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Aim: To evaluate the long-term efficacy, up to 2 years, of an advanced hybrid closed-loop (AHCL) system and to assess predictors of best results of the therapy. Methods: We retrospectively evaluated 296 adults with type 1 diabetes mellitus [mean age 42.8 - 16.5 years, men 42.9%, duration of diabetes 22.5 - 12.8 years, body mass index 24.9 - 4.7 kg/m2, baseline glycated hemoglobin (HbA1c) 63.4 - 12.2 mmol/mol (8.0 - 1.1%) ] who used the MiniMed_ 780G system. Demographic and clinical data were recorded. Continuous glucose monitoring (CGM)-derived metrics and insulin requirement were analyzed from the 4 weeks before and from every quarter after the switch to the AHCL system. Results: In the first quarter of AHCL treatment, all CGM metrics improved. Time in range (TIR) increased from 58.1 - 17.5% to 70.3 - 9.5% (P < 0.0001). The improvement lasted for up to 2 years of observation regardless of previous insulin therapies. Throughout the period of observation, 53.4% of participants achieved mean TIR >70%, 92.6% mean time below range <4%, and 46% mean glucose management indicator [removed]70%. At multivariable analysis, lower HbA1c remained independently associated with a better glycemic control. However, mean TIR increased more in participants with a higher baseline HbA1c. Conclusions: Switching to an AHCL leads to a rapid improvement in glycemic control lasting for up to 24 months along with a low risk for hypoglycemia, confirming the safety of the system. Lower baseline HbA1c was the main predictor of better efficacy of therapy, although higher baseline HbA1c was associated with the greatest improvement in mean TIR.

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels.

Purpose: Current treatment of acromegaly restores a normal life expectancy in most cases. So, the study of persistent complications affecting patients’ quality of life (QoL) is of paramount importance, especially motor disability and depression. In a large cohort of acromegalic patients we aimed at establishing the prevalence of depression, to look for clinical and sociodemographic factors associated with it, and to investigate the respective roles (and interactions) of depression and arthropathy in influencing QoL. Methods: One hundred and seventy-one acromegalic patients (95 women and 76 men, aged 20–85 years) among those recruited in a cross-sectional Italian multicentric study were investigated. Each patient filled in three validated questionnaires: AcroQoL, WOMAC (measuring articular pain, stiffness and functionality), and AIMS (evaluating articular symptoms and depression). Results: A very high (up to 28%) depression rate was detected in acromegalic subjects. Two patients showing pathological AIMS depression scores, committed suicide during the three years observational period. In our population poor psychological status was significantly associated with female sex. Furthermore, a significant strong correlation was found between AIMS depression score and WOMAC score. Both depression and arthropathy-related motor disability turned out to independently contribute with similar strength to the impairment of QoL. Conclusions: We report a high prevalence of depression in acromegaly, which is associated with female sex and arthropathy. Both depression and arthropathy strongly and independently contribute to the impaired QoL of patients. Our study shows that assessment and monitoring of psychological status is mandatory in acromegaly, also suggesting an inexpensive tool for this assessment.

The advent of intra-nasal esketamine (ESK), one of the first so called fast-acting antidepressant, promises to revolutionize the management of treatment resistant depression (TRD). This NMDA receptor antagonist has proven to be rapidly effective in the short- and medium-term course of the illness, revealing its potential in targeting response in TRD. Although many TRD ESK responders are able to achieve remission, a considerable portion of them undergo a metamorphosis of their depression into different clinical presentations, characterized by instable responses and high recurrence rates that can be considered closer to the concept of Difficult to Treat Depression (DTD) than to TRD. The management of these DTD patients usually requires a further complex multidisciplinary approach and can benefit from the valuable contribution of new personalized medicine tools such as therapeutic drug monitoring and pharmacogenetics. Despite this, these patients usually come with long and complex previous treatments history and, often, advanced and sophisticated ongoing pharmacological schemes that can make the finding of new alternative options to face the current recurrences extremely challenging. In this paper, we describe two DTD patients—already receiving intranasal ESK but showing an instable course—who were clinically stabilized by the association with minocycline, a semisynthetic second-generation tetracycline with known and promising antidepressant properties.

Introduction: Denosumab is a monoclonal antibody blocking the receptor activator of nuclear factor kappa-B/receptor activator of nuclear factor kappa-B ligand (RANK/RANKL) pathway, thus inhibiting osteoclastogenesis. Since RANK and RANKL are also involved in the immune system activation, denosumab might interfere with the response against infections. Our study aimed to explore the relationship between denosumab treatment and coronavirus disease 2019 (COVID-19). Design and methods: The occurrence and severity of COVID-19 were recorded in consecutive patients referred to the Endocrinology Department of Papa Giovanni XXIII Hospital, Bergamo, from 1 January 2020 to 1 January 2021. Patients treated with denosumab were compared to outpatient controls. Patients’ features were summarized by descriptive statistics. Multivariate logistic regression assessed the relationship between denosumab and COVID-19, adjusting for potential confounders. Subgroup analyses according to age, sex, body mass index (BMI), smoking status, and vitamin D levels were performed. Results: The final population included 331 patients treated with denosumab and 357 controls. COVID-19 incidence was lower in the denosumab group (7.6% vs. 14.6%, p = 0.004). COVID-19 severity was similar in both groups. Multiple logistic regression confirmed an association between denosumab and a reduced occurrence of symptomatic COVID-19 [odds ratio (OR) 0.46, 95% CI 0.21–0.98, p = 0.049]. Subgroup analyses suggested a potential protective effect of denosumab in patients over 75 years (OR 0.12, 95% CI 0.02–0.6, p = 0.011), with a significant interaction between denosumab and age categories (p = 0.047). Conclusion: Our study confirms that denosumab may be safely continued in COVID-19 patients. RANK/RANKL inhibition seems associated with a reduced incidence of symptomatic COVID-19, particularly among the elderly.

Introduction: Thyroid dysfunctions associated with SARS-CoV-2 acute infection have been extensively described since the beginning of COVID-19 pandemics. Conversely, few data are available on the occurrence of thyroid autoimmunity after COVID-19 resolution. We assessed the prevalence of autoimmune thyroid disease (ATD) and thyroid dysfunctions in COVID-19 survivors three months after hospital admission. Design and methods: Single-center, prospective, observational, cohort study performed at ASST Papa Giovanni XXIII Hospital, Bergamo, Italy. 599 COVID-19 survivors were prospectively evaluated for thyroid function and autoimmunity thyroperoxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb). When a positive antibody concentration was detected, thyroid ultrasound was performed. Multiple logistic regression model was used to estimate the association between autoimmunity and demographic characteristics, respiratory support, and comorbidities. Autoimmunity results were compared to a cohort of 498 controls referred to our Institution for non-thyroid diseases before the pandemic onset. A sensitivity analysis comparing 330 COVID-19 patients with 330 age and sex-matched controls was performed. Results: Univariate and multivariate analysis found that female sex was positively associated (OR 2.01, SE 0.48, p = 0.003), and type 2 diabetes (T2DM) was negatively associated (OR 0.36, SE 0.16, p = 0.025) with thyroid autoimmunity; hospitalization, ICU admission, respiratory support, or COVID-19 treatment were not associated with thyroid autoimmunity (p > 0.05). TPOAb prevalence was greater in COVID-19 survivors than in controls: 15.7% vs 7.7%, p = 0.002. Ultrasonographic features of thyroiditis were present in 94.9% of the evaluated patients with positive antibodies. TSH was within the normal range in 95% of patients. Conclusions: Autoimmune thyroid disease prevalence in COVID-19 survivors was doubled as compared to age and sex-matched controls, suggesting a role of SARS-Co

Aims: Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, are nephroprotective in case of diabetes, but whether a similar beneficial effect may be detectable also in case of chronic non-diabetic kidney diseases remains still unknown. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, on the progression of cyclosporine nephropathy, in the absence of diabetes. Methods: Sprague Dawley rats (n = 27) have been fed with low-salt diet starting 10 days before the beginning and finished at the end of the experimental period. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection, n = 8) and CsA plus empagliflozin (Empa, 10 mg/kg/day, per os, n = 7) were administered for 4 weeks. The control groups were treated with placebo (Control, n = 7) or empagliflozin (Control + Empa, n = 5). Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental period. At the end of the experimental protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages), type I and type IV collagen expression, and tyrosine hydroxylase expression, used as marker of sympathetic nerve activity. Results: CsA-treated rats showed a significant increase (p < 0.01) in blood pressure, which was reduced by administration of empagliflozin (p < 0.05). CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p < 0.05), renal inflammatory infiltrates (p < 0.05), type I and type IV collagen expression (p < 0.01), and tyrosine hydroxylase expression (p < 0.01) as compared to the control rats and control + Empa-treated rats. Treatment with empagliflozin in CsA-treated rats reduced glomerular (p < 0.01) and tubulo-interstitial fibrosis (p < 0.05), type I and type IV collagen expression (p < 0.01), inflammatory cell infiltr

Background: Clinical trials have shown that empagliflozin (Empa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, promotes nephroprotective effects in diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is not known whether the renal beneficial action is present even in non-diabetic kidney disease. The aim of this study was to evaluate the effect of Empa administration on the development of renal fibrosis in an experimental model of angiotensin II (Ang II)-dependent hypertension. Methods: Sprague Dawley rats (n = 31) were divided into 4 experimental groups. Ang II (200 ng/kg/min, osmotic minipumps, s.c., n = 9) or Ang II + Empa (10 mg/kg/day, per os, n = 10) were administered for 2 weeks. Control rats were treated with placebo (physiological saline, n = 6), and another group was treated with placebo plus Empa (n = 6) for the same period. Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental protocol. After 2 weeks, the rats were euthanized and the kidneys were excised for histomorphometric evaluation of glomerular and tubulo-interstitial fibrosis and for the immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages) and types I and IV collagen expression. Results: The administration of Ang II resulted in an increase in blood pressure (p < 0.01), glomerular (p < 0.05) and tubulo-interstitial (p < 0.01) fibrosis, renal inflammatory infiltrates (p < 0.01) and type I (p < 0.01) and type IV collagen expression (p < 0.05) compared to the control group. Treatment with Empa did not significantly modify the increase in blood pressure due to Ang II, but prevented the development of renal glomerular and tubulo-interstitial fibrosis, and the increase in inflammatory infiltrates and types I and IV collagen expression in Ang II-treated rats (p < 0.01). Conclusions: These data demonstrate that the treatment with Empa prevents the developmen

Hysteroscopic uterine evacuation of early pregnancy loss using tissue removal devices seems to be a safe and feasible procedure in selected cases. The hysteroscopic approach allows the precise localisation of the gestational sac inside the uterine cavity. The endoscopic approach allows one to perform hysteroembryoscopy before uterine evacuation and this technique appears to be more accurate than dilatation & curettage for fetal chromosome karyotyping, with lower maternal cell contamination. This "under vision" procedure may reduce retained products of conception rates and risk of intrauterine adhesions formation.

A link between hypertension and long-term bone health has been suggested. The aim of this study was to investigate the effects of chronic angiotensin II administration on urinary calcium/phosphate excretion, bone mineral density, bone remodeling and osteoblast population in a well-established experimental model of hypertension, in the absence of possible confounding factors that could affect bone metabolism. Male Sprague–Dawley rats, divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis, n = 8); (b) Ang II+losartan (Los, 50 mg/kg/day, per os, n = 6); (c) control group (physiological saline, sub cutis, n = 9); and (d) control+losartan (n = 6) were treated for four weeks. During the experimental period, 24-hour diuresis, urinary calcium, phosphate and sodium excretion were measured prior to the treatment, at two weeks of treatment, and at the end of the treatment. Systolic blood pressure was measured by plethysmography technique (tail cuff method). At the end of the experimental protocol, the rats were euthanized and peripheral quantitative computed tomography at the proximal metaphysis and at the diaphysis of the tibiae and quantitative bone histomorphometry on distal femora were performed. Angiotensin II-dependent hypertension is associated with increased calcium and phosphate excretion. AT1 receptor blockade prevented the increase of blood pressure and phosphate excretion but did not affect the increase of calcium excretion. These changes took place without significantly affecting bone density, bone histology or osteoblast population. In conclusion, in our experimental conditions, angiotensin II-dependent hypertension gave rise to an increased urinary excretion of calcium and phosphate without affecting bone density.

In the present manuscript, we review the recent research investigating the pathogenic association between most studied autoantibodies and recurrent pregnancy loss. Pregnancy loss represents a common obstetric complication occurring in about 15%-25% of all clinically recognized pregnancies. The recurrence of pregnancy loss identifies a distinct clinical entity, that is recurrent pregnancy loss (RPL), affecting about 2%-4% of couples. Several factors, including age, chromosomal abnormalities, uterine anomalies, thrombophilic disorders, endocrinopathies, hormonal and metabolic disorders, infections, sperm quality, and lifestyle issues, are involved in RPL. The role of autoantibodies in RPL is only partially determined. In some cases (antiphospholipid antibodies [aPL]), their involvement is well established. In other cases (anti-thyroid autoantibodies, antinuclear, anti-transglutaminase, and anti-endomysial antibodies), it is still debated, despite multiple, although not fully conclusive, evidences strongly suggest a possible involvement in RPL. Further extensive research is needed to definitively confirm or exclude their actual role.

OBJECTIVE: The vaginal microbiome is a dynamic environment, depending on the results of a complex interplay between microbiota and the host. In physiological conditions, Lactobacillus species are the most represented, regulating glycogen metabolism in order to maintain normal pH. Vaginal flora has been divided into five subtypes. Pattern recognition receptors are present on both squamous epithelial cells lining the vagina and columnar cells lining the upper female genital tract. They respond directly to bacterial product expressed by vaginal microbiome. The vagina contains different immune related cells and receptors which can recognize and react with the microbial environment. Altered microbiota and altered interplay between microbiota and immune system underlie several gynecologic diseases. MATERIALS AND METHODS: In this review, literature data related to vaginal microbiota, vaginal inflammation, immune system and menopause, preterm labor and miscarriage, were summarized. Relevant publications were retrieved from: PubMed, Medline, Scopus and Web of Science. RESULTS: The vaginal microbiome and the relationship with immune system has been analyzed in different gynecologic conditions. Menopause is associated to estrogen loss which causes vaginal atrophy, reduced abundance of Lactobacilli and increased amount of other bacterial species. Estrogens influence vaginal immunity through known and unknown mechanisms. In bacterial vaginosis (BV), due to many bacterial species, there has been found an inhibition of the chemotaxis and cytokine secretion. A decreased concentration of Lactobacilli seems to be playing a role in preterm labor as well as the increased levels of pro-inflammatory cytokines. Finally, the disequilibrium in theTh1/Th2 immune adaptive response, with a shift from Th2 to Th1, appears to be playing a role in miscarriage. CONCLUSIONS: The interplay between microbiota and the host closely involves the immune system. In particular, the vaginal microbiota is cla

Background: Pinopode expression has been suggested as a marker of endometrial receptivity. Methods: We set up an experimental study comparing endometrial tissue from recurrent pregnancy loss (RPL, n = 30) and fertile control (CTR, n = 20) women in terms of pinopode expression/morphology; expression of thrombomodulin (TM) and ezrin; cytoskeletal organization. Endometrial samples were collected during implantation window and evaluated by scanning electron microscopy, western blot, and immunofluorescence. Results: We found that RPL endometrial tissue showed: (i) increased pinopodes density (* p < 0.05); (ii) a reduced diameter of pinopodes (* p < 0.05); (iii) a decreased TM and ezrin expression (p < 0.05). Additionally, confocal images showed a significantly reduced expression of phosphorylated (p)-ezrin, confirming the results obtained through immunoblot analysis. Immunofluorescence staining showed that in CTR samples, junctions between cells are intact and clearly visible, whereas actin filaments appear completely lost in RPL endometrial samples; this suggests that, due to the impaired expression and activity of TM and ezrin, actin does not bind to plasma membrane in order to orchestrate the cytoskeletal actin filaments. Conclusions: Our findings suggest that an impaired expression of TM and expression/activation of ezrin may aect the connection between the TM and actin cytoskeleton, impairing the organization of cytoskeleton and, eventually, the adequate pinopode development.

Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed people in which the ingestion of gluten leads to damage in the small intestine that clinically presents with malabsorption-related symptoms. CD can also be the underlying cause of several nongastrointestinal symptoms. This review summarizes evidence on the relationship between CD and gynecological/obstetric disorders like reproductive failures. Although much has been reported on such a linkage, the pathogenic mechanisms remain unclear, especially those underlying extra-gastrointestinal clinical manifestations. Studies conducted on celiac subjects presenting gynecological/obstetric disorders have pointed to intestinal malabsorption, coagulation alterations, immune-mediated tissue damage, and endometrial inflammation as the main responsible pathogenic mechanisms. Currently, however, the knowledge of such mechanisms is insufficient, and further studies are needed to gain a more thorough understanding of the matter.

The adaptation of the uterine environment into a favorable immunological and inflammatory milieu is a physiological process needed in normal pregnancy. A uterine hyperinflammatory state, whether idiopathic or secondary to hormonal or organic uterine disorders (polycystic ovary syndromes, endometriosis/adenomyosis and fibroids), negatively influences the interactions between decidua and trophoblast, early in gestation, and between chorion and decidua later in pregnancy. Abnormal activation of uterine inflammatory pathways not only contributes to the pathogenesis of the obstetric syndromes, i.e. recurrent pregnancy loss (RPL), pre-term delivery (PTD) and pre-eclampsia (PE), but also to correlates with severity. In this review, we summarize recent advances in the knowledge of uterine molecular mechanisms of inflammatory modulation in normal pregnancy and obstetric syndromes (RPL, PTD and PE). In particular, we focus on two regulators of uterine/placental inflammation: the NLRP3 inflammasome and the chemokines decoy receptor D6. We performed comprehensive review of the literature in PubMed and Google Scholar databases from 1994 to 2018. The available evidence suggests that: (i) the expression of inflammasome NLRP3 is increased in the endometrium of women with unexplained RPL, in the chorioamniotic membranes of women with PTL and in the placenta of women with PE; (ii) there is a role for abnormal expression and function of D6 decoy receptor at the feto-maternal interface in cases of RPL and PTD and (iii) the function of placental D6 decoy receptor is impaired in PE. A wider comprehension of the inflammatory molecular mechanisms involved in the pathogenesis of the obstetric syndromes might lead to the identification of new potential therapeutic targets.

To determine whether differences are present in the time-to-pregnancy (TTP) between women with unexplained recurrent pregnancy loss (uRPL) and control women, in this case-control, retrospective study, carried out in tertiary university hospitals, the TTP, defined as the months needed to reach pregnancy from when the woman started to try to conceive, was determined in 512 women, 207 of which were diagnosed as having uRPL and 305 were normal healthy control women. The specific TTPs for each pregnancy, stratified by order of pregnancy occurrence, were also determined. Pregnancy rates by time were calculated by using the Kaplan-Meier method to construct the survival curves. The age at which the pregnancies occurred was determined. Comparisons were carried out between women with uRPL and controls. Overall, 1192 pregnancies occurred and were analyzed. Mean TTP in uRPL women was shorter than in controls (P < 0.001) when all the pregnancies were considered. Similarly, it was shorter in the first, second, third, and fifth pregnancy. The pregnancy rates of uRPL women were shorter than that of control women for the first three pregnancies, for which the numbers of subjects allowed the comparisons to be made. These findings were observed despite maternal age of uRPL women was higher than that of control women. TTP is shorter in uRPL than in normal women. This finding clinically supports to the hypothesis that women with uRPL could be, at least in early stages of pregnancy, more fertile or receptive toward the implanting embryo than healthy women.

In recent years, an aberrant gastrointestinal colonization has been found to be associated with an higher risk for postnatal sepsis, necrotizing enterocolitis (NEC) and growth impairment in preterm infants. As a consequence, the reasons of intestinal dysbiosis in this population of newborns have increasingly become an object of interest. The presence of a link between the gut and lung microbiome's development (gut-lung axis) is emerging, and more data show as a gut-brain cross talking mediated by an inflammatory milieu, may affect the immunity system and influence neonatal outcomes. A revision of the studies which examined gut and lung microbiota in preterm infants and a qualitative analysis of data about characteristic patterns and related outcomes in terms of risk of growing impairment, Necrotizing Enterocolitis (NEC), Bronchopulmonary Dysplasia (BPD), and sepsis have been performed. Microbiota take part in the establishment of the gut barrier and many data suggest its immune-modulator role. Furthermore, the development of the gut and lung microbiome (gut-lung axis) appear to be connected and able to lead to abnormal inflammatory responses which have a key role in the pathogenesis of BPD. Dysbiosis and the gut predominance of facultative anaerobes appear to be crucial to the pathogenesis and subsequently to the prevention of such diseases.

In recent years, extended scientific works shed light on the important role played by the endometrium in early pregnancy. This review examines our current knowledge about the delicate balance between microbial and cellular immune agents at endometrial level: All of them might affect endometrial receptivity. In contrast to the classical thinking of human endometrium as a sterile tissue, several recent studies have drawn attention to a resident population of microorganisms, which reaches only a 30% of concordance with those of the cervical‐vaginal flora. At present, the understanding of the microbiome in relation to human reproduction is in its infancy and further studies are needed to clarify the activity of endometrial microbiome and the possible effects of a “reproductive tract dysbiosis” on fertility. Moreover, in the human endometrium, there is a complex system works preventing the risk of infection as well as enabling, when pregnancy occurs, the acceptance of the blastocyst. In this way, the endometrium plays a central role in the uterine immune surveillance. A better understanding of the different agents that may affect endometrial receptivity would improve the diagnosis and treatment of obstetric complications related to defective implantation and placentation.