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Objective An evidence-based pubertal induction scheme in hypogonadal girls is still to be established. Interestingly, literature data reports suboptimal uterine longitudinal diameter (ULD) in >50% of treated hypogonadal women, negatively influencing their pregnancy outcomes. This study aims to investigate auxological and uterine outcomes of pubertal induction in girls in the light of underlying diagnosis and therapeutic schemes used. Design Retrospective analysis of longitudinal data from a multicentric registry. Methods Auxological, biochemical and radiological data were collected at baseline and during follow-up in 95 hypogonadal girls (chronological age>10.9 years, Tanner stage≤2) treated with transdermal 17β-oestradiol patches for at least one year. Induction was started at a median dose of 0.14 mcg/kg/day with a six-monthly increase and was considered completed for 49/95 patients who started progesterone with concomitant oestrogen adult dose. Results At the end of induction, the achievement of the complete breast maturation was associated with 17β-oestradiol dose at progesterone introduction. ULD showed a significant correlation with 17β-oestradiol dosage. Final ULD was>65 mm in only 17/45 girls. At multiple regression analysis, pelvic irradiation represented the major determinant of reduced final ULD. After correction for uterine irradiation, ULD was associated with the 17β-oestradiol dose at progesterone introduction. Final ULD was not significantly different from the one assessed after progesterone introduction. Conclusions Our results provide evidence that progestins, hampering further changes in uterine volume and breast development, should be introduced only in the presence of a concomitant adequate 17β-oestradiol dose and an appropriate clinical response.

We assessed the capability of an integrated multisensory patch-type monitor (RootiRx®) in detecting episodes of reflex (pre)syncope induced by tilt table test (TTT). Firstly, we performed an intrapatient comparison of cuffless systolic blood pressure (SBP), R–R interval (RRI) and variability (power spectrum analysis) obtained by means of the RootiRx® with those obtained with conventional methods (CONV) with validated finger pressure devices at baseline in supine position and repeatedly during TTT in 32 patients affected by likely reflex syncope. Secondly, the LF/HF values obtained with RootiRx® during TTT were analyzed in 50 syncope patients. Compared with baseline supine recordings, during TTT a decrement of median SBP was observed with CONV (−53.5 mmHg) but not with RootiRx® ®(−1 mmHg). Conversely, RRI reduction (CONV: 102 ms; RootiRx®: 127 ms) and RRI Low Frequency/High Frequency powers ratio (LF/HF) increase (CONV: 1.6; RootiRx®: 2.5) were similar. The concordance was good for RRI (0.97 [95% CI 0.96–0.98]) and fair for LF/HF ratio (0.69 [95% CI 0.46-0.83]). During the first 5 min of TTT the LF/HF ratio was higher in patients who later developed syncope than in no-syncope patients. This ratio was significantly different among patients with syncope, presyncope or without symptoms at the time of syncope (p value = 0.02). In conclusion, cuffless RootiRx® was unable to detect rapid drops of SBP occurring during impending reflex syncope and thus cannot be used as a diagnostic tool for hypotensive syncope. On the other hand, RRI mean values and LF/HF power ratios obtained with RootiRx® were consistent with those simultaneously obtained using conventional methods.

Aims: To describe the proportion of patients with syncope among those affected by hypertrophic cardiomyopathy (HCM) and the relevance of syncope as risk factor for sudden cardiac death and life-threatening arrhythmic events. Method and results: Systematic review of original articles that assessed syncope in HCM patients. Literature search of PubMed including all English publications from 1973 to 2021.We found 57 articles for a total of 21.791 patients; of these, 14 studies reported on arrhythmic events in the follow-up. Syncope was reported in 15.8% (3.452 of 21.791) patients. It was considered unexplained in 91% of cases. Life-threatening arrhythmic events occurred in 3.6% of non-syncopal patients and in 7.7% of syncopal patients during a mean follow-up of 5.6 years. A relative risk of 1.99 (95%CI 1.39 to 2.86) was estimated for syncope patients by the random effect model using Haldane continuity correction for 0 events. Conclusions: In the current practice, the cause of syncope remained unexplained in most patients affected by HCM. The management of patients seems mainly driven by risk stratification rather than identification of the aetiology of syncope. There is a need of precise instructions how to apply the recommendations of current guidelines to this disease, which tests are indicated and how to interpret their findings. The protocol was registered in Prospero (ID: 275963).

Purpose:To propose an algorithm of the major and minor diagnostic criteria for macular myopic choroidal neovascularization (mCNV). Methods:This single-center, retrospective, cross-sectional study was based in Istituto Auxologico Italiano, Milan, Italy. Two authors evaluated the clinical and imaging parameters of eyes with high myopia (spherical equivalent of -6D or less) and suspected to have naïve, recurrent, or inactive mCNV. Recordings of the eyes that met the inclusion criteria were then independently evaluated by two other senior retinal specialists. Fluorescein angiography (FA), spectral domain optical coherence tomography (SD-OCT), and OCT angiography were used for multimodal imaging. Results:One-hundred and twenty-two eyes (n = 107; 39 men, 68 women) were included in the study. The mean patient age was 66 years (range, 22-89 years). There were 83 and 39 eyes in the active mCNV and control groups, respectively. The best diagnostic algorithm had positive- and negative-predictive values of 89% and 85%, respectively, and was based on four criteria: leakage/staining on FA, retinal thickening, fuzzy area on SD-OCT, and recent metamorphopsia. When excluding FA-derived findings, retinal pigment epithelium (RPE) features played a diagnostic role in 33 eyes (27%). Twenty-seven eyes with active mCNV (32%) did not have the fuzzy area. Taken singularly, no clinical or imaging parameter had both sensitivity and specificity greater than 78%. Matching of 2 or 3 biomarkers did not yield a sensitivity or specificity greater than 79%. Sensitivities and specificities ≥ 90% were found in ten criteria combinations that included four to five biomarkers. The most frequent were metamorphopsia, fuzzy area, retinal thickening, and leakage. Less frequently, they included hemorrhage, staining, and RPE features such as elevation, flattening, and focal interruption. For all the parameters, the agreement between the investigators was good (Cohen k ≥ 0.66), being the lowest when detecting the ELM interruption within the lesion. Conclusions:A combination of at least four clinical and biological markers yielded the highest positive- and negative-predictive values. More ("major") and less ("minor") frequent diagnostic criteria are proposed.

Background and objective: Obstructive sleep apnea (OSA) is associated with heart derangements detected at echocardiography as higher left ventricular mass index (LVMI), higher left ventricular end-diastolic diameter, lower left ventricular ejection fraction (LVEF), and impaired diastolic function. However, the currently used parameter to define OSA diagnosis and severity, the apnea/hypopnea index (AHI), poorly predicts cardiovascular damage, cardiovascular events, and mortality. Our study aimed to assess if other polygraphic indices of OSA presence and severity, in addition to AHI, might better predict echocardiographic cardiac remodeling. Methods and results: We enrolled two cohorts of individuals referred for suspected OSA to the outpatient facilities of the IRCCS Istituto Auxologico Italiano, Milano, and of the Clinica Medica 3, Padova. All patients underwent home sleep apnea testing and echocardiography. Based on the AHI the cohort was divided into no-OSA (AHI

Background Among patients with heart failure and a preserved left ventricular ejection fraction (HFpEF), a distinct hemodynamic phenotype has been recently described, with potential clinical implication, i.e. latent pulmonary vascular disease (PVD). HFpEF patients with latent PVD have been shown to have worse outcome after creation of an interatrial septal shunt. However, the pathophysiological significance of latent PVD in HFpEF has not been thoroughly investigated. Methods We retrospectively analyzed our cohort of consecutive patients with HFpEF who have undergone a right heart catheterization at rest and during exercise between 2016 and 2020. HFpEF was defined based on a resting and/or exercise hemodynamics: pulmonary artery wedge pressure (PAWP) > 15 mmHg at rest; PAWP during exercise >= 25 mmHg; PAWP/cardiac output (CO) slope > 2 mmHg/L/min. Latent PVD was defined based on exercise pulmonary vascular resistance (PVR) > 1.74 WU. Results Out of 199 exercise right heart catheterization, 86 patients had a hemodynamic diagnosis of HFpEF. Of these, 68 (79%) qualified as HFpEF without PVD (HFpEF-PVR-) and 16 (21%) qualified as latent PVD (HFpEF-PVR+). HFpEF-PVR+ were older, presented more frequently with diabetes mellitus or glucose intolerance, had higher H2FPEF and HFA-PEFF scores, slightly lower LVEF, had more frequently a history of atrial fibrillation and had more frequently at tricuspid regurgitation ≥ moderate (p 2 WU) also at rest (72% vs 10%, p Conclusions HFpEF-PVR+ is associated with peculiar clinical and hemodynamic characteristics, reflecting a more advanced and polycomorbid HFpEF profile, characterized by heightened pulmonary vascular reactivity and overt cardiac limitation to exercise.

Background Both secondary tricuspid regurgitation (STR) and heart failure with preserved ejection fraction (HFpEF) are relevant public health problem in the elderly population, presenting with potential overlaps and sharing similar risk factors. However, the impact of severe STR on hemodynamics and cardiorespiratory adaptation to exercise in HFpEF remains to be clarified. Aim To explore the impact of severe STR on exercise hemodynamics and cardiorespiratory adaptation in HFpEF. Methods We analyzed invasive hemodynamics and gas-exchange data obtained at rest and during exercise from HFpEF patients with severe STR (HFpEF-STR), compared with 1:1 age, sex and body mass index matched HFpEF patients with mild or no STR (HFpEF-controls). Results 13 HFpEF-STR (mean age 72 years, 85% females, BMI 28 Kg/m2) and 13 age-, sex-, and BMI-matched HFpEF-controls patients were included. HFpEF-STR had higher (p Conclusions Severe STR complicating HFpEF impairs SV and CO reserve, leading to pulmonary vascular de-recruitment and relative left heart underfilling, mining the typical HFpEF pathophysiology. Exercise pathophysiology of secondary tricuspid regurgitation (STR) in heart failure with preserved ejection fraction (HFpEF).

Phase angle (PhA) is a recently proposed marker of nutritional status in many clinical conditions. Its use in patients with obesity presents different critical concerns due to the higher variability of the two measured parameters (resistance, R, and reactance, Xc) that contribute to the determination of PhA. Controversial is the relation between PhA and BMI that might vary with graded levels of obesity due to the variation in fat and free fat mass. Obesity is frequently associated with metabolic, hepatic, cardiovascular and kidney diseases that introduce variations in PhA values, in relation to multimorbidity and severity degree of these diseases. It is reported that the improvement of clinical condition is associated with a positive change in PhA. Also, the treatment of obesity with weight loss might confirm this effect, but with different responses in relation to the type and duration of the intervention applied. In fact, the effect appears not only related to the percentage of weight loss but also the possible loss of free fat mass and the nutritional, metabolic and structural modifications that might follow each therapeutic approach to decrease body weight. We can conclude that the PhA could be used as marker of health status in patients with obesity supporting an appropriate weight loss intervention to monitor efficacy and fat free mass preservation.

Background We hypothesized that cardiovascular physiology differs in reflex syncope patients compared with the general population, predisposing such individuals to vasovagal reflex. Methods In this multicohort cross-sectional study, we compared aggregate data of resting SBP, DBP, pulse pressure (PP) and heart rate (HR), collected from six community-based cohort studies (64 968 observations) with those from six databases of reflex syncope patients (6516 observations), subdivided by age decades and sex. Results Overall, in male individuals with reflex syncope, SBP (-3.4 mmHg) and PP (-9.2 mmHg) were lower and DBP (+2.8 mmHg) and HR (+5.1 bpm) were higher than in the general population; the difference in SBP was higher at ages above 60 years. In female individuals, PP (-6.0 mmHg) was lower and DBP (+4.7 mmHg) and HR (+4.5 bpm) were higher than in the general population; differences in SBP were less pronounced, becoming evident only above 60 years. Compared with male individuals, SBP in female individuals exhibited slower increase until age 40 years, and then demonstrated steeper increase that continued throughout remaining life. Conclusion The patients prone to reflex syncope demonstrate a different resting cardiovascular haemodynamic profile as compared with a general population, characterized by lower SBP and PP, reflecting reduced venous return and lower stroke volume, and a higher HR and DBP, suggesting the activation of compensatory mechanisms. Our data contribute to a better understanding why some individuals with similar demographic characteristics develop reflex syncope and others do not. Video abstract http://links.lww.com/HJH/B580.

Aims Diagnostic criteria for ambulatory blood pressure monitoring (ABPM) in patients with suspected reflex syncope are lacking. The study hypothesis was that patients with reflex syncope have a higher prevalence of systolic blood pressure (SBP) drops on ABPM. Methods and results ABPM data from reflex syncope patients and controls, matched by average 24 h SBP, age, sex, and hypertension were compared. Patients with constitutional hypotension, orthostatic hypotension, and predominant cardioinhibition during carotid sinus massage or prolonged electrocardiogram monitoring or competing causes of syncope were excluded. Daytime and nighttime SBP drops ( Conclusion SBP drops during ABPM are more common in reflex syncope patients than in controls. Cut-off values that may be applied in clinical practice are defined. This study expands the current indications for ABPM to patients with reflex syncope.

Objective: Diagnostic criteria for ambulatory blood pressure monitoring (ABPM) in patients with suspected reflex syncope are lacking. We hypothesized that patients with reflex syncope have a higher prevalence of systolic blood pressure (SBP) drops on ABPM. Design and method: We conducted a retrospective analysis comparing ABPM data from reflex syncope patients and controls, matched by average 24-hour SBP, age, sex and hypertension. Patients with constitutional hypotension, orthostatic hypotension, predominant cardioinhibition or competing causes of syncope were excluded. Daytime and night-time SBP drops ( 90% and 80–90%, respectively. Findings were validated in an independent sample. Results: In the Derivation cohort, daytime SBP drops were significantly more common in 158 syncope patients than 329 controls. One or more daytime drop < 90 mmHg provided the best diagnostic yield (91% specificity, 32% sensitivity, Odds Ratio [OR] = 4.6, p = 0.001). Two or more-daytime drops < 100 mmHg achieved 84% specificity and 40% sensitivity (OR = 3.5, p = 0.001). Results were confirmed in the Validation cohort: one or more daytime SBP drop < 90 mmHg provided 94% specificity and 29% sensitivity (OR = 6.2, p < 0.001), while two or more daytime SBP drops < 100 mmHg achieved 83% specificity and 35% sensitivity (OR = 3.5, p < 0.001) Conclusions: SBP drops during ABPM are more common in reflex syncope patients than in controls. Cut-off values that may be applied in clinical practice are defined. This study expands the current indications for ABPM to patients with reflex syncope.

Millions of people worldwide live at high altitude, being chronically exposed to hypobaric hypoxia. Hypertension is a major cardiovascular risk factor but data on its prevalence and determinants in highlanders are limited, and systematic studies with ambulatory blood pressure monitoring are not available. Aim of this study was to assess the prevalence of clinic and ambulatory hypertension and the associated factors in a sample of Andean highlanders. Hypertension prevalence and phenotypes were assessed with office and ambulatory blood pressure measurement in a sample of adults living in Cerro de Pasco, Peru (altitude 4340 m). Basic clinical data, blood oxygen saturation, hematocrit, and Qinghai Chronic Mountain Sickness score were obtained. Participants were classified according to the presence of excessive erythrocytosis and chronic mountain sickness diagnosis. Data of 289 participants (143 women, 146 men, mean age 38.3 years) were analyzed. Office hypertension was present in 20 (7%) participants, while ambulatory hypertension was found in 58 (20%) participants. Masked hypertension was common (15%), and white coat hypertension was rare (2%). Among participants with ambulatory hypertension, the most prevalent phenotypes included isolated nocturnal hypertension, isolated diastolic hypertension, and systodiastolic hypertension. Ambulatory hypertension was associated with male gender, age, overweight/obesity, 24-hour heart rate, and excessive erythrocytosis. Prevalence of hypertension among Andean highlanders may be significantly underestimated when based on conventional blood pressure measurements, due to the high prevalence of masked hypertension. In highlanders, ambulatory hypertension may be independently associated with excessive erythrocytosis.

International audience; No abstract available

Aims In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown. Methods and results In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10–0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22–0.73; P = 0.002]. Conclusions Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF. Study registration ClinicalTrials.gov Identifier: NCT02137187.

Aims Exercise right heart catheterization (RHC) is considered the gold-standard test to diagnose heart failure with preserved ejection fraction (HFpEF). However, exercise RHC is an insufficiently standardized technique, and current haemodynamic thresholds to define HFpEF are not universally accepted. We sought to describe the exercise haemodynamics profile of HFpEF cohorts reported in literature, as compared with control subjects. Methods and results We performed a systematic literature review until December 2020. Studies reporting pulmonary artery wedge pressure (PAWP) at rest and peak exercise were extracted. Summary estimates of all haemodynamic variables were evaluated, stratified according to body position (supine/upright exercise), and the PAWP/cardiac output (CO) slope during exercise was extrapolated. Twenty-eight studies were identified, providing data for 2230 HFpEF patients and 706 controls. At peak exercise, patients with HFpEF achieved higher PAWP [30 (29–31) vs. 16 (15–17) mmHg, P Conclusions The haemodynamic profile of HFpEF patients is consistent across studies and characterized by a higher left and right filling pressure at rest, magnified by physical exercise. Our analysis strongly suggests that PAWP/CO slope might allow for a more consistent identification of HFpEF, irrespective of body position. This variable likely overcomes the shortcomings of an isolated peak PAWP measurement, allowing for a more univocal identification of HFpEF in patients with unexplained dyspnoea.

Aims Long scanning times impede cardiac magnetic resonance (CMR) clinical uptake. A ‘one-size-fits-all’ shortened, focused protocol [e.g. only function and late-gadolinium enhancement (LGE)] reduces scanning time and costs, but provide less information. We developed two question-driven CMR and stress-CMR protocols, including tailored advanced tissue characterization, and tested their effectiveness in reducing scanning time while retaining the diagnostic performances of standard protocols. Methods and results Eighty-three consecutive patients with cardiomyopathy or ischaemic heart disease underwent the tailored CMR. Each scan consisted of standard cines, LGE imaging, native T1-mapping, and extracellular volume. Fat/oedema modules, right ventricle cine, and in-line quantitative perfusion mapping were performed as clinically required. Workflow was optimized to avoid gaps. See Figure 1 for protocol details. Time target was 30% (CMR: from 42 ± 8 to 28 ± 6min; stress-CMR: from 50 ± 10 to 34 ± 6min, both P 45% of cases. Quality grading was similar between the two protocols. Tailored protocols did not require additional staff. Conclusions Tailored CMR and stress-CMR protocols including advanced tissue characterization are accurate and time-effective for cardiomyopathies and ischaemic heart disease.

Phase angle (PhA) is a recently proposed marker of nutritional status in many clinical conditions. Its use in patients with obesity presents different critical concerns due to the higher variability of the two measured parameters (resistance, R, and reactance, Xc) that contribute to the determination of PhA. Controversial is the relation between PhA and BMI that might vary with graded levels of obesity due to the variation in fat and free fat mass. Obesity is frequently associated with metabolic, hepatic, cardiovascular and kidney diseases that introduce variations in PhA values, in relation to multimorbidity and severity degree of these diseases. It is reported that the improvement of clinical condition is associated with a positive change in PhA. Also, the treatment of obesity with weight loss might confirm this effect, but with different responses in relation to the type and duration of the intervention applied. In fact, the effect appears not only related to the percentage of weight loss but also the possible loss of free fat mass and the nutritional, metabolic and structural modifications that might follow each therapeutic approach to decrease body weight. We can conclude that the PhA could be used as marker of health status in patients with obesity supporting an appropriate weight loss intervention to monitor efficacy and fat free mass preservation.

Objective Among patients with type 2 diabetes (T2D), the prevalence of hidden hypercortisolism (HidHyCo, formally called subclinical hypercortisolism or mild autonomous cortisol secretion) was estimated to be 2.2-12.1%. The aim of this study was to investigate whether the available literature helps to identify the characteristics of T2D patients more frequently associated with HidHyCo. Methods A meta-analysis was performed using studies that assessed both the prevalence of HidHyCo in patients with T2D and the characteristics of these patients with and without HidHyCo. The DerSimonian and Laird (DSL) and the Hartung, Knapp, Sidik and Jonkman (HKSJ) methods were utilized. Results Among the 18 available studies, 6 studies provided the necessary data. The association between HidHyCo and advanced T2D (based on the patients’ description given in each study in presence of micro/ microvascular complications, or insulin treatment plus hypertension, or hypertension treated with ≥2 drugs), hypertension, insulin treatment and dyslipidemia was reported in 5 (2184 patients), 6 (2283 patients), 3 (1440 patients), and 3 (987 patients) studies, respectively. HidHyCo was associated with advanced T2D as assessed with both DSL (odds ratio, OR, 3.47, 95% Confidence Interval, 95%CI, 2.12-5.67) and HKSJ method (OR 3.60, 95%CI 2.03-6.41) and with the prevalence of hypertension or of insulin treatment as assessed by the DSL approach (OR 1.92, 95%CI 1.05-3.50 and OR 2.29, 95%CI 1.07-4.91, respectively), but not as assessed with HKSJ method. Conclusions Patients with advanced T2D have a higher prevalence of HidHyCo. These data inform about the selection of T2D patients for HidHyCo screening.

Funding Acknowledgements Type of funding sources: None. COVID-19 pandemic has induced governments to promote strict containment measures which inevitably altered patients’ lifestyle with potential effects on blood pressure (BP) control. We aimed to evaluate the changes in home BP (HBP) during the COVID-19 related lockdown in a cohort of hypertensive patients. Consecutive adult patients with arterial hypertension and stable medical treatment were recruited. HBP values were recorded before and after lockdown in March 2020. An additional set of HBP measurements, recorded one year before the pre-lockdown period, were also considered as reference because of similar environmental temperature. A total of 126 patients were included: 47% males, mean age 66 [58-72], reference HBP 124.78 (9.90)/76.19 (8.10) mmHg. In the whole group, patients during lockdown exhibited lower systolic and diastolic HBP values compared to the pre-lockdown period [123.23 vs 125.05 mmHg, p = 0.008 and 74.45 vs 75.28 mmHg, p = 0.023, respectively]. Patients with uncontrolled HBP showed the most consistent drop of systolic HBP [136.06 (8.36) and 138.0 (2.08) vs 130 (9.35) p = 0.001 and p In conclusion, this study reports for the first time the occurrence of no changes or even a reduction in home BP of treated hypertensive patients during lockdown due to COVID-19. These results may have implications for the management of patients with high blood pressure not only during the current pandemic but also in case of future lockdown conditions. Abstract Figure 1

Background Animal models used to study pathologies requiring rehabilitation therapy, such as cardiovascular and neurologic disorders or oncologic disease, must be as refined and translationally relevant as possible. Sometimes, however, experimental procedures such as those involving restraint may generate undesired effects which may act as a source of bias. However, the extent to which potentially confounding effects derive from such routine procedures is currently unknown. Our study was therefore aimed at exploring possible undesirable effects of acute restraint stress, whereby animals were exposed to a brightly lit enclosed chamber (R&L) similar to those that are commonly used for substance injection. We hypothesised that this would induce a range of unwanted physiological alterations [such as neuroinflammatory response and changes in body weight and in brown adipose tissue (BAT)] and behavioural modification, and that these might be mitigated via the use of non-aversive handling methods: Tunnel Handling (NAH-T) and Mechanoceptive Handling (NAH-M)) as compared to standard Tail Handling (TH). Methods Two indicators of physiological alterations and three potentially stress sensitive behavioural parameters were assessed. Physiological alterations were recorded via body weight changes and assessing the temperature of Brown Adipose Tissue (BAT) using infra-red thermography (IRT), and at the end of the experiment we determined the concentration of cytokines CXCL12 and CCL2 in bone marrow (BM) and activated microglia in the brain. Nest complexity scoring, automated home-cage behaviour analysis (HCS) and Elevated Plus Maze testing (EPM) were used to detect any behavioural alterations. Recordings were made before and after a 15-minute period of R&L in groups of mice handled via TH, NAH-T or NAH-M. Results BAT temperature significantly decreased in all handling groups following R&L regardless of handling method. There was a difference, at the limit of significance (p = 0.06), in CXCL12 BM content among groups. CXCL12 content in BM of NAH-T animals was similar to that found in Sentinels, the less stressed group of animals. After R&L, mice undergoing NAH-T and NAH-M showed improved body-weight maintenance compared to those exposed to TH. Mice handled via NAH-M spent a significantly longer time on the open arms of the EPM. The HCS results showed that in all mice, regardless of handling method, R&L resulted in a significant reduction in walking and rearing, but not in total distance travelled. All mice also groomed more. No difference among the groups was found in Nest Score, in CCL2 BM content or in brain activated microglia. Conclusions Stress induced by a common restraint procedure caused metabolic and behavioural changes that might increase the risk of unexpected bias. In particular, the significant decrease in BAT temperature could affect the important metabolic pathways controlled by this tissue. R&L lowered the normal frequency of walking and rearing, increased grooming and probably carried a risk of low-grade neuro-inflammation. Some of the observed alterations can be mitigated by Non-aversive handlings.

Objectives: Sex steroids, administered as a priming before GH stimulation tests (GHST) to differentiate between growth hormone deficiency (GHD) and constitutional delay of growth and puberty (CDGP) or as growth-promoting therapy using low-dose sex steroids (LDSS) in CDGP, are much debated. We aimed to compare auxological outcomes of CDGP or GHD children undergoing primed or unprimed GHST and to evaluate LDSS treatment in CDGP. Design: Retrospective study among three paediatric University Hospitals in Italy and UK. Methods: 184 children (72 females) aged 12.4±2.08years underwent primed (/P+) or unprimed (/P−) GHST and were followed up until final height (FH). CDGP patients were untreated (CDG P−) or received LDSS (CDGP+). The cohort included 34 CDG P−/P+, 12 CDGP+/P+, 51 GHD/P+, 29 CDG P−/P−, 2 CDGP+/P− and 56 GHD/P−. FH standard deviation score (SDS), Δ SDS FH-target height (TH) and degree of success (−1≤Δ SDS FH-SDS TH ≤ +1) were outcomes of interest. Results: GHD/P+ had better FH-SDS (−0.87 vs −1.49; P=.023) and ΔSDS FH-TH (−0.35 vs −0.77; P=.002) than CDGP−/P+. Overall, GHD/P+ showed the highest degree of success (90%, P=.006). Regardless of priming, both rhGH and LDSS improved degree of success compared to no treatment (89% and 86% vs 63%, P=.0009). GHD/P+ showed a trend towards a higher proportion of permanent GHD compared to GHD/P- (30.43% vs 15.09%; P=.067). Conclusion: In peripubertal children, priming before GHST improves diagnostic accuracy of GHST for idiopathic GHD. LDSS treatment improves auxological outcomes in CDGP.

Objective To evaluate the association of all RAAS inhibitors, ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on dementia onset (any dementia, Alzheimer’s disease and vascular dementia) using a meta-analytic approach. Methods A systematic MEDLINE search was carried out to identify all observational studies published up to the 30th September 2020 evaluating the association between RAAS inhibitors and risk of dementia. Studies were included if original investigations considering incident dementia cases, with ACEIs and/or ARBs as exposure and other antihypertensives (AHs) use as reference, and if reporting association estimates and relative variability measures. Random effect pooled relative risks (pRR) and the corresponding 95% confidence intervals (95%CI) were calculated according to DerSimonian and Laird’s (DL) or to Hartung Knapp Sidik Jonkman (HKSJ) method depending on the number of studies and between-studies heterogeneity. A linear mixed meta-regression model (MM) was applied to take into account correlation among association estimates from the same study. Results 15 studies were included in the meta-analysis. ARBs but not ACEIs’ use led to a significant reduction of the risk of any dementia (pRR 0.78, 95%CIMM 0.70–0.87) and Alzheimer’s disease (pRR 0.73, 95%CIMM 0.60–0.90). Moreover, when compared to ACEIs, ARBs reduced of 14% the risk of any dementia (pRR 0.86, 95%CIDL 0.79–0.94). Conclusions ARBs but not ACEIs led to a reduction in the risk of any dementia. The difference between ARBs and ACEIs in terms of preventive effectiveness could be due to distinct profiles of antagonism towards independent receptor pathways or to differential influences on amyloid metabolism.

Background & aims: Obesity is characterized by fat mass excess (FM), extra cellular water increase (ECW) and, with ageing, decrease in fat free mass (FFM). The validity of body impedance analysis (BIA) in patients with mild to severe obesity is still debated. The purpose of this study is to describe the Resistance (Rz) and Reactance (Xc) values obtained by Body Impedance Analysis (BIA) in a wide cohort of Italian patients with mild to severe obesity. The secondary endpoint is to describe the resulting body composition values (as percentage and indexes) in this population. Methods: The study enrolled adult in-patients with mild to severe obesity (classified with class I, II and III obesity) undergoing clinical care rehabilitation program for obesity complications and weight loss. BIA values were grouped by sex, BMI and age classes. Results: A total of 8303 patients with obesity, aged 18 to 90 y, were studied. The Resistance (Rz) and Reactance (Xc) were reported by sex, age and BMI classes. In women and men both, the phase angle (PhA) decreases with increasing BMI (kg/m2) and the resulting BIA vector was significantly shifted. The FM index (FMI) was higher (p < 0.0001) in women while FFM index (FFMI) was higher in men (p < 0.0001) and significantly associated with BMI. FFMI decreased with age in both sex (p < 0.0001). Skeletal mass (SM) presents a progressive reduction in relation to age and gender both. Conclusions: The present BIA-based body composition analysis in a wide cohort of mild to severe obese patients revealed a significantly decreased Rz and Xc values with a consequent significant decrease of PhA in a BMI-dependent manner. The body compartments estimation with available equations was BMI, sex and age dependent. These observational results could be the basis for the development of new equations adapted for patients suffering from obesity.