pH changes are a cardinal feature in metabolic disorders. Based on published literature, chronic metabolic acidosis is a major finding in type 2 diabetes (T2D), which is recently described as CMAD (chronic metabolic acidosis of T2D). Several disorders characterized by overt metabolic acidosis are recognized as T2D co-morbidities or are dual risk factors that pertain to their unique signs and symptoms in T2D. Over time, many terms were used for chronic metabolic acidosis (CMA) in different disorders. However, the lack of a unified term for CMA, delayed the recognition of CMAD as a prime feature of T2D, and the setting of the diagnostic criteria and management protocol for this disorder. Other than the classical diabetic complications, CMAD contributes to non-classical organ-specific local diabetic complications. Here we described the likely clinical features of CMAD in general, such as fatigue, tiredness, cramps, and aches, as well as organ/system-specific symptoms of T2D related to the liver, skeletal muscles, bones and joints, lungs, nervous system, eyes, kidneys and urinary tract, oral cavity and teeth, gastrointestinal tract, immune system, and skin. Diagnostic criteria and confirmatory tests are enlisted together with the laboratory tools used for pH estimation in different body compartments. Finally, a management protocol is proposed, which covers: 1) lifestyle (exercise, stress management); 2) nutrition (drinks, foods, and supplements); and 3) therapeutic pH correction: general proton pump inhibitor (PPI) and alkaline minerals; and organ-specific therapies with different modalities of action. In addition, the therapeutic potentials of nanomedicine and immune and gene therapies for pH correction are raised.

The gut microbiota plays a crucial role in the human body and has an impact on the physiological function of the host. In particular, changes in the gut microbiota are especially pronounced in patients with type 2 diabetes. There is ample evidence that glucose-lowering drugs exert their therapeutic effects precisely through their interactions with the gut microbiota, but there is a lack of summarization. An overall comparison of the effects of each hypoglycemic agent on the gut flora can provide new inspiration for combinations. In this paper, we selected several representative glucose-lowering drugs, such as metformin, sodium-dependent glucose transporters 2 inhibitors (dapagliflozin), glucagon-like peptide-1 receptor agonists (semaglutide, liraglutide), and the traditional Chinese medicine (berberine), and illustrated how they can affect the disease process by regulating metabolic homeostasis, immune response, and gut barrier. We found that each of these four hypoglycemic agents can have conflicting effects on the gut flora depending on the timing and mode of administration. Meanwhile, the potential impact of gut microbiota on drug safety is explored, and an outlook for the optimization of future type 2 diabetes treatment regimens is presented.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that can result in reduced health-related quality of life (HRQOL). Metabolic changes, particularly insulin resistance and obesity, play a significant role in PCOS pathogenesis. This study examined associations between metabolic factors and HRQOL in PCOS patients. A cross-sectional study of 77 patients was conducted at University Medical Center Mainz. At the time of inclusion in the study, patients had to be over 18 and not undergoing active PCOS therapy. A desire to conceive or fertility therapy led to exclusion. Participants were over 18, not undergoing PCOS therapy, and not seeking pregnancy. HRQOL and psychological distress were measured using the Modified-PCOS-Questionnaire (MPCOSQ) and Hospital Anxiety and Depression Scale (HADS). Linear regression analyses assessed associations between metabolic markers and HRQOL, with significant variables included in a multivariate model. Worsening metabolic markers were linked to lower HRQOL, especially in body hair and menstrual symptom domains. Markers such as HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) levels (P=0.040), elevated VAI (Visceral Adiposity Index) (P=0.035), and increased FLI (Fatty Liver Index) (P=0.023) were associated with diminished HRQOL. In the multivariate regression analysis, only a BMI ≥25kg/m2 (P=0.001) emerged as a statistically significant value. This study showed a significant correlation between metabolic markers, including BMI, FLI, VAI, HOMA-IR, and HRQOL in PCOS patients. BMI was the most meaningful predictor for HRQOL. BMI, despite being controversial and prone to errors, may be more indicative of HRQOL than specific metabolic markers.

The aim of our retrospective study was to describe the immunophenotypic characteristics of neuroendocrine breast neoplasm (BNEN), a peculiar and rare type of breast carcinoma. Pathological data from 51 patients affected by BNEN were retrospectively evaluated, and 44 patients were considered eligible (7 patients with incomplete data were excluded). The patients were followed in six different Italian hospitals between 2009 and 2019. The histological samples, collected by biopsies and/or surgery pieces, were analyzed to determine: 1) tumor histology; 2) immunophenotypic pattern; 3) presence of lymphatic infiltration; 4) presence of necrosis. The median age of the patients included in our analysis was 70 years (67.6±13.7 years). As concerns the histological type we identified 7 cases of well-differentiated neuroendocrine carcinomas (16%), 8 cases of poorly differentiated/small cell neuroendocrine carcinoma (18%), 29 cases of breast carcinomas with neuroendocrine differentiation (66%). From the analysis of breast-specific immunophenotype we identified: 24 cases (54%) of Luminal A pattern; 9 cases (20%) of Luminal B pattern; 8 case (18%) of triple negative pattern. The presence of lymphatic infiltration was assessed in 29 samples and it was observed in 13 cases (45%), necrosis was assessed in 29 samples and was absent in 72% of all cases (21 samples). Neuroendocrine markers expression was heterogeneous with a prevalence of synaptophysin (positivity in 95%); chromogranin A was evaluated in 31 samples and it was positive in 58% of cases. in our series BNENs mainly affect a post-menopausal population and luminal A pattern is the most frequent immunophenotype. As expected, lymphatic infiltration is most frequently reported in invasive breast cancer with neuroendocrine differentiation; necrosis is absent in well-differentiated neuroendocrine carcinomas. Synaptophysin and chromogranin A are important markers for the diagnosis of BNEN.

The Mediterranean diet (MD) is recognized as a cultural heritage by UNESCO, thus, is a nutritional model widely spread in all Mediterranean countries. As already demonstrated by several studies, high adherence to MD is a protective factor against many chronic diseases. Conversely, poor adherence to the diet is correlated with an increased prevalence of these pathologies. The aim of the current study was to investigate the relationship between the adherence to MD and the prevalence of benign and malignant thyroid disease. We analyzed the health status of 60 patients, referred to total thyroidectomy and histological examination, due to nodular thyroid disease. Eating habits were evaluated according to the PREDIMED questionnaire, and patients' results were evaluated according to histological findings of benign or malignant disease. PREDIMED Score was lower in patients with malignant thyroid disease (MTD) than those with benign thyroid disease (BTD) (5.27±0.87 vs. 7.00±1.23, respectively; P value <0.001). A significant correlation was found between poor adherence to MD and diagnosis of MTD (r=0.454; P<0.001). Excessive consumption of butter and sugary drinks, along with low consumption of pasta, white meat, and rice were found to be predictive factors of MTD. In our cohort, a PREDIMED Score ≤7 resulted significantly related to MTD diagnosis, while a good adherence to MD resulted associated with BTD. Moreover, high consumption of sweetened beverages seemed to predict MTD histologic diagnosis, while, conversely, low consumption resulted predictor of BTD. Nevertheless, more studies are needed to evaluate the effective impact of MD on MTD incidence on larger cohorts.

COVID-19-induced diabetes is a novel and enigmatic disease. Our aim was to evaluate a possible relationship between post-COVID-19 syndrome (PCS) and increased insulin resistance (IR) in non-diabetic outpatients after mild COVID-19. Repeated measures design. Three evaluations [1E (pre-COVID, baseline), 2E (3 months post-COVID) and 3E (21 months post-COVID)] were performed, directed to PCS+ and PCS- subjects. Triglyceride-glucose (TyG) index ≥8.74 was considered IR, and albumin-to-globulin ratio (AGR) <1.50, inflammation. We analyzed 112 individuals (median [IQR] age=44 [20] years, 58% women, 36 PCS+, 76 PCS-). PCS+ with very low basal IR (TyG <7.78, lowest quartile) showed a reduced inflammatory burden (basal AGR=1.81 [0.4] vs. 1.68 [0.2] in 2E; P=0.23), and increased TyG across evaluations (from basal 7.62 [0.2] to 8.29 [0.5]; P=0.018]. Conversely, PCS+ subjects with high basal TyG (TyG ≥8.65, highest quartile) did not show significant variations in TyG, but a greater inflammatory load (basal AGR=1.69 [0.3] vs. 1.44 [0.3] in 2E; P=0.10). In multivariable models addressing groups with reduced basal IR (TyG <8.01), PCS has been a consistent predictor for TyG, after adjusting for confounders. Partial correlation and multivariable analyses showed similarities involving acute polysymptomatic COVID-19 and PCS regarding IR. PCS was associated with increased IR, being more evident when the baseline degree of IR was very low. PCS and increased IR were separately associated with inflammation. Acute polysymptomatic COVID-19 and PCS could be clinical expressions of underlying inflammatory state, which in turn may also trigger IR.

Type 1 diabetes (T1D) is an organ-specific chronic autoimmune disease mediated by autoreactive T cells. ZnT8 is a pancreatic islet-specific zinc transporter that is mainly located in β cells. It not only participates in the synthesis, storage and secretion of insulin but also maintains the structural integrity of insulin. ZnT8 is the main autoantigen recognized by autoreactive CD8⁺ T cells in children and adults with T1D. This article summarizes the latest research results on the T lymphocyte epitope and B lymphocyte epitope of ZnT8 in the current literature. The structure and expression of ZnT8, the role of ZnT8 in insulin synthesis and its role in autoimmunity are reviewed. ZnT8 is the primary autoantigen of T1D and is specifically expressed in pancreatic islets. Thus, it is one of biomarkers for the diagnosis of T1D. It has broad prospects for further research on immunomodulators for the treatment of T1D.

The aim of this study was to analyze the prevalence of primary and secondary hyperparathyroidism in patients with primary aldosteronism (PA), and its implication on cardiovascular and metabolic outcomes. A retrospective study of patients with PA (exposed cohort, N.=44) and all hypertensive (EH) patients with adrenal lesions without PA nor other adrenal hypersecretion (non-exposed cohort, N.=41) on follow-up at our center between 2016 and 2020. The mean age of patients with PA and EH was 55.1±14.13 and 66.3±10.93 (P<0.001), and 50% of PA and 39.0% of EH were women (P=0.309). At diagnosis, the prevalence of primary hyperparathyroidism in PA was of 18.2%, and all were normocalcemic hyperparathyroidism cases. Globally, no differences were found in the prevalence of primary hyperparathyroidism compared to EH (18.2% vs. 29.3%, P=0.229), but hypercalcemic primary hyperparathyroidism was significantly more prevalent in EH patients than in PA (22.0% vs. 0%, P=0.001). There were 47.7% (N.=21) cases of secondary hyperparathyroidism in patients with PA (4 due to chronic kidney disease (CKD) and vitamin D deficiency, and 17 due to vitamin D deficiency alone). The cardiometabolic profile of patients with PA and hyperparathyroidism (N.=29) was similar to of those patients without hyperparathyroidism (N.=15) at diagnosis and after a median follow-up of 3.6 years (interquartile range 1.1-5.9). Although primary and secondary hyperparathyroidism are common in patients with PA, their prevalence was similar than the observed in EH patients. Primary hyperparathyroidism is usually mild in PA, appearing as normocalcemic forms. No negative implications of the hyperparathyroidism in the cardiometabolic profile of PA were observed.

The predictive value of American Joint Committee on Cancer (AJCC) 8 for recurrence in differentiated thyroid cancer (DTC) is not known. We aimed to compare AJCC 7 and 8 regarding the differences in staging and recurrence predictors in DTC. Demographic, clinical (duration of disease and follow-up, the extent of surgery), laboratory (TSH, fT4, thyroglobulin, and antithyroglobulin), pathological (type of thyroid cancer, localization, multifocality, diameter, extrathyroidal extension [ETE], and lymph node [LN] metastasis), and imaging findings (sonography, and whole-body scan), and follow-up features (metastases, recurrence and/or persistence, and RAI need) were retrospectively analyzed in adult patients with DTC followed-up for at least six months. Staging was determined in accordance with AJCC 7 and AJCC 8, prediction of recurrence and persistence by ATA risk stratification, and death risk by AMES systems. The alterations in staging and recurrence predictors were analyzed. A majority of study patients (N.=524) were female (N.=424) and diagnosed with papillary cancer (N.=511), the median age at diagnosis was 44. 97.89% (N.=93) of stage 2-4 patients (N.=95) in AJCC 7 were down-staged in AJCC 8. We down-staged 41 patients of 45-55 years of age into stage 1 in AJCC 8 independent of LN status. A percentage of 26.71% of patients (N.=140) did have persistence, 9.54% (N.=50) persistence at the last follow-up, and 9.54% (N.=50) had recurrence. According to AJCC 8, T4 and AMES high risk were predictors for recurrence (hazard ratio: 3.053, P=0.023; hazard ratio:2.465, and P=0.005; respectively). Both AJCC 7 and 8 were associated with recurrence (P=0.008 and P<0.001, respectively). Stage 4 in AJCC 7, and stages 3 and 4 in AJCC 8 better predicted the probability of recurrence. Our findings suggest that AJCC 8 better predicted the recurrence in DTC than AJCC 7. In AJCC 8, T4 tumor, AMES high risk, stages 3 and 4 predicted recurrence. The vast majority of patients with stages 2-4 in AJCC 7 were down-staged in AJCC 8.