Sublingual sufentanil, a new opportunity for the improvement of postoperative pain management in Italy

Despite the availability of national and international guidelines, adequate postoperative pain (POP) management is still a challenge in Italy. One of the potential reasons for the high incidence of surgical patients complaining moderate to severe pain is the difficult application of the currently recommended analgesic techniques in clinical practice. In particular, morphine, the most commonly used systemic opioid in the POP treatment, has some unfavorable pharmacodynamic and pharmacokinetic characteristics for POP management, suggesting a potential relevant improvement by using different opioids. Many of sufentanil properties make it particularly suitable for POP control: a high affinity for the µ opioid receptor, the highest therapeutic index compared to any other opioid used in clinical practice and the absence of clinically relevant active metabolites. The elevated potency, together with the high lipophilicity of sufentanil, allow the preparation of a nanotablet, 3 mm of diameter and 0.75 mm of thickness, containing 15 µg of active drug. The sublingual route allows a longer time of drug plasmatic permanence in comparison to IV route, overcoming the need for continuous dosing. The patient-controlled system, considered in the present review, is preprogrammed to deliver one sublingual tablet of sufentanil with a 20-minute lockout period with a radiofrequency identification thumb tag allowing only the patient to activate the on demand button. Phase II and III studies have assessed the efficacy of this system in POP management, showing that it was considered more satisfactory than the IV PCA morphine system by both patients and nurses. The introduction of this simple and innovative system of patient-controlled analgesic administration could represent an opportunity for Italy to update the current practice in POP management

Neuroactive Steroids in First-Episode Psychosis: A Role for Progesterone?

Neuroactive steroids may play a role in the pathophysiology of psychotic disorders, but few studies examined this issue. We compared serumlevels of cortisol, testosterone, dehydroepiandrosterone, and progesterone between a representative sample of firstepisode psychosis (FEP) patients and age- and gender-matched healthy subjects. Furthermore, we analyzed the associations between neuroactive steroids levels and the severity of psychotic symptom dimensions.Male patients had lower levels of progesterone than controls

Body mass index rather than the phenotype impacts precocious ultrasound cardiovascular risk markers in polycystic ovary syndrome

Objective Research into cardiovascular disease (CV) prevention has demonstrated a variety of ultrasound (US) markers predicting risk in the general population but which have been scarcely used for polycystic ovary syndrome (PCOS). Obesity is a major factor contributing to CV disease in the general population, and it is highly prevalent in PCOS. However, it is still unclear how much risk is attributable to hyperandrogenism. This study evaluates the most promising US CV risk markers in PCOS and compares them between different PCOS phenotypes and BMI values. Design Women fulfilling the Rotterdam criteria for PCOS were recruited from our outpatient clinic for this cross-sectional study. Methods Participants (n\u2009=\u2009102) aged 38.9 \ub1 7.4 years were stratified into the four PCOS phenotypes and the three BMI classes (normal-weight, overweight, obese). They were assessed for clinical and biochemical parameters together with the following US markers: coronary intima-media thickness (cIMT), flow-mediated vascular dilation (FMD), nitroglycerine-induced dilation (NTG), and epicardial fat thickness (EFT). Results There was no statistical difference among the four phenotypes in terms of cIMT, FMD, NTG or EFT, however all the US parameters except NTG showed significant differences among the three BMI classes. Adjusting for confounding factors in multiple regression analyses, EFT retained the greatest direct correlation with BMI and cIMT remained directly correlated but to a lesser degree. Conclusions This study showed that obesity rather than the hyperandrogenic phenotype negatively impacts precocious US CV risk markers in PCOS. In addition, EFT showed the strongest association with BMI, highlighting its potential for estimating CV risk in PCOS

Primary, secondary and compensated male biochemical hypogonadism in people living with HIV (PLWH): relevance of sex hormone-binding globulin (SHBG) measurement and comparison between liquid chromatography-tandem mass spectrometry (LC-MS/MS) and chemiluminescent immunoassay for sex steroids assay

Background: Data about classification of hypogonadism and estrogen deficiency in male people living with HIV (PLWH) are scanty. Aim: To investigate the prevalence and characterization of biochemical hypogonadism and relative estrogen deficiency in male PLWH aged < 50 comparing liquid chromatography-tandem mass spectrometry (LC-MS/MS) with chemiluminescent immunoassay (CI), and combining gonadotropin, sex hormone-binding globulin (SHBG) and serum estradiol (E2) measurements. Methods: Prospective, cross-sectional, observational study. Serum total testosterone (TT), E2, gonadotropins, SHBG were measured by CI. TT and E2 were also assessed by LC-MS/MS. Free testosterone (cFT) was calculated by Vermeulen equation. Results: A total of 316 PLWH (45.3 ± 5.3 years) were enrolled. TT and cFT by LC-MS/MS were lower compared to CI (p < 0.0001). The prevalence of biochemical hypogonadism was higher with LC-MS/MS than CI, both for TT (5.1% vs 3.2%, p < 0.0001) or cFT (9.5% vs 7%, p < 0.0001). The prevalence of hypogonadism (overt + compensated) was 17.1% for cFT using LC-MS/MS. Secondary form of hypogonadism was more prevalent than primary. The prevalence of relative estrogen deficiency was of 30.0% among hypogonadal patients and 15.5% among eugonadal. Conclusions: The prevalence of male hypogonadism results underestimated by CI compared to LC-MS/MS in PLWH, both for TT and cFT. SHBG and gonadotropins are essential for detecting T deficiency.Background: Data about classification of hypogonadism and estrogen deficiency in male people living with HIV (PLWH) are scanty. Aim: To investigate the prevalence and characterization of biochemical hypogonadism and relative estrogen deficiency in male PLWH aged < 50 comparing liquid chromatography-tandem mass spectrometry (LC-MS/MS) with chemiluminescent immunoassay (CI), and combining gonadotropin, sex hormone-binding globulin (SHBG) and serum estradiol (E2) measurements. Methods: Prospective, cross-sectional, observational study. Serum total testosterone (TT), E2, gonadotropins, SHBG were measured by CI. TT and E2 were also assessed by LC-MS/MS. Free testosterone (cFT) was calculated by Vermeulen equation. Results: A total of 316 PLWH (45.3 ± 5.3 years) were enrolled. TT and cFT by LC-MS/MS were lower compared to CI (p < 0.0001). The prevalence of biochemical hypogonadism was higher with LC-MS/MS than CI, both for TT (5.1% vs 3.2%, p < 0.0001) or cFT (9.5% vs 7%, p < 0.0001). The prevalence of hypogonadism (overt + compensated) was 17.1% for cFT using LC-MS/MS. Secondary form of hypogonadism was more prevalent than primary. The prevalence of relative estrogen deficiency was of 30.0% among hypogonadal patients and 15.5% among eugonadal. Conclusions: The prevalence of male hypogonadism results underestimated by CI compared to LC-MS/MS in PLWH, both for TT and cFT. SHBG and gonadotropins are essential for detecting T deficiency

Multi-omics gut microbiome signatures in obese women: role of diet and uncontrolled eating behavior

Background: Obesity and related co-morbidities represent a major health challenge nowadays, with a rapidly increasing incidence worldwide. The gut microbiome has recently emerged as a key modifier of human health that can affect the development and progression of obesity, largely due to its involvement in the regulation of food intake and metabolism. However, there are still few studies that have in-depth explored the functionality of the human gut microbiome in obesity and even fewer that have examined its relationship to eating behaviors. Methods: In an attempt to advance our knowledge of the gut-microbiome-brain axis in the obese phenotype, we thoroughly characterized the gut microbiome signatures of obesity in a well-phenotyped Italian female cohort from the NeuroFAST and MyNewGut EU FP7 projects. Fecal samples were collected from 63 overweight/obese and 37 normal-weight women and analyzed via a multi-omics approach combining 16S rRNA amplicon sequencing, metagenomics, metatranscriptomics, and lipidomics. Associations with anthropometric, clinical, biochemical, and nutritional data were then sought, with particular attention to cognitive and behavioral domains of eating. Results: We identified four compositional clusters of the gut microbiome in our cohort that, although not distinctly associated with weight status, correlated differently with eating habits and behaviors. These clusters also differed in functional features, i.e., transcriptional activity and fecal metabolites. In particular, obese women with uncontrolled eating behavior were mostly characterized by low-diversity microbial steady states, with few and poorly interconnected species (e.g., Ruminococcus torques and Bifidobacterium spp.), which exhibited low transcriptional activity, especially of genes involved in secondary bile acid biosynthesis and neuroendocrine signaling (i.e., production of neurotransmitters, indoles and ligands for cannabinoid receptors). Consistently, high amounts of primary bile acids as well as sterols were found in their feces. Conclusions: By finding peculiar gut microbiome profiles associated with eating patterns, we laid the foundation for elucidating gut-brain axis communication in the obese phenotype. Subject to confirmation of the hypotheses herein generated, our work could help guide the design of microbiome-based precision interventions, aimed at rewiring microbial networks to support a healthy diet-microbiome-gut-brain axis, thus counteracting obesity and related complications

Efficacy of very low-calorie ketogenic diet with the Pronokal® method in obese women with polycystic ovary syndrome: a 16-week randomized controlled trial

Objective: The aim of this study isto assess the efficacy of a very low-calorie ketogenic diet (VLCKD) method vs a Mediterranean low-calorie diet (LCD) in obese polycystic ovary syndrome (PCOS) women of a reproductive age.Design: Randomized controlled open-label trial was performed in this study. The treatment period was 16 weeks; VLCKD for 8 weeks then LCD for 8 weeks, according to the Pronokal (R) method (experimental group; n = 15) vs Mediterranean LCD for 16 weeks (control group; n = 15). Ovulation monitoring was carried out at baseline and after 16 weeks, while a clinical exam, bioelectrical impedance analysis (BIA), anthropometry, and biochemical analyses were performed at baseline, at week 8, and at week 16.Results: BMI decreased significantly in both groups and to a major extent in the experimental group (-13.7% vs -5.1%, P = 0.0003). Significant differences between the experimental and the control groups were also observed in the reduction of waist circumference (-11.4% vs -2.9%), BIA-measured body fat (-24.0% vs -8.1%), and free testosterone (-30.4% vs -12.6%) after 16 weeks (P = 0.0008, P = 0.0176, and P = 0.0009, respectively). Homeostatic model assessment for insulin resistance significantly decreased only in the experimental group (P = 0.0238) but without significant differences with respect to the control group (-23% vs -13.2%, P > 0.05). At baseline, 38.5% of participants in the experimental group and 14.3% of participants in the control group had ovulation, which increased to 84.6% (P = 0.031) and 35.7% (P > 0.05) at the end of the study, respectively.Conclusion: In obese PCOS patients, 16 weeks of VLCKD protocol with the Pronokal (R) method was more effective than Mediterranean LCD in reducing total and visceral fat, and in ameliorating hyperandrogenism and ovulatory dysfunction.Significance statements: To the best of our knowledge, this is the first randomized controlled trial on the use of the VLCKD method in obese PCOS. It demonstrates the superiority of VLCKD with respect to Mediterranean LCD in reducing BMI with an almost selective reduction of fat mass and a unique effect of VLCKD in reducing visceral adiposity, insulin resistance, and in increasing SHBG with a consequent reduction of free testosterone. Interestingly, this study also demonstrates the superiority of the VLCKD protocol in improving ovulation, whose occurrence increased by 46.1% in the group treated by the VLCKD method against a rise of 21.4% in the group treated by Mediterranean LCD. This study extends the therapeutic approach possibilities in obese PCOS women

CB1 Signaling in Forebrain and Sympathetic Neurons Is a Key Determinant of Endocannabinoid Actions on Energy Balance

SummaryThe endocannabinoid system (ECS) plays a critical role in obesity development. The pharmacological blockade of cannabinoid receptor type 1 (CB1) has been shown to reduce body weight and to alleviate obesity-related metabolic disorders. An unsolved question is at which anatomical level CB1 modulates energy balance and the mechanisms involved in its action. Here, we demonstrate that CB1 receptors expressed in forebrain and sympathetic neurons play a key role in the pathophysiological development of diet-induced obesity. Conditional mutant mice lacking CB1 expression in neurons known to control energy balance, but not in nonneuronal peripheral organs, displayed a lean phenotype and resistance to diet-induced obesity. This phenotype results from an increase in lipid oxidation and thermogenesis as a consequence of an enhanced sympathetic tone and a decrease in energy absorption. In conclusion, CB1 signaling in the forebrain and sympathetic neurons is a key determinant of the ECS control of energy balance

Profession, Professionalität, Professionalisierung

Alignment of LH receptor amino acid sequences obtained from the UniProt database ( http://www.uniprot.org ). Homo sapiens LHCGR (UniProt identifier: P22888), Mus musculus Lhr (P30730) and Rattus norvegicus Lhr (P16235) sequences were aligned by the UniProt online tool Clustal Omega 1.2.1 ( http://www.uniprot.org/align ). Boxes indicate sequence divergence; :=conservation of strong groups;. = conservation of weak groups or no consensus. (DOC 92 kb

Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). Interpretation: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. Funding: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo