Initial Clinical Experience With a Novel Robotically Assisted Platform for Combined Mini-Percutaneous Nephrolithotomy and Flexible Ureteroscopic Lithotripsy.

PURPOSE: We sought to evaluate the technical feasibility of performing a combined robotically assisted mini-percutaneous nephrolithotomy (PCNL) and flexible ureteroscopy (URS) procedure by a single urologist using the MONARCH Platform, Urology (Johnson & Johnson MedTech, Redwood City, California). MATERIAL AND METHODS: In this prospective, first-in-human clinical trial, 13 patients underwent robotically-assisted PCNL for renal calculi at the University of California-Irvine, Department of Urology. Successful completion of the procedure was assessed as the primary endpoint. Postoperative adverse events were monitored for 30 days following the completion of the procedure. Stone ablation efficiency was evaluated on postoperative day 30 with low-dose 2-3 mm slice CT scans. Patients were classified according to the maximum length of their residual stone fragments as either absolute stone-free (Grade A), < 2 mm remnants (Grade B), or 2.1-4.0 mm remnants (Grade C). RESULTS: The combined robotic mini-PCNL and URS procedure was successfully completed in 12 of 13 procedures. No robotic device-related adverse events occurred. Preoperative stone burden was quantified by both maximum linear measurement (median 32.8 mm) as well as by CT-based volume (median 1645.9 mm3). Using the unique robotically assisted targeting system, percutaneous access was gained directly through the center of the renal papilla in a single pass in all cases. Median operative time was 187 minutes (range: 83-383 minutes). On postoperative day 30, a 98.7% (range: 72.9%-100.0%) volume reduction was achieved, with 5 Grade A (38.5%), 1 Grade B (7.7%), and 2 Grade C (15.4%). Three patients experienced complications (2 grade 1 and one grade 2 Clavien-Dindo). CONCLUSIONS: Our preliminary investigation demonstrates the safety, efficacy, and feasibility of a unique robotic-assisted combined mini-PCNL and URS platform.

Evaluation of antibody response anti SARS-Cov-2: A retrospective observational study (Marche-Italy).

BACKGROUND: COVID-19 has hit every country in the world. Almost a quarter of a billion cases and nearly 5 million deaths reported globally as of late September 2021. Compared to over 6 billion doses of COVID-19 vaccine administered, the pandemic does not seem to disappear. The duration of protective immunity is currently not defined. Primary immune responses are inevitably declining and the continuous transmission of increasingly worrying viral variants. OBJECTIVE: The primary objective of the study is to evaluate the antibody response at 120 and 180 days in employees of an hospital of Marche (Italy) who have completed the vaccination cycle with Pzifer-Biontech vaccine and to highlight the correlation with quantitative and qualitative variables. The secondary objective is to study the nature and frequency of adverse events in relation to variables such as comorbidity, age, gender, working areas and developed antibody titer. MATERIALS AND METHODS: An observational retrospective study was carried out to evaluate the antibody response at 120 and 180 days. Subjects receiving a double dose of vaccine at least 21 days apart and those receiving the second dose of the same vaccine between 18 January 2021 and 31 March 2021 shall be considered. The study included non-probability sampling of convenience. All parties have provided informed written consent to access personal and clinical data. RESULTS: The sample is composed by 1.115 subjects. The results of the study reveal an important immune response detected by IgG dosage, both at 120 and 180 days after the second dose of Sars-Cov-2 vaccine mRNA BNT162b2 vaccine (Pzifer-Biontech), other than very rare exceptions. Antibody values are higher among hospital workers compared to those working in other areas, both 120 and 180 days. These values are even higher in the health professionals who provide assistance in wards with positive Covid patients, both at 120 days (p=0.06) and at 180 days; the mean values of IgG are statistically higher in direct assistance of Covid patients at 180 days(p=0.029). The most frequent adverse drug events after the second dose of vaccine were pain at the site of inoculation of the vaccine (70.7%), fatigue (35%) and arthralgia (19%). It was finally shown that people with diabetes or smokers had an average antibody response statistically lower than 120 days and 180 days from the second dose. DISCUSSION AND CONCLUSION: This study leads to the conclusion that the second dose of vaccine Sars-Cov-2 vaccine mRNA BNT162b2 vaccine allows a consistent antibody response. Further multicentric studies are needed to investigate the antibody response to vaccination Sars-Cov-2 mRNA BNT162b2.

Antidepressant continuation and adherence in pregnancy, and risk of antenatal hospitalization for unipolar major depressive and/or anxiety disorders.

BACKGROUND: Knowledge about the effectiveness of antidepressants in pregnancy is limited. We aimed to evaluate the association of antidepressant continuation in pregnancy and adherence with the risk of antenatal hospitalization for depression/anxiety. METHODS: In a population-based study based on the healthcare databases of the Lombardy region, Italy (2010-2020), we included 17,033 live-birth pregnancies within 16,091 women with antidepressant use before pregnancy. Antidepressant exposure was classified as continued in pregnancy versus discontinued proximal to pregnancy. Outcome measure was antenatal hospitalization for depression/anxiety. Propensity score matching analysis was performed to control for measured confounding. Stratification by pre-pregnancy antidepressant adherence based on the proportion of days covered (PDC) with antidepressants served to address confounding by disease severity. We applied 60 days lag-time for antidepressant exposure to minimize the risk of protopathic bias. RESULTS: There were 362 (2.1 %) antenatal hospitalizations for depression/anxiety. Among the matched pairs, the cumulative incidence was 3.5 (continued antidepressant) versus 2.1 (discontinued antidepressant) per 1000 person-months, yielding a hazard ratio (HR) of 1.76 (95 % confidence interval (CI): 1.34-2.33)). The HR declined to the null (1.02, 95 % CI: 0.62-1.69) in the stratified analysis of pregnancies with moderate-high adherence pre-pregnancy. Moderate-high adherence in pregnancy was associated with 85 % greater risk of the antenatal outcome, but the HR decreased with the 60 days lag-time (HR: 1.40, 95 % CI: 0.79-2.50). LIMITATIONS: Lack of information regarding antidepressant dosage. CONCLUSION: We found no difference in risk for antenatal hospitalization for depression/anxiety with antidepressant continuation or higher adherence in pregnancy, relative to discontinuation or lower adherence.

Impact of Work Motivation on Occupational Health in Healthcare Workers.

OBJECTIVES: The present cross-sectional study investigated, in a group of Italian healthcare workers (HCWs), the association between work motivation and occupational health and the impact of socio-demographic and job-related variables on this association. METHODS: A total of 656 subjects (nurses, technicians, midwives and physiotherapists) completed the survey. Linear regression models were used to correlate motivation types (by Scale of Motivation At Work) with health indicators (general health, depression, professional exhaustion, satisfaction and turnover intention) and burnout's subscales (emotional exhaustion, depersonalization and reduced professional achievement). FINDINGS: Autonomous motivation correlated positively with general health and work satisfaction and negatively with depression, exhaustion and turnover intention. Scoring high on intrinsic/integrated regulation was associated with better health and job satisfaction and with turnover intention, depression and emotional exhaustion. Controlled motivation, demotivation and external regulation nourished burnout's indicators, while autonomous motivation was protective. Operating in intensive care or surgical areas negatively affected general health; working as a nurse manager or midwife increased one's depressive risk and reduced satisfaction; being older than 60 increased emotional exhaustion and turnover intention; having a master's degree protected from exhaustion and depression. IMPLICATIONS: Collectively, our findings extend evidence on the role of work motivation in shaping occupational health and underline the importance for healthcare organizations of promoting actions to reinforce autonomous motivation at work.

Pulsatile stretch induces release of angiotensin II and oxidative stress in human endothelial cells: effects of ACE inhibition and AT1 receptor antagonism.

Mechanical forces and the activation of the renin-angiotensin system (RAS) may alter the NO/O2(*-) balance, imparing endothelial nitric oxide (NO) availability. This study investigates the link between RAS and NO/O2(*-) balance in human aortic endothelial cells (HAEC) exposed to pulsatile stretch with and without ACE inhibitor quinaprilat or angiotensin II type 1 (AT(1)) receptor antagonist losartan. Pulsatile stretch increased Ang II levels and O2(*-) production, reducing NO release. RAS blockade with quinaprilat or losartan restored the balance between NO and O2(*-). These results provide a molecular basis for understanding the vascular protective effects of ACE inhibition and AT(1) receptor antagonism.

Adenosine A1 receptor expression during the transition from compensated pressure overload hypertrophy to heart failure.

OBJECTIVES: Myocardial adenosine is increased in pressure-overload hypertrophy (POH) and exerts important cardioprotective effects that delay transition to left ventricular failure. Adenosine-mediated signaling is attenuated in POH, but whether this depends on receptor or postreceptor defects is unknown. We therefore examined left ventricular adenosine A1-receptor gene and protein expression in experimental POH. METHODS: Six week-old Sprague-Dawley rats were subjected to abdominal aortic banding (group B) or sham operation (group S). Echocardiography and left ventricular catheterization were performed 10 weeks later under ketamine anesthesia. Left ventricular and lung weight indices were obtained postmortem. A1-Receptor mRNA and protein expression were measured in samples from left ventricular, right ventricular and aortic arch tissue. Group B rats were subgrouped as having compensated or decompensated hypertrophy according to the absence or presence of lung congestion (lung weight index below or above mean +/- 2SD compared with group S rats). RESULTS: Both mRNA and protein A1-receptor expression were significantly increased in compensated group B versus group S rats (by, respectively, 37 and 77%; both P < 0.01). This was not observed in decompensated group B rats. No consistent gene or receptor expression changes were observed in right ventricular or aortic tissues. CONCLUSIONS: In compensated POH, increased interstitial adenosine concentrations are accompanied by increased expression of the specific receptor mediating the major cardioprotective effects of this autacoid. Such overexpression is no longer detectable once the transition from POH to left ventricular failure has occurred. These observations may have pathophysiological and, in perspective, therapeutic relevance to the course of hypertensive heart disease.

Matrix metalloprotease activity is enhanced in the compensated but not in the decompensated phase of pressure overload hypertrophy.

BACKGROUND: During the transition of pressure overload hypertrophy (POH) to heart failure (HF) there is intense interstitial cardiac remodeling, characterized by a complex balance between collagen deposition and degradation by matrix metalloproteases (MMPs). This study was aimed at investigating the process of cardiac remodeling during the different phases of the transition of POH to HF. METHODS: Guinea pigs underwent thoracic descending aortic banding or sham operation. Twelve weeks after surgery, left-ventricular (LV) end-diastolic internal dimension and ventricular systolic pressure were measured by combined M-mode echocardiography and micromanometer cathetherization. The MMP activity, tissue-specific MMP inhibitors (TIMPs), and collagen fraction were evaluated in LV tissue samples by zymography, ELISA, and computer-aided analysis, respectively. RESULTS: Banded animals were divided by lung weight values into either compensated left-ventricular hypertrophy (LVH) or HF groups, as compared with sham-operated controls. All HF animals exhibited a restrictive pattern of Doppler transmitral inflow, indicative of diastolic dysfunction, and developed lung congestion. Compensated LVH was associated with increased MMP-2 activity, which was blunted after transition to HF, at a time when TIMP-2 levels and collagen deposition were increased. CONCLUSIONS: The cardiac remodeling process that accompanies the development of POH is a phase-dependent process associated with progressive deterioration of cardiac function.

Deletion of p66shc gene protects against age-related endothelial dysfunction.

BACKGROUND: Enhanced production of reactive oxygen species (ROS) has been recognized as the major determinant of age-related endothelial dysfunction. The p66shc protein controls cellular responses to oxidative stress. Mice lacking p66shc (p66shc-/-) have increased resistance to ROS and a 30% prolonged life span. The present study investigates age-dependent changes of endothelial function in this model. METHODS AND RESULTS: Aortic rings from young and old p66shc-/- or wild-type (WT) mice were suspended for isometric tension recording. Nitric oxide (NO) release was measured by a porphyrinic microsensor. Expression of endothelial NO synthase (eNOS), inducible NOS (iNOS), superoxide dismutase, and nitrotyrosine-containing proteins was assessed by Western blotting. Nitrotyrosine residues were also identified by immunohistochemistry. Superoxide (O2-) production was determined by coelenterazine-enhanced chemiluminescence. Endothelium-dependent relaxation in response to acetylcholine was age-dependently impaired in WT mice but not in p66shc-/- mice. Accordingly, an age-related decline of NO release was found in WT but not in p66shc-/- mice. The expression of eNOS and manganese superoxide dismutase was not affected by aging either in WT or in p66shc-/- mice, whereas iNOS was upregulated only in old WT mice. It is interesting that old WT mice displayed a significant increase of O2- production as well as of nitrotyrosine expression compared with young animals. Such age-dependent changes were not found in p66shc-/- mice. CONCLUSIONS: We report that inactivation of the p66shc gene protects against age-dependent, ROS-mediated endothelial dysfunction. These findings suggest that the p66shc is part of a signal transduction pathway also relevant to endothelial integrity and may represent a novel target to prevent vascular aging.

High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species.

BACKGROUND: Prostaglandins generated by cyclooxygenase (COX) have been implicated in hyperglycemia-induced endothelial dysfunction. However, the role of individual COX isoenzymes as well as the molecular mechanisms linking oxidative stress and endothelial dysfunction in diabetes remains to be clarified. METHODS AND RESULTS: Human aortic endothelial cells were exposed to normal (5.5 mmol/L) and high (22.2 mmol/L) glucose. Glucose selectively increased mRNA and protein expression of COX-2. Its upregulation was associated with an increase of thromboxane A2 and a reduction of prostacyclin (PGI2) release. Glucose-induced activation of PKC resulted in the formation of peroxynitrite and tyrosine nitration of PGI2 synthase. NO release was reduced despite 2-fold increase of endothelial NO synthase expression. Phorbol ester caused an increase of COX-2 and endothelial NO synthase expression similar to that elicited by glucose. These effects were prevented by the PKC inhibitor calphostin C. N-acetylcysteine, vitamin C, and calphostin C prevented ROS formation, restored NO release, and reduced colocalization of nitrotyrosine and PGI2 synthase. Expression of p22(phox), a subunit of NAD(P)H oxidase, was increased, and diphenyleneiodonium inhibited ROS formation. By contrast, indomethacin did not affect glucose-induced ROS generation. CONCLUSIONS: Thus, high glucose, via PKC signaling, induces oxidative stress and upregulation of COX-2, resulting in reduced NO availability and altered prostanoid profile.

The question of disability in the post-human debate. Critical remarks.

The issue of disability represents a test case for the sustainability, practical and theoretical, of transhumanist theories that lead to the advent of a posthuman era. In fact, dealing with mankind implies also the possibility that man has a disability. So, seeing whether, in the posthuman debate, persons with disability are respected, will show us if every man is respected. In this paper we start by analyzing the definition of disability given by the posthuman theorists. As we will see, this definition is deficient because it is strictly linked with the transhumanists' refusal of the distinction between therapeutic treatment and enhancement. The field of enhancement is very wide, and the moral judgment on it cannot be generalized. Nowadays, many developments made possible by human enhancement theories remain only speculated upon. However, those theories are already influential in the field of studying the beginning of life. Indeed, the possibility "to choose children" is real: here the issue of disability is decisive and the risk of discrimination is very high. So, looking at the issue of disability will allow us to explore the ethical weight of the post-human project. In the background, it will be possible to glimpse the question of what is the essence of man, an issue not considered enough in the post-human debate. On the contrary, it is a fundamental question which should be answered before proceeding to a substantial alteration of humanity.

Survival benefits of different antiadrenergic interventions in pressure overload left ventricular hypertrophy/failure.

We observed previously that in rats with aortic banding (Bd), development of left ventricular (LV) hypertrophy is opposed by beta-blockade, whereas interventions interfering with alpha-adrenoceptor function also inhibit interstitial fibrosis. To assess whether these differential structural effects do translate into different effects on LV function and on heart failure mortality, Bd or sham Bd 8-week-old rats were randomized to vehicle treatment (Vh), chemical sympathectomy ([Sx] 6-hydroxydopamine, 150 mg/kg IP twice a week), beta-adrenoceptor blockade (propranolol [Pro], 40 mg/kg per day PO), or alpha-adrenoceptor blockade (doxazosin [Dox], 5 mg/kg per day PO). After monitoring survival for 10 weeks, the survivors were anesthetized to undergo echocardiography and intraarterial blood pressure measurement. Bd-Vh rats showed increased LV and lung weights, as well as LV dilation, depressed endocardial and midwall fractional shortening and a restrictive transmitral diastolic flow velocity pattern. Compared with Bd-Vh rats, all of the actively treated Bd rats showed less LV hypertrophy, LV dilation, and lung congestion but no less depression of midwall fractional shortening. In contrast, Sx and Dox but not Pro treatment were also associated with lesser degrees of diastolic dysfunction and, even more importantly, with a striking increase in survival (sham banded rats, 100%; Bd-Vh, 40%; Bd-Pro, 51%; Bd-Sx, 83%; and Bd-Dox, 82%). Although Pro, Sx, and Dox provide similar midterm protection from development of LV hypertrophy and dysfunction and from circulatory congestion, only Sx and Dox favorably affected mortality. These findings indicate that in the aortic banding rat model, alpha-adrenoceptors are importantly involved in the pathogenesis of cardiovascular deterioration and disease progression.