed to fully understand the exact mechanisms by which testosterone regulates vascular homeostasis.

There is mounting evidence that bariatric surgery leads to higher remission rates of type 2 diabetes than any conventional medical treatment, lifestyle intervention, or medically supervised weight loss program. Although remission rates of type 2 diabetes may be as high as 66.7 % after gastric bypass and 28.6 % after gastric band, very few bariatric surgery studies report long-term results with sufficient patient follow-up to minimize biased results. Hence, trials that directly compare bariatric surgery procedures with medical and lifestyle intervention for patients with type 2 diabetes are the best candidate for assessing the role of bariatric surgery in diabetes remission. Three randomized controlled trials and one prospective study have so far been published comparing the effect of Roux-en-Y gastric bypass (RYGB) procedure against optimal medical therapy, with a follow-up ranging from 1 to 6 years: the percentage of diabetic patients in remission (hemoglobin A1C < 6-6.5 % without medications) ranged from 38 to 75 % at the end of follow-up. Intensive lifestyle intervention is also superior to conventional treatment for inducing remission of type 2 diabetes, with remission rates of type 2 diabetes between 10 and 15 % at 1 year of follow-up. Bariatric surgical procedures, especially RYGB, are more effective at inducing initial type 2 diabetes remission in obese patients, but more information is needed about the long-term durability of comorbidity control and complications after bariatric procedures. In the meantime, all efforts should be directed toward primary prevention of type 2 diabetes, given the encouraging results of lifestyle intervention studies.

In the last decades, a surprising increased incidence of differentiated thyroid cancer (DTC), along with a precocious diagnosis of "small" tumors and microcarcinomas have been observed. In these cases, better oncological outcomes are expected, and a "tailored" and "less aggressive" multimodal therapeutic protocol should be considered, avoiding an unfavorable even if minimal morbidity following an "overtreatment." In order to better define the most suitable surgical approach, its benefits and risks, we discuss the role of surgery in the current management of DTCs in the light of data appeared in the literature. Even if lymph node metastases are commonly observed, and in up to 90 % of DTC cases micrometastases are reported, the impact of lymphatic involvement on long-term survival is still argument of intensive research, and indications and extension of lymph node dissection (LD) are still under debate. In particular, endocrine and neck surgeons are still divided between proponents and opponents of routine central LD (RCLD). Considering the available evidence, there is agreement about total thyroidectomy, therapeutic LD in clinically node-positive DTC patients, and RCLD in "high risk" cases. Nevertheless, indications to the best surgical treatment of clinically node-negative "low risk" patients are still subject of research. Considering on the one hand, the recent trend toward routine central lymphadenectomy, avoiding radioactive treatment, and on the other hand, the satisfactory results obtained reserving prophylactic LD to "high risk" patients, we think that further prospective randomized trials are needed to evaluate the best choice between the different surgical approaches.

No specific diet is recommended to prevent type 2 diabetes. We did a meta-analysis of prospective cohort studies to assess the association between different diets and prevention of type 2 diabetes. We did a comprehensive search of multiple electronic databases (Medline, Scopus, EMBASE, and ISI web of knowledge) until August 2013 using predefined criteria. We included prospective cohort studies that evaluated the role of different diets in type 2 diabetes prevention. Studies were selected by 2 independent reviewers. We did random-effects meta-analyses to determine the relative risk (RR) of incident diabetes associated with healthful dietary patterns. A total of 21,372 cases of incident diabetes, from 18 prospective studies, with 20 cohorts, in 4 world regions were identified. In the random-effect meta-analysis of the 20 cohorts, RR was 0.80 (95 % confidence interval (CI) = 0.74-0.86, P < 0.001), with high heterogeneity (I (2) = 57 %, P = 0.001) and no evidence of publication bias (Egger's test, P = 0.653). Exclusion of two cohorts produced identical RR (0.80, 95 % CI 0.76-0.84), with nonsignificant heterogeneity (I (2) = 9 %). The risk of incident diabetes did not appreciably change considering the geography (USA, Europe, and Asia), the duration of follow-up (≤10 and >10 years), and type of diets (Mediterranean and DASH, Dietary Approaches to Stop Hypertension, diets). There was a difference between at risk and general population (P = 0.0487), but the evidence was limited to two studies only. The results of our study demonstrate that several healthy diets are equally and consistently associated with a 20 % reduced risk of future type 2 diabetes.

Evidence-based medicine replaced eminence-based medicine as a way to manage unavoidable clinical uncertainty. Moving away from "one-size-fits-all" medicine, personalized medicine seemed to have the potential of tailoring therapies to subsets of patients. Despite the rapid progress in drug development for diabetes, it is still challenging to achieve good glycemic control in a substantial population. Different diabetes management algorithms have been proposed: most agree with a HbA1c target of <7.0 % for the majority of people with diabetes, except the American Association of Clinical Endocrinologists (AACE) that claims for a lower HbA1c target (<6.5 %). The recently released American guidelines on the treatment of blood cholesterol recommends moderate-intensity statin therapy for primary prevention for persons aged 40-75 years with type 1 or 2 diabetes and LDL-cholesterol levels between 70 and 189 mg/dl. The Eighth Joint National Committee recommends pharmacologic treatment in the population aged 18 years or older with diabetes, with a goal systolic blood pressure of lower than 140 mmHg and a goal diastolic blood pressure lower than 90 mmHg. There are differences and similarities among these recent guidelines for people with diabetes, with the main differences related to the level of the evidence. There are recommendations based on expert opinions (insufficient evidence or existing evidence unclear or conflicting) in almost all guidelines. The ultimate decision about care of a particular patient is left to clinicians, as the way to manage unavoidable guideline uncertainty: clinician's opinion does matter.

The association between metabolic syndrome and cancer continues to be acknowledged. Metabolic syndrome is a common long-term complication in cancer survivors; on the other hand, findings from several recent meta-analyses suggest that the presence of metabolic syndrome is associated with increased risk of future cancer at specific sites. Approximately one-third of cancer deaths occurring in the USA each year may be caused by unhealthy lifestyle habits, including poor nutrition. Worldwide, diets low in fruits rank third for deaths attributable to individual risk factors. Metabolic syndrome may be a surrogate marker for dietary risk factors for cancer, a sentinel for the deleterious effect of unhealthy diet in susceptible individuals, who may first manifest metabolic consequences (visceral obesity, dysglycemia, hypertension, and dyslipidemia), and then an increased risk of cancer. From the standpoint of preventive oncology, people with the metabolic syndrome should be encouraged, more than sex- and age-matched counterparts, to undergo appropriate cancer screenings.

Ability to predict which patients might benefit more of therapy might facilitate personalization of treatment. The aim of this study was to obtain information about clinical characteristics which might predict the HbA1c response to DPP-4 inhibitors. We conducted an electronic search without restriction for randomized controlled trials (RCTs) involving DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, and alogliptin). RCTs were included if they lasted at least 12 weeks, reported the effect of DPP-4 inhibitors on HbA1c level, and the number of patients in any arm was >30. We did a meta-regression analysis. Seventy-eight articles were eligible, with 79 arms and 20,503 patients. For all arms, the decrease of HbA1c was -0.74 % (95 % CI -0.80 to -0.67 %), with considerable heterogeneity (I (2) = 97 %, P < 0.0001): the greatest HbA1c decrease was seen at 52 weeks (8 arms, 3,338 patients, -0.88 %, 95 % CI -1.10 to -0.66 %). In univariate meta-regression analysis, baseline HbA1c explained 22 % of variance of the HbA1c response to treatment, while fasting glucose and type of DPP-4 inhibitor explained an additional 19 and 12 %, respectively; age, duration of treatment, previous therapy, and type of statistical analysis of RCTs were without influence. In the multivariate meta-regression model, baseline HbA1c, fasting glucose, and type of DPP-4 inhibitor explained 61 % of total variance. The HbA1c response to DPP-4 inhibitors can be modulated mainly by baseline HbA1c and fasting glucose levels: a greater absolute reduction of baseline HbA1c is seen in patients with higher baseline HbA1c and lower fasting glucose level.

Metabolic syndrome has become a major public health problem worldwide and represents a common clinical condition in countries with a high incidence of obesity and western dietary patterns. Metabolic syndrome associates with common cancers at many sites, including liver, colorectal, and bladder cancers in men, and endometrial, pancreatic, breast post-menopausal, and colorectal cancers in women. However, the role played by each single component of the syndrome on cancer risk is still unclear. For endometrial cancer, obesity and/or high circumference waist explain all the risk associated with the full metabolic syndrome, while for post-menopausal breast cancer, the risk conveyed by metabolic syndrome appears to be greater than its parts, as no single component explains the full risk associated with the syndrome. Future research should cover other avenues in order to elucidate the complexity of biological processes linking metabolic syndrome and cancer.

We performed a systematic review and meta-analysis on the association of metabolic syndrome with endometrial cancer. A systematic literature search of electronic databases (Medline, ISI Web of Knowledge and Scopus) was conducted and complemented by cross-referencing to identify studies published before 31 January 2013. Core items of identified studies were independently extracted by two reviewers, and results were summarized by random effects meta-analysis. We identified six studies, which reported on 3,132 cancer cases. Metabolic syndrome was associated with an increased risk of endometrial cancer (RR: 1.89, 95 % CI 1.34-2.67, P < 0.001), with significant heterogeneity among studies (I (2) = 92 %, P < 0.001), but no indication for publication bias in the Egger's test (P = 0.240). A sensitivity analysis omitting two studies produced no heterogeneity (I (2) = 0 %) and attenuated the association (RR: 1.39, 1.31-1.48, P < 0.001). The risk estimates for any single factor of the syndrome were 2.21 (P < 0.001) for higher values of body mass index and/or waist, 1.81 (P = 0.044) for hyperglycemia, 1.81 (P = 0.024) for higher blood pressure values, and 1.17 (P < 0.001) for high triglyceride levels; there was no significant association with low HDL-cholesterol. Metabolic syndrome is associated with an increased risk of endometrial cancer; among the components of the syndrome, obesity/high waist is that more strongly associated with endometrial cancer.

We performed a systematic review and meta-analysis of the empirical evidence on the association of metabolic syndrome and its components with colorectal cancer incidence and mortality. A systematic literature search of multiple electronic databases was conducted and complemented by cross-referencing to identify studies published before 31 October 2012. Every included study was to report risk estimates with 95 % confidence intervals for the association between metabolic syndrome and colorectal cancer (incidence or mortality). Core items of identified studies were independently extracted by two reviewers, and results were summarized by standard methods of meta-analysis. We identified 17 studies, which reported on 49 data sets with 11,462 cancer cases. Metabolic syndrome was associated with an increased risk of colorectal cancer incidence and mortality in both men (RR: 1.33, 95 % CI 1.18-1.50, and 1.36, 1.25-1.48, respectively) and women (RR: 1.41, 1.18-1.70, and 1.16, 1.03-1.30, respectively). The risk estimates changed little depending on type of study (cohort vs non cohort), populations (US, Europe, Asia), cancer site (colon and rectum), or definition of the syndrome. The risk estimates for any single factor of the syndrome were significant for higher values of BMI/waist (RR: 1.19, 95 % CI 1.10-1.28), dysglycemia (RR: 1.29, 1.11-1.49), and higher blood pressure (RR: 1.09, 1.01-1.18). Dysglycemia and/or higher BMI/waist explained most of the risk associated with metabolic syndrome. Metabolic syndrome is associated with an increased risk of colorectal cancer incidence and mortality in both sexes. The risk conveyed by the full syndrome is not superior to the sum of its parts.

Uncertainties abound in clinical management of type 2 diabetes. Sources of uncertainty specific to type 2 diabetes originate from the panoply of glycemic (HbA1c) targets, the complexity of drug therapy, the ideal sequence of drugs after metformin failure, the possible harms of anti-hyperglycemic drugs, the outcomes of treatment (surrogate versus clinical) and the hierarchy of risk factors to treat in order to prevent the vascular complications. Ironically, multiple treatment guidelines and algorithms periodically released to improve guidance may generate confusion into clinicians. Moreover, treatment algorithms cannot be truly evidence-based because of a lack of studies comparing all available treatment combination options. Personalized therapy essentially identifies patients who could have major benefits from the therapy as compared with other patients. Personalized medicine for type 2 diabetic has the potential to improve the quality health-care practice of diabetes management, but specific research is needed.

Osteoporosis increases dramatically with age. About 40 % of women in developed countries will experience an osteoporosis-related fracture in the course of their lifetime, with men experiencing approximately one-third to one-half the risk of women. The "lipid hypothesis of osteoporosis" claims for a role of oxidized lipids as a contributing factor in osteoporosis. On the other hand, statins are supposed to exert anabolic effects on the bone, either through their lipid-lowering action or signal pathways that are independent of their effects on lipid levels. The epidemiological evidence seems to suggest that higher triglycerides may give some protection against fracture, although no association with reduced fracture risk has been reported between lipid-lowering drug (except statins) users and non-users. The epidemiological evidence for a role of statins in osteoporosis is strong, with a lower fracture risk ranging from 30 to 40 % in statin users versus non-users. However, some pitfalls inherent to observational studies (high heterogeneity, residual confounding, potential publication bias) and the lack of association in randomized trials suggest caution. At the moment, the evidence for a role of statins in prevention of osteoporosis is insufficient to recommend starting statin therapy with the aim to prevent osteoporosis.

Total thyroidectomy (TT) is the standard of care for differentiated thyroid cancer (DTC), but still there is no consensus about the role of routine use of prophylactic central lymph node dissection. The aim of this study was to analyze our results of TT without prophylactic central lymphadenectomy in the treatment of DTC. Clinical records, between January 1998 and December 2005, of 221 patients undergoing TT, without prophylactic central lymph node dissection, were retrospectively evaluated. Two hundred and eleven patients (95.47 %) also underwent radioiodine (RAI) ablation followed by thyroid stimulating hormone (TSH) suppression therapy. In patients with loco-regional lymph nodal recurrence, lateral and central lymph node dissection was performed. The incidence of permanent hypoparathyroidism (iPTH <10 pg/ml) and permanent vocal fold paralysis were, respectively, 0.91 and 0.91 %. After a 9.6 ± 3.5 years mean follow-up, the rate of loco-regional recurrence, with positive cervical lymph nodes, was 3.16 % (7/221 patients). In these cases a lateral and central lymphadenectomy was carried out without significant complications. Our results showed that TT without prophylactic central lymph node dissection, followed by RAI ablation, was associated with low morbidity and low loco-regional recurrence rate, even if the lack of a control group treated with TT plus prophylactic central lymphadenectomy suggests caution against generalization of our assumption. Such last combined procedure could be indicated in high-risk patients, in whom loco-regional recurrence is more frequent. However, given the trend in the literature toward prophylactic lymphadenectomy and the avoidance of RAI treatment, prospective randomized trials should be conducted to better clarify this issue.