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Patients with type 2 diabetes (T2D) are characterized by blunted immune responses, which are affected by glycaemic control. Whether glycaemic control influences the response to COVID-19 vaccines and the incidence of SARS-CoV-2 breakthrough infections is unknown. Here we show that poor glycaemic control, assessed as mean HbA1c in the post-vaccination period, is associated with lower immune responses and an increased incidence of SARS-CoV-2 breakthrough infections in T2D patients vaccinated with mRNA-BNT162b2. We report data from a prospective observational study enroling healthcare and educator workers with T2D receiving the mRNA-BNT162b2 vaccine in Campania (Italy) and followed for one year (5 visits, follow-up 346 ± 49 days) after one full vaccination cycle. Considering the 494 subjects completing the study, patients with good glycaemic control (HbA1c one-year mean < 7%) show a higher virus-neutralizing antibody capacity and a better CD4 + T/cytokine response, compared with those with poor control (HbA1c one-year mean ≥ 7%). The one-year mean of HbA1c is linearly associated with the incidence of breakthrough infections (Beta = 0.068; 95% confidence interval [CI], 0.032-0.103; p  < 0.001). The comparison of patients with poor and good glycaemic control through Cox regression also show an increased risk for patients with poor control (adjusted hazard ratio [HR], 0.261; 95% CI, 0.097-0.700; p  = 0.008). Among other factors, only smoking (HR = 0.290, CI 0.146-0.576 for non-smokers; p  < 0.001) and sex (HR = 0.105, CI 0.035-0.317 for females; p  < 0.001) are significantly associated with the incidence of breakthrough infections. In this study, Marfella et al. show that patients with diabetes and poor glycaemic control have a blunted response to COVID-19 vaccine and are more prone to develop breakthrough infections, with further analysis suggesting smoking and male sex as potential risk factors to get COVID-19 despite vaccination.

Adiponectin (ADPN) is a plasma protein secreted by adipose tissue showing pleiotropic effects with anti-diabetic, anti-atherogenic, and anti-inflammatory properties. Initially, it was thought that the main role was only the metabolism control. Later, ADPN receptors were also found in the central nervous system (CNS). In fact, the receptors AdipoR1 and AdipoR2 are expressed in various areas of the brain, including the hypothalamus, hippocampus, and cortex. While AdipoR1 regulates insulin sensitivity through the activation of the AMP-activated protein kinase (AMPK) pathway, AdipoR2 stimulates the neural plasticity through the activation of the peroxisome proliferator-activated receptor alpha (PPARα) pathway that inhibits inflammation and oxidative stress. Overall, based on its central and peripheral actions, ADPN appears to have neuroprotective effects by reducing inflammatory markers, such as C-reactive protein (PCR), interleukin 6 (IL6), and Tumor Necrosis Factor a (TNFa). Conversely, high levels of inflammatory cascade factors appear to inhibit the production of ADPN, suggesting bidirectional modulation. In addition, ADPN appears to have insulin-sensitizing action. It is known that a reduction in insulin signaling is associated with cognitive impairment. Based on this, it is of great interest to investigate the mechanism of restoration of the insulin signal in the brain as an action of ADPN, because it is useful for testing a possible pharmacological treatment for the improvement of cognitive decline. Anyway, if ADPN regulates neuronal functioning and cognitive performances by the glycemic metabolic system remains poorly explored. Moreover, although the mechanism is still unclear, women compared to men have a doubled risk of developing cognitive decline. Several studies have also supported that during the menopausal transition, the estrogen reduction can adversely affect the brain, in particular, verbal memory and verbal fluency. During the postmenopausal period, in obese and insulin-resistant individuals, ADPN serum levels are significantly reduced. Our recent study has evaluated the relationship between plasma ADPN levels and cognitive performances in menopausal women. Thus, the aim of this review is to summarize both the mechanisms and the effects of ADPN in the central nervous system and the relationship between plasma ADPN levels and cognitive performances, also in menopausal women.

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are linked with immune-related adverse events (irAEs), including cardiac events. Objective: This study aims to assess the reporting frequency of atrial fibrillation with ICIs using data from the Food and Drug Administration Adverse Event Reporting System (FAERS). Design: It is an observational, retrospective, pharmacovigilance study. Methods: Individual Case Safety Reports (ICSRs) were retrieved from FAERS up to September 24, 2024. Cases reporting one or more ICIs (atezolizumab, avelumab, cemiplimab, dostarlimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and tremelimumab) and atrial fibrillation were selected. Disproportionality analyses were performed by applying the reporting odds ratio (ROR) and the Informational Component (IC) with a 95% confidence interval (95% CI). Results: A total of 1228 ICSRs were retrieved, of which 218 (17.75%) were related to combinations of ICIs. Most ICSRs (N = 812; 66.1%) referred to male patients and the age group most represented was ⩾65 years (N = 772; 62.9%). Atrial fibrillation was serious in 99.3% (N = 1220) of cases and had a fatal outcome (N = 248; 20.3%). Atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab were associated with a statistically significant higher reporting frequency of atrial fibrillation compared to all other drugs (ROR: 1.90, IC: 0.91; ROR: 1.94, IC: 0.92; ROR: 1.52, IC: 0.60; ROR: 1.30, IC: 0.38; ROR: 1.66, IC: 0.72, respectively). The anti-CTLA-4 ipilimumab showed a statistically significant lower reporting frequency of atrial fibrillation compared to all other drugs (ROR: 0.69, IC: −0.53) and to all other ICIs (ROR: 0.45, IC: −1.02). Moreover, anti-PD-L1 (ROR: 2.60, IC: 0.47) and anti-PD-1 (ROR: 2.12, IC: 0.16) were associated with a higher reporting of atrial fibrillation compared to anti-CTLA-4. Conclusion: ICI-induced atrial fibrillation was serious and had severe outcomes. The anti-CTLA-4 showed a lower likelihood of reporting atrial fibrillation, while higher reporting was found with anti-PD-1 and anti-PD-L1. Further studies are needed to confirm this safety aspect. Plain language summary Assessing atrial fibrillation reports with immune checkpoint inhibitors: FDA insights Why was the study done? Immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment by stimulating the immune system to fight cancer. However, these drugs can cause side effects, including heart problems such as atrial fibrillation, which is a type of irregular heartbeat. This study aimed to understand how commonly atrial fibrillation occurs in patients using ICIs. What did the researchers do? The research team evaluated the characteristics and reporting frequency of ICIs-related atrial fibrillation by analyzing data from the Food and Drug Administration Adverse Event Reporting System (FAERS) up to September 24, 2024. What did the researchers find? The study found 1,228 reports of atrial fibrillation in patients using ICIs. The majority of cases were serious and involved adult males. The anti-PD-1 and anti-PD-L1 were associated with a higher reporting of atrial fibrillation compared to anti-CTLA-4. Among the individual ICIs assessed, ipilimumab was associated with a lower reporting frequency of atrial fibrillation. On the other hand, atezolizumab showed a high reporting frequency of this event compared to all other drugs. What do the findings mean? The study highlights the importance of monitoring and further investigating the safety profile of ICIs, particularly regarding cardiac events such as atrial fibrillation, which is a serious adverse event with severe outcomes. Further studies are needed to confirm these findings and better understand the underlying mechanisms of ICI-induced atrial fibrillation.

A possible association could exist between type 2 diabetes mellitus (T2DM) and Coronavirus-19 (Covid-19) infection. Indeed, patients with T2DM show high prevalence, severity of disease and mortality during Covid-19 infection. However, the rates of severe disease are significantly higher in patients with diabetes compared with non-diabetes (34.6% vs. 14.2%; p < 0.001). Similarly, T2DM patients have higher rates of need for Intensive Care Unit (ICU, 37.0% vs. 26.7%; p = 0.028). Thus, about the pneumonia of Covid-19, we might speculate that the complicated alveolar-capillary network of lungs could be targeted by T2DM micro-vascular damage. Therefore, T2DM patients frequently report respiratory symptoms and are at increased risk of several pulmonary diseases. In addition, pro-inflammatory pathways as that involving interleukin 6 (IL-6), could be a severity predictor of lung diseases. Therefore, it looks intuitive to speculate that this condition could explain the growing trend of cases, hospitalization and mortality for patients with T2DM during Covid-19 infection. To date, an ongoing experimental therapy with monoclonal antibody against the IL-6 receptor in Italy seems to have beneficial effects on severe lung disease and prognosis in patients with Covid-19 infection. Therefore, should patients with T2DM be treated with more attention to glycemic control and monoclonal antibody against the IL-6 receptor during the Covid-19 infection?

We investigated seasonal prevalence of hyponatremia in the emergency department (ED). A cross-sectional study using clinical chart review. University Hospital ED, with approximately 28 000 patient visits a year. We reviewed 15 049 patients, subdivided in 2 groups: the adult group consisting of 9822 patients aged between 18 and 64years old and the elderly group consisting of 5227 patients aged over 65years presenting to the ED between January 1st, 2014 and December 31st, 2015. Emergency patients were evaluated for the presence of hyponatremia by clinical chart review. Hyponatremia was defined as a serum sodium level<135mmol/l. Mean monthly prevalence of hyponatremia was of 3.74±0.5% in the adult group and it was significantly increased to 10.3±0.7% in the elderly group (p<0.05 vs adults). During the summer, hyponatremia prevalence was of 4.14±0.2% in adult and markedly increased to 12.52±0.7% (zenith) in elderly patients (p<0.01 vs adult group; p<0.05 vs other seasons in elderly group). In the elderly group, we reported a significant correlation between weather temperature and hyponatremia prevalence (r: 0.491; p<0.05). We observed a major influence of climate on the prevalence of hyponatremia in the elderly in the ED. Decline in renal function, salt loss, reduced salt intake and increased water ingestion could all contribute to developing hyponatremia in elderly patients during the summer. These data could be useful for emergency physicians to prevent hot weather-induced hyponatremia in the elderly.

Sarcopenia is a geriatric syndrome characterized by the progressive degeneration of muscle mass and function, and it is associated with severe complications, which are falls, functional decline, frailty, and mortality. Sarcopenia is associated with cognitive impairment, defined as a decline in one or more cognitive domains as language, memory, reasoning, social cognition, planning, making decisions, and solving problems. Although the exact mechanism relating to sarcopenia and cognitive function has not yet been defined, several studies have shown that skeletal muscle produces and secrete molecules, called myokines, that regulate brain functions, including mood, learning, locomotor activity, and neuronal injury protection, showing the existence of muscle-brain cross-talk. Moreover, studies conducted on physical exercise supported the existence of muscle-brain cross-talk, showing how physical activity, changing myokines' circulating levels, exerts beneficial effects on the brain. The review mainly focuses on describing the role of myokines on brain function and their involvement in cognitive impairment in sarcopenia.

The high mortality observed in Covid-19 patients may be related to unrecognized pulmonary embolism, pulmonary thrombosis, or other underlying cardiovascular diseases. Recent data have highlighted that the mortality rate of Covid-19 seems to be higher in male patients compared to females. In this paper, we have analyzed possible factors that may underline this sex difference in terms of activity of the immune system and its modulation by sex hormones, coagulation pattern, and preexisting cardiovascular diseases as well as effects deriving from smoking and drinking habits. Future studies are needed to evaluate the effects of sex differences on the prevalence of infections, including Covid-19, its outcome, and the responses to antiviral treatments.

Leukocyte telomere length (LTL) and rate of telomere shortening are known biomarkers of aging while, numerous studies showed that Mediterranean diet (MD) may boost longevity. We studied association between telomere length, telomerase activity and different adherence to MD and its effects on healthy status. The study was conducted in 217 elderly subjects stratified according Mediterranean diet score (MDS) in low adherence (MDS≤3), medium adherence (MDS 4-5) and high adherence (MDS≥6) groups. LTL was measured by quantitative polymerase chain reaction and telomerase activity by a PCR-ELISA protocol. High adherence group showed longer LTL (p = 0.003) and higher telomerase activity (p = 0.013) compared to others. Linear regression analysis including age, gender, smoking habit and MDS showed that MDS was independently associated with LTL (p = 0.024) and telomerase activity levels (p = 0.006). Telomerase activity was independently associated with LTL (p = 0.007) and negatively modulated by inflammation and oxidative stress. Indeed, telomerase levels were associated with healthy status independently of multiple covariates (p = 0.048). These results support a novel role of MD in promoting health-span suggesting that telomere maintenance, rather than LTL variability is the major determinant of healthy status among elderly.

Background Several evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated the molecular processes underlying the protective effect of Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA)/ GLP-1RA, against learning and memory disorders. Methods We investigated the effects of TIR on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3 and SORBS1) in a neuroblastoma cell line (SHSY5Y) exposed to normal and high glucose concentration. The potential role on DNA methylation of genes involved in neuroprotection and epigenetic modulators of neuronal growth (miRNA 34a), apoptosis (miRNA 212), and differentiation (miRNA 29c) was also investigated. The cell proliferation was detected by measuring Ki-67 through flow cytometry. The data were analysed by SPSS IBM Version 23 or GraphPad Prism 7.0 software and expressed as the means ± SEM. Differences between the mean values were considered significant at a p-value of < 0.05. GraphPad Prism software was used for drawing figures. Results For the first time, it was highlighted: (a) the role of TIR in the activation of the pAkt/CREB/BDNF pathway and the downstream signaling cascade; (b) TIR efficacy in neuroprotection; (c) TIR counteracting of hyperglycemia and insulin resistance-related effects at the neuronal level. Conclusions We demonstrated that TIR can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance. Thus, this study provides new insight into the potential role of TIR in improving diabetes-related neuropathy. Graphical Abstract