Efficacy of a training programme for the management of diabetes mellitus in the hospital: A randomized study (stage 2 of GOVEPAZ healthcare).

AIMS: To assess the efficacy of a structured educational intervention for health professionals on the appropriateness of inpatient diabetes care and on some clinical outcomes in hospitalised subjects. METHODS: A multicentre (6 regional hospitals) cluster-randomized (2:1) two parallel-group pragmatic intervention trials, as a part of the GOVEPAZ study, was conducted in three clinical settings, that is, Internal Medicine, Surgery and Intensive Care. Intervention consisted of a 2-month structured education of clinical staff to inpatient diabetes care. Twelve wards - 2 for each hospital - and 6 wards - 1 for each hospital - were randomized to usual care and to the intervention arm, respectively. Consecutively hospitalised diabetic subjects (n = 524, age 74 ± 14 years, 57% males, median HbA1C 57 mmol/mol) were included. The clinical appropriateness of inpatient diabetes management was assessed by a previously validated multi-domain performance score (PS). Clinical outcomes included hypoglycemia, glucose control biomarkers, clinical conditions at discharge and inpatient mortality rate. RESULTS: A numerically, but not statistically significant, higher PS (+0.94; 95% C.I.: -0.53 - +2.4) was achieved in the intervention than in the usual care wards. Hypoglycemias (p = 0.32), glucose control (p = 0.89) and survival rates (p = 0.71) were similar in the two experimental arms. Plasma glucose on admission (OR = 1.52 per 1 SD; C.I. 1.07-2.17; p = 0.021) and the number of hypoglycemic events per patient (OR = 1.55 per 1 SD; C.I.:1.11-2.16; p = 0.011) were independently associated with the inpatient mortality rate. CONCLUSIONS: Structured education of the clinical staff failed to improve the inpatient appropriateness of diabetes care or clinical outcomes. In-hospital hypoglycemia was confirmed to be an independent indicator of death risk.

Diabetes is most important cause for mortality in COVID-19 hospitalized patients: Systematic review and meta-analysis.

The presence of SARS-CoV-2 was officially documented in Europe at the end of February 2020. Despite many observations, the real impact of COVID-19 in the European Union (EU), its underlying factors and their contribution to mortality and morbidity outcomes were never systematically investigated. The aim of the present work is to provide an overview and a meta-analysis of main predictors and of country differences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-associated mortality rate (MR) in hospitalized patients. Out of 3714 retrieved articles, 87 studies were considered, including 35,486 patients (mean age 60.9 ± 8.2 years) and 5867 deaths. After adjustment for confounders, diabetes mellitus was the best predictors of MR in an age- and sex-dependent manner, followed by chronic pulmonary obstructive diseases and malignancies. In both the US and Europe, MR was higher than that reported in Asia (25[20;29] % and 20[17;23] % vs. 13[10;17]%; both p < 0.02). Among clinical parameters, dyspnea, fatigue and myalgia, along with respiratory rate, emerged as the best predictors of MR. Finally, reduced lymphocyte and platelet count, along with increased D-dimer levels, all significantly contributed to increased mortality. The optimization of glucose profile along with an adequate thrombotic complications preventive strategy must become routine practice in diseased SARS-CoV-2 infected patients.

A performance score of the quality of inpatient diabetes care is a marker of clinical outcomes and suggests a cause-effect relationship between hypoglycaemia and the risk of in-hospital mortality.

AIMS: To build a tool to assess the management of inpatients with diabetes mellitus and to investigate its relationship, if any, with clinical outcomes. MATERIALS AND METHODS: A total of 678 patients from different settings, Internal Medicine (IMU, n = 255), General Surgery (GSU, n = 230) and Intensive Care (ICU, n = 193) Units, were enrolled. A work-flow of clinical care of diabetes was created according to guidelines. The workflow was divided into five different domains: (a) initial assessment; (b) glucose monitoring; (c) medical therapy; (d) consultancies; (e) discharge. Each domain was assessed by a performance score (PS), computed as the sum of the scores achieved in a set of indicators of clinical appropriateness, management and patient empowerment. Appropriate glucose goals were included as intermediate phenotypes. Clinical outcomes included: hypoglycaemia, survival rate and clinical conditions at discharge. RESULTS: The total PS and those of initial assessment and glucose monitoring were significantly lower in GSU with respect to IMU and ICU (P < .0001). The glucose monitoring PS was associated with lower risk of hypoglycaemia (OR = 0.55; P < .0001), whereas both the PSs of glucose monitoring and medical therapy resulted associated with higher in-hospital survival only in the IMU ward (OR = 6.67 P = .001 and OR = 2.38 P = .03, respectively). Instrumental variable analysis with the aid of PS of glucose monitoring showed that hypoglycaemia may play a causal role in in-hospital mortality (P = .04). CONCLUSIONS: The quality of in-hospital care of diabetes may affect patient outcomes, including glucose control and the risk of hypoglycaemia, and through the latter it may influence the risk of in-hospital mortality.

Impact of Metabolically Healthy Obesity in Patients with Andrological Problems.

BACKGROUND: Although the pathogenic role of metabolically complicated obesity (MCO) in erectile dysfunction (ED), major adverse cardiovascular events (MACE), and male infertility has been widely studied, that of metabolically healthy obesity (MHO) has been poorly investigated. AIM: To assess the role of MHO in the pathogenesis of ED, prediction of MACE, and male reproductive health. METHODS: A consecutive series of 4,945 men (mean age, 50.5 ± 13.5 years) with sexual dysfunction (SD) (cohort 1) and 231 male partners of infertile couples (mean age, 37.9 ± 9.1 years; cohort 2) were studied. A subset of men with SD (n = 1,687) was longitudinally investigated to evaluate MACE. All patients underwent clinical, biochemical, erectile function, and flaccid penile color Doppler ultrasound (PCDU) assessment. Infertile men also underwent scrotal and transrectal ultrasound; semen analysis, including interleukin (IL-) 8; and prostatitis-like symptom assessment. MHO was defined as body mass index >30 kg/m2 with high-density lipoprotein cholesterol level >40 mg/dL and absence of diabetes or hypertension. The rest of the obesity sample was defined as MCO. MHO or MCO were compared with the rest of the sample, defined as normal weight (NW) individuals. OUTCOMES: Clinical, biochemical, erectile, and PCDU assessment in MHO, MCO and NW men in both cohorts; longitudinal MACE incidence assessment in cohort 1. RESULTS: In cohort 1, 816 men (16.5%) were obese, 181 (3.7%) were MHO, and 635 (12.8%) were MCO. In cohort 2, 68 men (28.4%) were obese, 19 (8.2%) were MHO, and 49 (21.2%) were MCO. After adjusting for confounders, in both samples, the men with MHO and MCO had lower total testosterone levels and worse PCDU parameters compared with the NW men. However, only MCO men had worse erectile function compared with NW men. In the longitudinal study, both MHO and MCO men independently had a higher incidence of MACE compared with NW men (P < .05 for both). In cohort 2, MHO and MCO men had a larger prostate volume, and MCO men also had higher ultrasound and biochemical (IL-8) features of prostatic inflammation compared with NW men, but no differences in prostatitis-like symptoms or seminal parameters. CLINICAL IMPLICATIONS: MHO men should be considered at high cardiovascular risk like MCO men and followed-up for erectile dysfunction and prostate abnormalities overtime. STRENGTHS & LIMITATIONS: The study simultaneously examined several endpoints with validated instruments within 2 different male populations, 1 with SD and 1 with infertility. As for limitations, there is no consensus in the scientific community regarding the definition of MHO, and the results are derived from patients with SD or infertility, which could have different characteristics than the general male population. CONCLUSION: MHO is associated with subclinical ED, increased cardiovascular risk, and prostate enlargement. Lotti F, Rastrelli G, Maseroli E, et al. Impact of Metabolically Healthy Obesity in Patients with Andrological Problems. J Sex Med 2019:16;821-832.

Hyponatremia, falls and bone fractures: A systematic review and meta-analysis.

OBJECTIVE: To perform a meta-analysis based on published studies that compared falls and bone fractures between patients with and without hyponatremia. CONTEXT: There is evidence suggesting that hyponatremia is associated with an increased risk of falls and bone fractures. DESIGN: An extensive Medline, Embase and Cochrane search was performed to retrieve all studies published up to, 30 April 2017, using the following words: "hyponatremia" or "hyponatraemia" AND "falls" and "bone fractures." A meta-analysis was performed including all studies comparing falls and bone fractures in subjects with or without hyponatremia. PATIENTS AND RESULTS: Of 216 retrieved articles, 15 studies satisfied inclusion criteria encompassing a total of 51 879 patients, of whom 2329 were hyponatremic. Across all studies, hyponatremia was associated with a significantly increased risk of falls (MH-OR = 2.14[1.71; 2.67]. This result was confirmed when only hospitalized patients were considered (MH-OR = 2.44 [1.97; 3.02]). A meta-regression analysis showed that the hyponatremia-related risk of falls was higher in those studies considering a lower serum [Na+ ] cut-off to define hyponatremia. Interestingly, the estimated risk of falls related to hyponatremia was already significantly higher when a serum [Na+ ] cut-off of 135 mmol/L was considered (MH-OR = 1.26[1.23;1.29]). The presence of hyponatremia was also associated with a higher risk of fractures, particularly hip fractures (MH-OR = 2.00[1.43;2.81]). CONCLUSIONS: This study confirms that hyponatremia is associated with an increased risk of falls and bone fractures. The clinical, social and economic relevance of such association is strengthened by the increased incidence of hyponatremia in older people.

Endogenous Testosterone Levels and Cardiovascular Risk: Meta-Analysis of Observational Studies.

INTRODUCTION: The relationship between endogenous testosterone (T) levels and cardiovascular (CV) risk in men is conflicting. AIM: To verify whether endogenous T levels represent a possible risk factor for CV morbidity and mortality. METHODS: We conducted a random effect meta-analysis considering all the available data from prospective observational studies comparing subjects with baseline reduced endogenous T levels to those with higher T levels as derived from an extensive MEDLINE, Embase, and Cochrane search. The identification of relevant studies was performed independently by 2 of the authors (G.R. and G.C.), and conflicts resolved by the third investigator (M.M.). MAIN OUTCOME MEASURES: CV mortality and morbidity were investigated. RESULTS: After screening, 37 observational studies, published between 1988 and 2017 including 43,041 subjects with a mean age of 63.5 years and mean follow-up of 333 weeks, were considered. Low endogenous T at enrollment predicted overall and CV mortality, as well as CV morbidity, when both unadjusted and fully adjusted models were considered (odds ratio = 1.26 [CI, 1.17; 1.36], 1.54 [CI, 1.25; 1.89], and 1.17 [CI, 1.01; 1.36]; all P < .05 when overall mortality, CV mortality, and CV incidence and fully adjusted models were considered, respectively). The data were confirmed even when nonpopulation-based studies were excluded from the analysis. Metaregression analysis applied to the fully adjusted model showed that the risk of CV mortality was inversely related to mean age at enrollment (S = -0.014 [-0.017;-0.010] and I = 1.073 [0.806;1.339]; both P < .0001) and directly related to the prevalence of diabetes and to the proportion of active smokers. CLINICAL IMPLICATIONS: Low endogenous T levels in aging men can represent a possible CV risk factor. STRENGTHS & LIMITATIONS: The present data demonstrated, for the first time, that low T predicts not only CV mortality but also CV morbidity. Data derived from studies reporting information on CV mortality suggested major publication bias although they were confirmed applying Duval and Tweedie trim and fill method. However, observational studies should be considered with caution due to the lack of complete follow-ups and due to the poor management of missing data. CONCLUSION: The present meta-analysis shows that low T in aging men is a marker of CV risk. The possible benefits of T treatment in reducing this risk should be examined in longer-term, specifically designed trials. Corona G, Rastrelli G, Di Pasquale G, et al. Endogenous Testosterone Levels and Cardiovascular Risk: Meta-Analysis of Observational Studies. J Sex Med 2018;15:1260-1271.

Testosterone and Cardiovascular Risk: Meta-Analysis of Interventional Studies.

BACKGROUND: The relationship between testosterone (T) and cardiovascular (CV) risk in men is conflicting. AIM: To verify whether T therapy (TTh) represents a possible risk factor for CV morbidity and mortality. METHODS: We conducted a random effect meta-analysis considering all available data from pharmaco-epidemiological studies as well as randomized placebo-controlled trials (RCTs). OUTCOMES: CV mortality and morbidity were investigated. RESULTS: After screening, 15 pharmaco-epidemiological and 93 RCT studies were considered. The analysis of pharmaco-epidemiological studies documented that TTh reduces overall mortality and CV morbidity. Conversely, in RCTs, TTh had no clear effect, either beneficial or detrimental, on the incidence of CV events. However, a protective role of TTh on CV morbidity was observed when studies enrolling obese (body mass index >30 kg/m2) patients were scrutinized (Mantel-Haenszel odds ratio 0.51 [95% CI 0.27-0.96]; P = .04), although this association disappeared when only high-quality RCTs were considered (Mantel-Haenszel odds ratio 0.64 [95% CI 0.22-1.88]; P = .42). Finally, an increased risk of CV diseases was observed in RCTs when T preparations were prescribed at dosages above those normally recommended, or when frail men were considered. CLINICAL IMPLICATIONS: Pharmaco-epidemiological studies showed that TTh might reduce CV risk, but this effect was not confirmed when RCTs were considered. STRENGTHS & LIMITATIONS: Meta-analysis of pharmaco-epidemiological studies indicates that TTh reduces overall mortality and CV morbidity. In addition, even in RCTs, a protective role of TTh on CV morbidity was envisaged when studies enrolling obese (body mass index >30 kg/m2) patients were considered. Pharmaco-epidemiological studies should be considered with caution due to the lack of completeness of follow-up and of the management of missing data. In addition, properly powered placebo-controlled RCTs with a primary CV end point, in men with late-onset hypo-gonadism, are not yet available. Finally, the duration of all studies evaluated in the present meta-analysis is relatively short, reaching a maximum of 3 years. CONCLUSIONS: Data from RCTs suggest that treatment with T is not effective in reducing CV risk, however, when TTh is correctly applied, it is not associated with an increase in CV risk and it may have a beneficial effect in some sub-populations. Corona G, Rastrelli G, Di Pasquale G, et al. Testosterone and Cardiovascular Risk: Meta-Analysis of Interventional Studies. J Sex Med 2018;15:820-838.

High Triglycerides Predicts Arteriogenic Erectile Dysfunction and Major Adverse Cardiovascular Events in Subjects With Sexual Dysfunction.

INTRODUCTION: The atherogenic role of triglycerides (TG) remains controversial. The aim of the present study is to analyze the contribution of TG in the pathogenesis of erectile dysfunction (ED) and to verify the value of elevated TG in predicting major adverse cardiovascular events (MACE). METHODS: An unselected series of 3,990 men attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (n = 1,687) was enrolled in a longitudinal study. MAIN OUTCOME MEASURES: Several clinical, biochemical, and instrumental (penile color Doppler ultrasound; PCDU) factors were evaluated. RESULTS: Among the patients studied, after adjustment for confounders, higher TG levels were associated with arteriogenic ED and a higher risk of clinical and biochemical hypogonadism. Conversely, no association between TG and other sexual dysfunctions was observed. When pathological PCDU parameters-including flaccid acceleration (<1.17 m/sec(2)) or dynamic peak systolic velocity (PSV <35 cm/sec)-were considered, the negative association between impaired penile flow and higher TG levels was confirmed, even when subjects taking lipid-lowering drugs or those with diabetes were excluded from the analysis (OR = 6.343 [1.243;32.362], P = .026 and 3.576 [1.104;11.578]; P = .34 for impaired acceleration and PSV, respectively). Similarly, when the same adjusted models were applied, TG levels were associated with a higher risk of hypogonadism, independently of the definition criteria (OR = 2.892 [1.643;5.410], P < .0001 and 4.853 [1.965;11.990]; P = .001 for total T <12 and 8 nM, respectively). In the longitudinal study, after adjusting for confounders, elevated TG levels (upper quartile: 162-1686 mg/dL) were independently associated with a higher incidence of MACE (HR = 2.469 [1.019;5.981]; P = .045), when compared to the rest of the sample. CONCLUSION: Our data suggest an association between elevated TG and arteriogenic ED and its cardiovascular (CV) risk stratification. Whether the use of TG lowering drugs might improve ED and its associated CV risk must be confirmed through specific trials.

Interplay Between Premature Ejaculation and Erectile Dysfunction: A Systematic Review and Meta-Analysis.

INTRODUCTION: The specific determinants and underlying factors linking erectile dysfunction (ED) and premature ejaculation (PE) have yet to be clearly identified. AIM: The aim of this study was to review and meta-analyze all available data regarding the link between ED and PE. METHODS: An extensive Medline Embase and Cochrane search was performed including the following words: "premature ejaculation" and "erectile dysfunction". MAIN OUTCOME MEASURES: All observational trials comparing the risk of ED in relation to PE were included. Data extraction was performed independently by two of the authors (G.R, G.C.), and conflicts resolved by the third investigator (M.M.). RESULTS: Out of 474 retrieved articles, 18 were included in the study for a total of 57,229 patients, of which 12,144 (21.2%) had PE. The presence of PE, however defined, was associated with a significant increase in ED risk (odds ratio: 3.68[2.61;5.18]; P < 0.0001). Meta-regression analysis showed that the risk of ED in PE subjects was higher in older individuals as well as in those with a lower level of education and in those who reported a stable relationship less frequently. In addition, subjects with PE and ED more often reported anxiety and depressive symptoms and a lower prevalence of organic associated morbidities, including diabetes mellitus, hypertension and dyslipidemia. All the latter associations were confirmed even after adjustment for age. Finally the risk of PE-related ED increased with the increased proportion of acquired ejaculatory problems (adj r = 0.414; P < 0.0001 after the adjustment for age). CONCLUSIONS: In conclusion, the present data showed that ED and PE are not distinctly separate entities, but should be considered from a dimensional point of view. Understanding this dimensional perspective might help sexual health care professionals in providing the most appropriate therapeutic approach to realistically increase patient related outcomes in sexual medicine.

Erectile Dysfunction is Common among Men with Acromegaly and is Associated with Morbidities Related to the Disease.

INTRODUCTION: The prevalence of erectile dysfunction (ED) and its correlates in men with acromegaly has never been investigated. AIM: The aim of this study was to evaluate sexual function in men with acromegaly. METHODS: Multicenter-based, retrospective analysis of a nonselected series of 57 acromegalic subjects (mean age: 52.7 ± 14.2 years) was performed. Acromegalic subjects reporting ED (n = 24) were compared with matched ED patients without acromegaly or pituitary disease (controls), selected from a cohort of more than 4,000 subjects enrolled in the Florence Sexual Medicine and Andrology Unit. MAIN OUTCOME MEASURES: Patients were interviewed using Structured Interview on Erectile Dysfunction (SIEDY) structured interview, a 13-item tool for the assessment of ED-related morbidities. Several clinical and biochemical parameters were taken. Penile color Doppler ultrasound (PCDU) was performed in a subgroup of 37 acromegalic subjects. RESULTS: ED was reported by 42.1% of acromegalic subjects. After adjusting for age and testosterone, acromegalic subjects with ED had a higher prevalence of hypertension and more often reported an impairment of sleep-related erections and a longer smoking habit. Accordingly, acromegaly-associated ED was characterized by a higher organic component and worse PCDU parameters. No relationship between ED and testosterone levels or other acromegaly-related parameters was found. However, acromegalic subjects with severe ED reported a longer disease duration. In a case-control analysis, comparing acromegalic subjects with ED-matched controls free from acromegaly (1:5 ratio), acromegalic men had a worse ED problem and a higher organic component of ED, as derived from SIEDY score. In line with these data, acromegalic patients with ED had a higher prevalence of major adverse cardiovascular events history at enrollment and lower PCDU parameters. CONCLUSIONS: Subjects with complicated acromegaly are at an increased risk of developing ED, especially those with cardiovascular morbidities. Our data suggest including a sexual function evaluation in routine acromegaly follow-up.

Characteristics of compensated hypogonadism in patients with sexual dysfunction.

INTRODUCTION: In the last few years, a view that subclinical endocrine disorders represent milder forms of the clinically overt disease has emerged. Accordingly, it has been proposed that compensated hypogonadism represents a genuine clinical subset of late-onset hypogonadism. AIM: The aim of the present study is to investigate the associations of compensated hypogonadism with particular clinical and psychological characteristics of male subjects complaining of sexual dysfunction. METHODS: After excluding documented genetic causes of hypogonadism, an unselected consecutive series of 4,173 patients consulting our unit for sexual dysfunction was studied. Compensated hypogonadism was identified according to the European Male Ageing study criteria: total testosterone ≥10.5 nmol/L and luteinizing hormone >9.4 U/L. MAIN OUTCOME MEASURES: Several hormonal, biochemical, and instrumental (penile Doppler ultrasound) parameters were studied, along with results of the Structured Interview on Erectile Dysfunction (SIEDY) and ANDROTEST. RESULTS: One hundred seventy (4.1%) subjects had compensated hypogonadism, whereas 827 (19.8%) had overt hypogonadism. After adjustment for confounding factors, no specific sexual symptoms were associated with compensated hypogonadism. However, compensated hypogonadism individuals more often reported psychiatric symptoms, as detected by Middlesex Hospital Questionnaire score, when compared with both eugonadal and overt hypogonadal subjects (adjusted odds ratios = 1.018 [1.005;1.031] and 1.014 [1.001;1.028], respectively; both P < 0.005). In addition, subjects with compensated or overt hypogonadism had an increased predicted risk of cardiovascular events (as assessed by Progetto Cuore risk algorithm) when compared with eugonadal individuals. Accordingly, mortality related to major adverse cardiovascular events (MACEs), but not MACE incidence, was significantly higher in subjects with both compensated and overt hypogonadism when compared with eugonadal subjects. CONCLUSIONS: The present data do not support the concept that compensated (subclinical) hypogonadism represents a new clinical entity. The possibility that subclinical hypogonadism could be a normal response of the hypothalamus-pituitary-testis axis to somatic illness should be considered. Further studies are urgently needed to clarify this latter point.

Testosterone supplementation and sexual function: a meta-analysis study.

INTRODUCTION: The role of testosterone supplementation (TS) as a treatment for male sexual dysfunction remains questionable. AIM: The aim of this study was to attempt a meta-analysis on the effect of TS on male sexual function and its synergism with the use of phosphodiesterase type 5 inhibitor (PDE5i). METHODS: An extensive Medline, Embase, and Cochrane search was performed. MAIN OUTCOME MEASURES: All randomized controlled trials (RCTs) comparing the effect of TS vs. placebo or the effect of TS as add on to PDE5is on sexual function were included. Data extraction was performed independently by two of the authors (A. M. Isidori and G. Corona), and conflicts resolved by the third investigator (M. Maggi). RESULTS: Out of 1,702 retrieved articles, 41 were included in the study. In particular, 29 compared TS vs. placebo, whereas 12 trials evaluated the effect of TS as add on to PDE5is. TS is able to significantly ameliorate erectile function and to improve other aspects of male sexual response in hypogonadal patients. However, the presence of possible publication bias was detected. After applying "trim and fill" method, the positive effect of TS on erectile function and libido components retained significance only in RCTs partially or completely supported by pharmaceutical companies (confidence interval [0.04-0.53] and [0.12; 0.52], respectively). In addition, we also report that TS could be associated with an improvement in PDE5i outcome. These results were not confirmed in placebo-controlled studies. The majority of studies, however, included mixed eugonadal/hypogonadal subjects, thus imparting uncertainty to the statistical analyses. CONCLUSIONS: TS plays positive effects on male sexual function in hypogonadal subjects. The role of TS is uncertain in men who are not clearly hypogonadal. The apparent difference between industry-supported and independent studies could depend on trial design more than on publication bias. New RCTs exploring the effect of TS in selected cases of PDE5i failure that persistently retain low testosterone levels are advisable.

A case of osmotic demyelination syndrome occurred after the correction of severe hyponatraemia in hyperemesis gravidarum.

BACKGROUND: Osmotic demyelination syndrome (ODS) may be observed as a result of a rapid change in serum osmolarity, such as that induced by an overly rapid correction of serum sodium levels in hyponatraemic patients. CASE PRESENTATION: We describe the case of a 21-year-old woman who was hospitalized at week 10 of gestation because of severe hyperemesis. At admission the patient appeared restless and confused and severe hyponatraemia (serum sodium 107 mmol/L) and hypokalemia (serum potassium 1.1 mmol/L) were detected. Active and simultaneous correction of these imbalances led to an overly rapid increase of serum sodium levels (17 mmol/L in the first 24 hours). Isotonic saline solution was stopped and replaced by 5% dextrose solution infusion. However, the neurological alterations worsened and the radiological features were consistent with the diagnosis of extra-pontine ODS. Steroids were administered intravenously with progressive improvement of biochemical and clinical abnormalities. At the time of discharge, 20 days later, the patient was able to walk and eat autonomously with only minimal external support. CONCLUSIONS: This report illustrates an unusual case of ODS, occurred after an excessive rate of correction of hyponatraemia obtained with isotonic saline infusion. Hypokaliemia and its active correction very likely played a crucial role in facilitating the onset of ODS. This interesting aspect will be explained in detail in the article. A more cautious and thoughtful correction of electrolyte alterations, would have probably prevented the onset of ODS in this patient. Physicians should be aware of the possibly fatal consequences that an exceedingly rapid change of serum osmolarity may have and should strictly follow the known safety measures in order to prevent it to occur.

Pharmacological management of testosterone deficiency in men current advances and future directions.

INTRODUCTION: Testosterone deficiency (TD) is relatively common in aging men, affecting around 2% of the general population. Testosterone replacement therapy (TRT) represents the most common medical approach for subjects who are not interested in fathering. AREAS COVERED: This review summarizes advances in TRT, including approved or non-approved pharmacological options to overcome TD. When possible, a meta-analytic approach was applied to minimize subjective and biased interpretations of the available data. EXPERT OPINION: During the last decade, several new TRT formulations have been introduced on the market, including oral, transdermal, and parenteral formulations. Possible advantages and limitations have been discussed appropriately. Anti-estrogens, including selective estrogen modulators or aromatase inhibitors still represent further possible off-label options. However, long-term side effects on sexual function and bone parameters constitute major limitations. Glucagon-like peptide 1 analogues can be an alternative option in particular for massive obesity-associated TD. Weight loss obtained through lifestyle modifications including diet and physical exercise should be encouraged in all overweight and obese patients. A combination of TRT and lifestyle changes can be considered in those subjects in whom a reversal of the condition cannot be expected in a reasonable time frame.

Advances in the treatment of functional male hypogonadism.

INTRODUCTION: Functional hypogonadism is frequently found in obese men, particularly those with metabolic complications. Several possible therapeutic approaches could be considered. AREAS COVERED: An extensive search on Medline, Embase, and Cochrane databases was performed to retrieve the available studies assessing the change of testosterone (T) and sexual function upon dieting or physical activity programs, as well as glucagon-like peptide 1 analogues. The role of lifestyle interventions associated with T replacement therapy (TRT) was also evaluated. The expert opinion provided here has been corroborated by meta-analyzing the results of the retrieved studies. EXPERT OPINION: Current evidence supports the beneficial role of lifestyle modifications in increasing T and improving sexual function as a function of weight loss. While dieting programs are associated with greater effects in younger populations, physical exercise has major effects in older ones. Among the dieting programs, a very low-calorie ketogenic diet shows the best results; aerobic or endurance physical exercise perform similarly. The advantages of functional hypogonadism in lifestyle modifications are empowered by the association with TRT. Therefore, TRT may be a valuable complementary strategy to increase muscle mass and facilitate physical exercise while improving sexual symptoms, thus favoring the motivation and compliance for lifestyle interventions.

Cardiovascular safety of testosterone replacement therapy in men: an updated systematic review and meta-analysis.

INTRODUCTION: The cardiovascular (CV) safety of testosterone (T) replacement therapy (TRT) is still conflicting. Recent data suggested a TRT-related increased risk of atrial fibrillation (AF). The aim of this study was to systematic review and meta-analyze CV risk related to TRT as derived from placebo controlled randomized trials (RCTs). AREAS COVERED: An extensive Medline, Embase, and Cochrane search was performed. All placebo-controlled RCTs reporting data on TRT-related CV safety were considered. To better analyze the role of T on AF, population-based studies investigating the relationship between endogenous circulating T levels and AF incidence were also included and analyzed. EXPERT OPINION: Out of 3.615, 106 studies were considered, including 8.126 subjects treated with TRT and 7.310 patients allocated to placebo. No difference between TRT and placebo was observed when major adverse CV events were considered. Whereas the incidence of non-fatal arrhythmias and AF was increased in the only trial considering CV safety as the primary endpoint, this was not confirmed when all other studies were considered (MH-OR 1.61[0.84;3.08] and 1.44[0.46;4.46]). Similarly, no relationship between endogenous T levels and AF incidence was observed after the adjustment for confounders Available data confirm that TRT is safe and it is not related to an increased CV risk.

Effectiveness of the flash glucose monitoring system in preventing severe hypoglycemic episodes and in improving glucose metrics and quality of life in subjects with type 1 diabetes at high risk of acute diabetes complications.

AIMS: To assess the effectiveness of the intermittent-scanned continuous glucose monitoring (isCGM) system in preventing severe hypoglycemic episodes and in improving glucose parameters and quality of life. METHODS: Four hundred T1D individuals were enrolled in a prospective real-word study with an intermittently scanned continuous glucose monitoring device during the 12-months follow-up. The primary endpoint was the incidence of severe hypoglycemic events. RESULTS: 82% of subjects were naïve to the use of the device (group A) and 18% were already wearing the system (group B). The cumulative incidence of severe hypoglycemia (SH) at 12 months was 12.06 per 100 person-year (95% CI: 8.35-16.85) in group A and 10.14 (95% CI: 4.08-20.90) in group B without inter-group differences. In group A there was a significant decrease in SH at 12 months compared to 3 months period (p = 0.005). Time in glucose range significantly increased in both groups accompanied with a significant decrease in glucose variability. HbA1c showed a progressive significant time-dependent decrease in group A. The use of the device significantly improved the perceived quality of life. CONCLUSION: This study confirmed the effectiveness of the isCGM in reducing hypoglycemic risk without glucose deterioration, with potential benefits on adverse outcomes in T1D individuals. TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT04060732.

The identification of prediabetes condition with ARIC algorithm predicts long-term CV events in patients with erectile dysfunction.

INTRODUCTION: The Atherosclerosis Risk in Communities (ARIC) algorithm is one of the most efficient instruments for the prediction of incident type 2 diabetes. Recently, it has been shown to predict another relevant cardiovascular (CV) risk factor, such as chronic kidney disease. AIM: To verify whether, in patients with erectile dysfunction (ED), the use of ARIC diabetes risk score might improve the efficacy in predicting major CV events of other CV risk algorithms specifically developed for the assessment of CV risk. METHODS: A consecutive series of 2,437 men (mean age 52.5 ± 12.9 years) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (N = 1,687) was enrolled in a longitudinal study (mean follow-up of 4.3 ± 2.6 years). MAIN OUTCOME MEASURES: The assessment of metabolic risk was evaluated with the ARIC algorithm. The assessment of CV risk was evaluated using the Progetto Cuore risk engine. RESULTS: In the cross-sectional study, ARIC score was inversely related with testosterone levels, sexual functioning, and penile blood flow. When longitudinal sample was analyzed, higher baseline ARIC score significantly predicted major adverse cardiovascular event (MACE) even when subjects with diabetes mellitus at baseline were excluded from the analysis (hazard ratio = 1.522 [1.086-2.135]; P = 0.015 for trend). In addition, among subjects classified as "low risk" (CV risk <20% at 10 years corresponding to <9% at 4.3 years) by Progetto Cuore, a receiving operating curve (ROC) analysis for ARIC (vs. MACE) allowed the identification of a threshold of 0.22, which had a positive predictive value for 4.3-year MACE of 9%. Applying the ARIC score (with a threshold of 0.22) to Progetto Cuore "low-risk" subjects, we could classify as "at high risk" 89.8% of subjects with incident MACE vs. 79.6% with Progetto Cuore only. CONCLUSIONS: In patients with ED, identifying prediabetes, even with algorithms, predicts long-term CV events.

Risk factors associated with primary and secondary reduced libido in male patients with sexual dysfunction.

INTRODUCTION: Hypoactive sexual desire is defined as a persistent or recurrent deficient or absent sexual fantasies or desire for sexual activity that should not be comorbid with other medical conditions or with the use of psychoactive medications. Reduced libido is a symptom referring more to a reduction in sexual drive for sexual activity. AIM: To investigate the risk factors of primary reduced libido (i.e., not associated with conditions causing loss of libido such as hypogonadism, hyperprolactinemia, psychopathology, and/or psychoactive medications) or secondary reduced libido (i.e., with aforementioned conditions) in male patients with sexual dysfunction. METHOD: A consecutive series of 3,714 men (mean age 53.2 ± 12.5 years) was retrospectively studied. MAIN OUTCOME MEASURES: Patient's reduced libido was evaluated using question #14 of structured interview for erectile dysfunction (SIEDY) ("Did you have more or less desire to make love in the last 3 months?"). RESULTS: Reduced libido was comorbid with erectile dysfunction, premature ejaculation, and delayed ejaculation in 38%, 28.2%, and 50%, respectively, whereas it was isolated in 5.1%. Reduced libido prevalence was substantially increased by hypogonadism, almost doubled by psychopathology and universally present in subjects with hyperprolactinemia (secondary reduced libido). Subjects with primary reduced libido are characterized by higher postschool qualification, more disturbances in domestic and dyadic relationships, and an overall healthy body (lower glycemia and triglyceride levels). Accordingly, in patients with primary reduced libido, the risk of major cardiovascular events as calculated with the Progetto Cuore algorithm was lower than in the rest of the sample. Features of hypogonadism- or psychopathology-associated reduced libido essentially reflect their underlying conditions. Comorbidity with other sexual dysfunctions did not affect the main characteristics of primary or secondary reduced libido. CONCLUSIONS: Primary and secondary reduced libido have different risk factors and clinical characteristics. Recognizing primary or secondary reduced libido will help clinicians to identify comorbidities and to tailor appropriate treatments.