Advanced Hybrid Closed-Loop System Achieves and Maintains Recommended Time in Range Levels for Up To 2 Years: Predictors of Best Efficacy.

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 <53 mmol/mol (7.0%). At univariable logistic regression older age, lower baseline HbA1c and insulin requirement were associated with mean TIR >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.

Does denosumab exert a protective effect against COVID-19? Results of a large cohort study.

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.

Cardioprotective Effects of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension Are Mediated by the Local Reduction of Sympathetic Activity and Inflammation.

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.

The diagnostic performances of the Atellica® 1500 automated urinalysis system for ruling out bacterial urinary tract infection.

Urinary tract infection (UTI) is one of the most common diseases occurring in both hospitalized and community subjects. Urine culture is the gold standard test for the diagnosis of UTI, but approximately 80% are negative. The aim of this study was to evaluate the performance of the automated urinalysis system Atellica® 1500 (Siemens Healthineers, Erlangen, Germany) as screening tool for ruling out UTI. A total of 5,490 urine specimens from outpatients, that had simultaneous requests for urinalysis and urine culture, were evaluated. Of the 5,490 samples, 833 (15.2 %) resulted positive for urine culture. Among UTI-related parameters, bacterial count was considered the most apt to be diagnostic of subjects affected by UTI. Using a cutoff value for bacteria count equal to 180 elements/µL, Atellica® 1500 detected bacteriuria with diagnostic sensitivity (Se) of 88.1 %, diagnostic specificity (Sp) of 82.1 %, and negative predictive value (NPV) of 95.2 %. Comparing our results with the literature's data, we observed that our Se and NPV were lower, while our Sp was higher. Our data showed that the Atellica® 1500 system detected bacteria with satisfactory analytical performance, but the results obtained do not make it a reliable tool for excluding UTI with urinalysis.

Investigating the "Fetal Side" in Recurrent Pregnancy Loss: Reliability of Cell-Free DNA Testing in Detecting Chromosomal Abnormalities of Miscarriage Tissue.

(1) Background: The aim of our study is to evaluate whether cell-free DNA testing can overlap the genetic testing of miscarriage tissue in women with early pregnancy loss (EPL) and length of recurrent pregnancy loss (RPL); (2) Methods: We conducted a prospective cohort study at the Pregnancy Loss Unit of the Fondazione Policlinico Universitario A. Gemelli (IRCCS), Rome, Italy between May 2021 and March 2022. We included women with EPL and length of RPL. Gestational age was >9 weeks + 2 days and <12 weeks + 0 days of gestation corresponding to a crown rump length measurement of >25 and <54 mm. Women underwent both dilation and curettage for the collection of miscarriage tissue and for blood sample collection. Chromosomal microarray analysis (CMA) on miscarriage tissues was performed by oligo-nucleotide- and single nucleotide polymorphisms (SNP)-based comparative genomic hybridization (CGH+SNP). Maternal blood samples were analyzed by Illumina VeriSeq non-invasive prenatal testing (NIPT) to evaluate the cell-free fetal DNA (cfDNA) and the corresponding fetal fraction and the presence of genetic abnormalities; (3) Results: CMA on miscarriage tissues revealed chromosome aneuploidies in 6/10 cases (60%), consisting of trisomy 21 (5 cases) and monosomy X (one case). cfDNA analysis was able to identify all cases of trisomy 21. It failed to detect monosomy X. A large 7p14.1p12.2 deletion concomitant to trisomy 21 was, in one case, detected by cfDNA analysis but it was not confirmed by CMA on miscarriage tissue. (4) Conclusions: cfDNA largely reproduces the chromosomal abnormalities underlying spontaneous miscarriages. However, diagnostic sensitivity of cfDNA analysis is lower with respect to the CMA of miscarriage tissues. In considering the limitations when obtaining biological samples from aborted fetuses suitable for CMA or standard chromosome analysis, cfDNA analysis is a useful, although not exhaustive, tool for the chromosome diagnosis of both early and recurrent pregnancy loss.

Increased prevalence of autoimmune thyroid disease after COVID-19: A single-center, prospective study.

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-CoV-2 in eliciting thyroid autoimmunity.

Diagnostic factors for recurrent pregnancy loss: an expanded workup.

PURPOSE: There is limited information on the risk factors for recurrent pregnancy loss (RPL). METHODS: In this study, a patient-based approach was used to investigate the possible involvement and relative relevance of a large number of diagnostic factors in 843 women with RPL who underwent an extensive diagnostic workup including 44 diagnostic factors divided into 7 major categories. RESULTS: The rates of abnormalities found were: (1) genital infections: 11.74%; (2) uterine anatomic defects: 23.72%; (3) endocrine disorders: 29.42%; (4) thrombophilias: 62%; (5) autoimmune abnormalities: 39.2%; (6) parental karyotype abnormalities 2.25%; (7) clinical factors: 87.78%. Six hundred and fifty-nine out of eight hundred and forty-three women (78.17%) had more than one abnormality. The mean number of pregnancy losses increased by increasing the number of the abnormalities found (r = 0.86949, P < 0.02). The factors associated with the highest mean number of pregnancy losses were cervical isthmic incompetence, anti-beta-2-glycoprotein-1 antibodies, unicornuate uterus, anti-prothrombin A antibodies, protein C deficiency, and lupus anticoagulant. The majority of the considered abnormalities had similar, non-significant prevalence between women with 2 versus ≥ 3 pregnancy losses with the exception of age ≥ 35 years and MTHFR A1298C heterozygote mutation. No difference was found between women with primary and secondary RPL stratified according to the number of abnormalities detected (Chi-square: 8.55, P = 0.07). In these women, the only factors found to be present with statistically different rates were age ≥ 35 years, cigarette smoking, and genital infection by Ureaplasma. CONCLUSION: A patient-based diagnostic approach in women with RPL could be clinically useful and could represent a basis for future research.

Antiphospholipid Syndrome in Pregnancy: New and Old Pathogenetic Mechanisms.

The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized, according to the Sydney criteria, by the persistent presence of autoantibodies directed against phospholipid-binding proteins associated with thrombosis and/or obstetrical complications. The most frequent complications in obstetric antiphospholipid syndrome are recurrent pregnancy losses and premature birth due to placental insufficiency or severe preeclampsia. In recent years, vascular APS (VAPS) and obstetric APS (OAPS) have been described as two different clinical entities. In VAPS, antiphospholipid antibodies (aPL) interfere with the mechanisms of coagulation cascade and the 'two hit hypothesis' has been suggested to explain why aPL positivity does not always lead to thrombosis. OAPS seems to involve additional mechanisms, such as the direct action of anti-ß2 glycoprotein-I on trophoblast cells that can lead to a direct placental functional damage. Furthermore, new actors seem to play a role in the pathogenesis of OAPS, including extracellular vesicles, micro-RNAs and the release of neutrophil extracellular traps. The aim of this review is to investigate the state-of-the-art antiphospholipid syndrome pathogenesis in pregnancy, in order to provide a comprehensive overview of both old and new pathogenetic mechanisms involved in this complex disease.

Sperm DNA fragmentation and idiopathic recurrent pregnancy loss: Results from a multicenter case-control study.

BACKGROUND: Sperm DNA fragmentation was hypothesized to have a role in the pathogenesis of recurrent pregnancy loss. Unfortunately, the quality of already published evidence is low. OBJECTIVES: To investigate the association between sperm DNA fragmentation and idiopathic recurrent pregnancy loss by limiting, as much as possible, the interference of confounding factors. MATERIALS AND METHODS: This was a retrospective multicenter case-control study conducted in two Italian University Hospitals (i.e., Policlinico Gemelli, Rome and Humanitas S. Pio X, Milan) from July 2020 to March 2022. Cases were men belonging to couples affected by first trimester idiopathic recurrent pregnancy loss, defined as the previous loss of two or more pregnancies. Two control groups were selected: (i) men belonging to couples with proven fertility (i.e., at least two previous full-term pregnancies) (control group A); (ii) men belonging to couples with proven infertility (i.e., the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse) (control group B). The sperm DNA fragmentation index was measured by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. RESULTS: We included 74 cases, 37 men with proven fertility (control group A) and 100 men belonging to infertile couples (control group B). The median sperm DNA fragmentation index was significantly lower in control group A (17%, interquartile range: 14.3%-20.6%) compared to both case group (24.5%, interquartile range: 17%-32%; p < 0.0001) and control group B (24%, interquartile range: 18.9%-30%; p = 0.001). The rate of subjects with sperm DNA fragmentation index greater than 30% was significantly higher in both case groups (28%, 95% confidence interval [18%-40%]) and control group B (26%, 95% confidence interval [18%, 36%]) compared to control group A (0%, 95% confidence interval [0%-10%]) (p < 0.001). Multivariate regression models yielded a significant association between sperm DNA fragmentation index and recurrent pregnancy loss (adjusted odds ratio 1.13, 95% confidence interval [1.04-1.23], p = 0.006), but failed to show an association between sperm DNA fragmentation index and infertility (adjusted odds ratio 1.13, 95% CI [1-1.29], p = 0.05). CONCLUSIONS: Men within couples affected by recurrent pregnancy loss or infertility had a significantly higher rate of sperm DNA fragmentation compared to fertile controls. However, after adjusting for covariates, sperm DNA fragmentation index was associated only with recurrent pregnancy loss.

Celiac Disease Predisposition and Genital Tract Microbiota in Women Affected by Recurrent Pregnancy Loss.

The incidence of Idiopathic Recurrent Pregnancy Loss (RPL) is doubled in patients suffering from Celiac Disease (CD) compared to healthy populations. CD genetic components are HLA class II genes known as HLA-DQ2 and DQ8. Genetically susceptible women can remain asymptomatic even though they are exposed to a doubled risk of RPL compared to the general population. Furthermore, CD has been associated with microbiota alterations. The aim of this study is to evaluate endometrial and vaginal microbiota in HLA-DQ2/DQ8 positive and negative RPL patients compared to healthy pregnant women. Endometrial and vaginal microbiota of 3 subgroups were evaluated: 15 HLA-DQ2/DQ8 positive RPL women, 25 HLA DQ2/DQ8 negative RPL women (for a total of 40 RPL women) and 7 healthy fertile controls with previous uncomplicated pregnancies (all HLA-DQ2/DQ8 negative). The 2 RPL subgroups (HLA-DQ2/DQ8 positive and negative) showed a different endometrial and vaginal composition in the Lactobacillacae family compared to controls: Lactobacillus acidophilus was absent both in the vaginal and endometrial samples of RPL women, while Lactobaciluus iners, which can favor a less stable vaginal microbiota, was found only in RPL women (26.4% in HLA DQ2/DQ8 positive and 22.1% HLA DQ2/DQ8 negative) in both the vaginal and endometrial districts. In conclusion, both HLA DQ2/DQ8 positive-RPL and HLA DQ2/DQ8 negative-RPL women showed different endometrial and vaginal microbiota composition compared to healthy controls.

Angiotensin II Modulates Calcium/Phosphate Excretion in Experimental Model of Hypertension: Focus on Bone.

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.

Possible Use of Minocycline in Adjunction to Intranasal Esketamine for the Management of Difficult to Treat Depression following Extensive Pharmacogenomic Testing: Two Case Reports.

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.

The Relationship Between Maternal and Neonatal Microbiota in Spontaneous Preterm Birth: A Pilot Study.

The newborn's microbiota composition at birth seems to be influenced by maternal microbiota. Maternal vaginal microbiota can be a determining factor of spontaneous Preterm Birth (SPPTB), the leading cause of perinatal mortality. The aim of the study is to investigate the likelihood of a causal relationship between the maternal vaginal microbiota composition and neonatal lung and intestinal microbiota profile at birth, in cases of SPPTB. The association between the lung and/or meconium microbiota with the subsequent development of bronchopulmonary dysplasia (BPD) was also investigated. Maternal vaginal swabs, newborns' bronchoalveolar lavage fluid (BALF) (1st, 3rd, 7th day of life) and first meconium samples were collected from 20 women and 23 preterm newborns with gestational age ≤ 30 weeks (12 = SPPTB; 11 = Medically Indicated Preterm Birth-MIPTB). All the samples were analyzed for culture examination and for microbiota profiling using metagenomic analysis based on the Next Generation Sequencing (NGS) technique of the bacterial 16S rRNA gene amplicons. No significant differences in alpha e beta diversity were found between the neonatal BALF samples of SPPTB group and the MIPTB group. The vaginal microbiota of mothers with SPPTB showed a significant difference in alpha diversity with a decrease in Lactobacillus and an increase in Proteobacteria abundance. No association was found between BALF and meconium microbiota with the development of BPD. Vaginal colonization by Ureaplasma bacteria was associated with increased risk of both SPPTB and newborns' BPD occurrence. In conclusion, an increase in α-diversity values and a consequent fall in Lactobacillus in vaginal environment could be associated to a higher risk of SPPTB. We could identify neither a specific neonatal lung or meconium microbiota profiles in preterm infants born by SPPTB nor a microbiota at birth suggestive of subsequent BPD development. Although a strict match has not been revealed between microbiota of SPPTB mother-infant couples, a relationship cannot be excluded. To figure out the reciprocal influence of the maternal-neonatal microbiota and its potential role in the pathogenesis of SPPTB and BPD further research is needed.

Psychological complications in patients with acromegaly: relationships with sex, arthropathy, and quality of life.

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.

Intestinal Permeability and Dysbiosis in Female Patients with Recurrent Cystitis: A Pilot Study.

Recurrent cystitis (RC) is a common disease, especially in females. Anatomical, behavioral and genetic predisposing factors are associated with the ascending retrograde route, which often causes bladder infections. RC seems to be mainly caused by agents derived from the intestinal microbiota, and most frequently by Escherichia coli. Intestinal contiguity contributes to the etiopathogenesis of RC and an alteration in intestinal permeability could have a major role in RC. The aim of this pilot study is to assess gut microbiome dysbiosis and intestinal permeability in female patients with RC. Patients with RC (n = 16) were enrolled and compared with healthy female subjects (n = 15) and patients with chronic gastrointestinal (GI) disorders (n = 238). We calculated the Acute Cystitis Symptom Score/Urinary Tract Infection Symptom Assessment (ACSS/UTISA) and Gastrointestinal Symptom Rating Scale (GSRS) scores and evaluated intestinal permeability and the fecal microbiome in the first two cohorts. Patients with RC showed an increased prevalence of gastrointestinal symptoms compared with healthy controls. Of the patients with RC, 88% showed an increased intestinal permeability with reduced biodiversity of gut microbiota compared to healthy controls, and 68% of the RC patients had a final diagnosis of gastrointestinal disease. Similarly, GI patients reported a higher incidence of urinary symptoms with a diagnosis of RC in 20%. Gut barrier impairment seems to play a major role in the pathogenesis of RC. Further studies are necessary to elucidate the role of microbiota and intestinal permeability in urinary tract infections.

Pre-existing Thyroid Autoimmunity and Risk of Papillary Thyroid Cancer: A Nested Case-Control Study of US Active-Duty Personnel.

PURPOSE: Thyroid autoimmunity has been associated with differentiated thyroid cancer although multiple potential biases might have influenced the results of previous studies. METHODS: We conducted a case-control study nested within the cohort of US active-duty personnel 1996-2014 to assess the association between thyroid autoimmunity, defined by serology, and thyroid cancer diagnosis. The primary exposure was thyroid peroxidase (TPO) antibody status 7-10 years before the thyroid cancer index date. We also assessed whether diagnosis of thyroid autoimmunity mediated any associations identified and if thyroid cancer features differed by autoimmunity status. RESULTS: Among 451 incident cases of papillary thyroid cancer and matched controls (median age 36 years, 61.4% men), TPO antibody positivity (v negative) 7-10 years prediagnosis was associated with thyroid cancer (odds ratio [OR] 1.90 [95% CI, 1.33 to 2.70]). Exploratory analyses suggested an increasing risk of thyroid cancer with higher TPO antibody titer (TPO antibody 550-1,399 IU/mL: OR 2.95 [95% CI, 1.37 to 6.36]; and ≥ 1,400 IU/mL: OR 3.91 [95% CI, 1.66 to 9.24]). Positive TPO antibody status remained associated with thyroid cancer after those with diagnosed autoimmunity were excluded, and the association was not mediated by diagnosis of thyroid autoimmunity. Among the cases with diagnosed autoimmunity, 58% thyroid cancers were ≤ 10 mm diameter. CONCLUSION: Longstanding prior thyroid autoimmunity up to 10 years before thyroid cancer diagnosis was associated with papillary thyroid cancer risk. The results could not be fully explained by diagnosis of thyroid autoimmunity although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage.

Management of Graves' hyperthyroidism: present and future.

INTRODUCTION: Graves' disease (GD) is an autoimmune disorder due to loss of tolerance to the thyrotropin receptor (TSHR) and ultimately caused by stimulatory TSHR antibodies (TSHR-Ab). GD may be associated with extrathyroidal manifestations, mainly Graves' orbitopathy. Treatment of GD relies on antithyroid drugs (ATDs), radioactive iodine (RAI), thyroidectomy. The major ATD limitation is the high recurrence rate after treatment. The major drawback of RAI and thyroidectomy is the inevitable development of permanent hypothyroidism. AREAS COVERED: Original articles, clinical trials, systematic reviews, meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, management of Graves' disease, antithyroid drugs, radioactive iodine, thyroidectomy, Graves' orbitopathy, thyroid-eye disease. EXPERT OPINION: ATDs are the first-line treatment worldwide, are overall safe and usually given for 18-24 months, long-term treatment may decrease relapses. RAI is safe, although associated with a low risk of GO progression, particularly in smokers. Thyroidectomy requires skilled and high-volume surgeons. Patients play a central role in the choice of treatment within a shared decision-making process. Results from targeted therapies acting on different steps of the autoimmune process, including iscalimab, ATX-GD-59, rituximab, blocking TSHR-Ab, small molecules acting as antagonists of the TSHR, are preliminary or preclinical, but promising in medium-to-long perspective.

Is There a Role for SARS-CoV-2/COVID-19 on the Female Reproductive System?

Coronavirus disease (COVID-19) has emerged as a very serious pandemic caused by the rapidly evolving transmission of the coronavirus SARS-CoV-2. Since its outbreak in 2020, the SARS CoV-2 has represented an important challenge for the physicians due to its well known respiratory sequelae. To date, the role of SARS-CoV-2 infection on organs and systems other than lungs and respiratory tract remains less clear. In particular, it remains to be investigated whether the reproductive system can be affected by the SARS-CoV-2 in the long term-period or, in alternative, drugs used to treat COVID-19 might impact the reproductive systems and, in turn, fertility. What is known is that SARS-Cov-2 binds to target cells of host through different receptors including angiotensin-converting enzyme 2 (ACE2), neuropilin-1, AXL and antibody-FcɣR complexes. ACE2 physiologically regulates both the expression of angiotensin II (Ang II) as well as Ang-(1-7) to exerts its physiological functions. The reproductive system abundantly expresses ACE2 and produces Ang-(1-7), starting from precursors which are locally generated or derived from systemic circulation. Ang-(1-7) plays an important role of stimulus to the growth and maturation of ovarian follicle as well as to ovulation. Also human endometrium expresses Ang-(1-7), mainly during the post-ovulatory phase. Animal and human observational studies demonstrated that Ang-(1-7) is involved in the maternal immune response to pregnancy and its deficiency is associated with a defective placenta development. In our manuscript, we review the current knowledge about whether SARS-CoV-2 may impact the female reproductive system. We further explain the possible molecular mechanism by which SARS-CoV-2 might affect ovarian, endometrial and female genital tract cells.