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The present study was undertaken to evaluate the probability of achieving the Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) treatment targets of remission or low disease activity (LDA) with apremilast based on disease activity categories and corresponding responses in arthritis and other domains of psoriatic arthritis (PsA) not included in the cDAPSA. Pooled analyses from the Psoriatic Arthritis Long‐term Assessment of Clinical Efficacy studies 1, 2, and 3 were performed. Probability analyses assessing the likelihood of achieving cDAPSAtreatment targets by week 52 were performed using multiple imputation for discontinuations and missing values. Longitudinal analyses were performed in patients grouped by cDAPSAcategory at week 52. Among 494 patients in the probability analyses, 46.9% with moderate disease activity and 24.9% with high disease activity at baseline achieved treatment targets (remission or LDA) by week 52. For patients with moderate disease activity at baseline, small improvements (cDAPSAreductions ≥30%) by week 16 were associated with achieving targets. Patients achieving remission or LDAby week 16 had high probabilities of remaining at treatment targets at week 52. Of 375 patients with cDAPSAcomponents available at week 52, achieving targets with apremilast was associated with continuous disease activity improvements and no or mild arthritis and other PsA manifestations. The probability of achieving treatment targets (remission or LDA) at week 52 was greater for patients with moderate versus high disease activity at baseline. At a mean level, partial improvements by week 16 were associated with achieving treatment targets. Patients receiving apremilast who achieved cDAPSAtargets by week 52 also had no or mild arthritis or other PsA manifestations.

Advancements in sample preparation for performing elemental analysis are coming from the dissemination of microwave-assisted procedures, but there is still room for improvements by looking for fast and easily applicable procedures. In the present study, open-vessel digestion sample treatment (19–21 °C or 95 °C) was compared with closed-vessel microwave-assisted digestion (180 °C). Detection and quantification limits, accuracy, precision, residual carbon content, and residual acidity were quantified with certified and in-field hair samples. Human hair samples (0.02 g) were digested with HNO3/H2O2(2 : 1) in an open vessel heated to 95 °C. The residual carbon content was <87 ± 6 mg L−1and the residual acidity was <0.86 ± 0.10 mol L−1in the final digested samples. The elements (Al, As, B, Ba, Be, Bi, Ca, Cd, Ce, Co, Cr, Cs, Cu, Fe, Ga, K, La, Li, Mg, Mn, Mo, Na, Nb, Ni, P, Pb, Rb, Sb, Se, Si, Sn, Sr, Te, Ti, Tl, U, V, W, Zn, and Zr) were determined with a quadrupole inductively coupled plasma mass spectrometer equipped with a collision–reaction interface. A detection limit of 0.00002–30 mg kg−1, a (repeatability of <11%, an intermediate precision of <13%, a trueness bias of −4 to 9%, and a recovery of 90–110% for all the elements except for Cr = 65% and Fe = 79% were observed. The results indicate that the proposed method is suitable for routine multi-elemental analysis in human hair studies.

The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse. Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge‐like alcohol consumption, as measured by the “drinking in the dark” (DID) model in C57BL/6J mice. We found that 2 potent and selective NOP agonists AT‐202 (0, 0.3, 1, 3 mg/kg) and AT‐312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT‐202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol‐containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB‐612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB‐612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB‐612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB‐612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2‐bottle choice DID model that can assess moderate alcohol intake. The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking. Binge drinking represents an enormous public health concern in the United States and worldwide. We report experiments showing that treatment with antagonists of the receptor of the Nociceptin Orphanin FQPeptide (NOPreceptor) decreases excessive alcohol consumption in mouse models of binge‐like alcohol drinking. These experiments demonstrate that NOPreceptor inhibition rather than activation represents a valuable approach for treatment of alcohol use disorders characterized by excessive alcohol consumption in humans.

AbstractThe World Bank has reviewed its environmental and social policies at a moment of intense production of international instruments dealing with land tenure, all of which take the form of soft law. This endeavour is motivated by the progressive acknowledgement of the importance of secure and equitable access to land for the realization of human rights and food security. The latest contribution of the World Bank to this debate is of great significance. This article aims to unveil the effects that the new Environmental and Social Framework is likely to generate in this context. It analyses the protection of access to land and security of tenure contained in the World Bank’s Environmental and Social Standards in light of the developments occurring at the international level. To this end, the article reviews the changes to the standards in the context of the social impacts when a lending project affects land holders or users directly or indirectly; addresses the mechanisms for protecting, compensating and improving livelihood opportunities for those affected by the projects; and comments on the safeguarding of indigenous peoples’ lands. The article finds that the World Bank, by incorporating some of these emerging standards, has confirmed the relevance of emerging principles and guidelines on land, even if they are contained in non-binding instruments. On a critical note, the article recognizes the refusal of the World Bank to adopt the underlying discourse and fully embrace human rights achievements in the context of land issues.

We integrate paleoseismic data sets along the Mt. Vettore‐Mt. Bove normal fault system rupturing at the surface in the 30 October 2016 Norcia earthquake. Through the analysis of new trenches from this work and a review of the preexisting data, we correlate events among trench sites along antithetic and synthetic fault splays. We recognize seven M 6.5, 2016 Norcia‐type (or larger) surface‐faulting events in the last ~22 kyr, including 2016. Before 2016, one event occurred in the past two millennia (260–575 CE) and possibly corresponds to the event damaging Rome in 443 or 484/508 CE. Three previous events occurred between 10590 and 415 BCE, whereas the two oldest ones date between 19820 and 16540 BCE. The average recurrence time is 3,360–3,640 years for the last ~22 kyr and 1,220–1,970 years for the last ~4 kyr. We infer a minimum dip‐slip rate of 0.26–0.38 mm/year on the master fault in the central portion of the Mt. Vettore–Mt. Bove normal fault system and a dip‐slip rate of at least 0.10 mm/year on the southernmost portion. We infer a Middle–Late Pleistocene inception of the long‐term scarp of the investigated splays. The along‐strike variation of slip rates well reproduces the trend of the 2016 surface slip; thus, the time window exposed in the trenches is representative for the present fault activity. Based on trenching data, different earthquake rupture scenarios should be also considered for local hazard assessment. We integrate paleoseismic datasets along the Mt. Vettore‐Mt. Bove normal fault system rupturing on 30 October 2016, M6.5, Norcia EarthquakeSeven surface faulting events ruptured the Mt. Vettore-Mt. Bove fault systemin the past ~22 kyrPaleoseismologic slip rates, recurrence intervals, and rupture scenarios contribute to the understanding of seismogenic processes in central pennines

The Renal Expert in Vascular Access (REVAC) is one of the four modules of the Nephrology Partnership for Advancing Technology in Healthcare (N-PATH) project, the first European-wide advanced training course in diagnostics and interventional nephrology, funded by Erasmus+ Knowledge Alliance, a European Commission program. The N-PATH primary goal was to train 40 young European nephrologists in both theoretical knowledge and practical skills related to interventional nephrology. The REVAC module focused on the crucial aspects of vascular access (VA) care in nephrology practice, as a complementary training path to the actual residency program. The aim was to provide nephrology fellows with comprehensive knowledge and skills related to VA management. The methodology was based on face-to-face meetings and online learning, modern facilities, experienced tutors, cutting edge simulators, augmented reality tools by means of a multidisciplinary international faculty and hands-on-courses. A feedback survey reported the experience of fellows who attended the REVAC module, confirming the positive impact on their ongoing nephrology training. We are confident that this project will revitalize their nephrology careers and will help training the next generation of nephrologists; they will be able to manage VA needs with the help of multi-disciplinary teams to safely optimize the care of hemodialysis patients.

Background: Since in Italy there are no official data on vascular access (VA) for hemodialysis the Vascular Access Project Group (VAPG) of the Italian Society of Nephrology (SIN) designed a national survey.Methods: A 35-question survey was designed and sent it to the Italian facilities through the SIN website. The basic questions were the prevalence, the location, and the surveillance of VA, the bedside use of ultrasound, the use of fluoroscopy for central venous catheter (CVC) placement, and of buttonhole technique, the role of nephrologist in the access creation.Result: The questionnaire was completed in June 2022 by 161 facilities. The survey registered 15,499 patients, approximately one-third of the Italian dialysis population. The prevalence of arteriovenous fistula (AVF), arteriovenous Graft (AVG), and CVC were 61.8%, 3.7%, and 34.5% respectively. The AVF location was 50% in distal forearm, 20% in meanproximal forearm, 30% in upper arm. For AVF creation, nephrologists were involved in 72% of facilities while for CVC placement in 62%. As regards VA monitoring, 21% of the facilities did not have a surveillance protocol; 60% did not register AVF thrombosis and 53% did not register CVC infections. Most of facilities use the fluoroscope during CVC placement, 37% when needed, and 22% never. Ultrasound-guided puncture of complex AVFs was used by 80% of facilities. Buttonhole puncture was used in 5% of patients.Conclusions: Some considerations emerge from the survey data: (1) The increasing CVC prevalence compared to DOPPS 5 study. (2) The low rate of AVG prevalence. (3) The nephrologist is the operator in many VA procedures. (4) The fluoroscopy for CVC placement and the US-guide puncture of the complex AVF are widely used in most facilities. (5) The practice of the buttonhole is not widespread. (6) When the operator is the nephrologist more distal fistulas are performed.

During the past three years, -skopìa[EDUCATION], the educational branch of the recently established start-up of the University of Trento, -skopìa, has conducted an extensive series of future laboratories in the classroom, working in particular with students aged twelve years old (second year of “medie inferiori”) and fifteen years old (second year of “medie superiori”). Future labs follow an explicit protocol (initial and final tests, three major steps, respectively, focused on the past, the future and the present). Teachers wanting to conduct a lab in their classroom must attend a preliminary training course. Furthermore, all the labs are monitored by -skopìa.

We conducted paleoseismic studies along the Montereale fault system (MFS; central Italy). The MFS shows geomorphological evidence of Late Quaternary activity and falls within the highest seismic hazard zone of central Apennines, between the epicentral areas of two recent earthquake sequences: 2009 L'Aquila and 2016–2017 central Italy. We excavated two trenches along the San Giovanni fault splay of the system, one intercepting the N140° striking bedrock main fault plane and the other cutting two subparallel fault scarps on the colluvial/alluvial deposits on the fault hanging wall. Excavations revealed repeated fault reactivation with surface faulting in prehistorical and historical times. We recognized and dated seven events in the last 26 kyr. The most recent ground‐rupturing event (evb1) possibly occurred 650–1,820 AD, consistent with one of the three main shocks that struck the area in 1,703 AD. A previous event (evb2) occurred between 5,330 bcand 730 bc, while older events occurred at 6,590–5,440 bc(evb3), 9,770–6,630 bc(evb4), and 16,860–13,480 bc(evb5). We documented two older displacement events (evb7 and evb6) between 23,780 bcand 16,850 bc. The minimum vertical slip rate at the trench site in the last 28–24 kyr is 0.3–0.4 mm/year. The inferred average recurrence interval for surface‐faulting events along the MFS is no longer than ~4 kyr. Based on the surface fault length ranging between 12 and 20 km, earthquakes with ≥M6.0 are possible for the MFS. The MFS is an independent earthquake source, and its paleoseismic data are fully comparable with those known for faults in central Apennines. Seven earthquakes ruptured the Montereale fault system (central Italy) since 26 kyrFirst estimates of the Montereale fault parameters: length, earthquake recurrence, and slip rateThe Montereale fault system is an individual earthquake source within the central Apennines seismogenic belt (Italy)

The Italian nephrology has a long tradition and experience in the field of dietetic-nutritional therapy (DNT), which is an important component in the conservative management of the patient suffering from a chronic kidney disease, which precedes and integrates the pharmacological therapies. The objectives of DNT include the maintenance of an optimal nutritional status, the prevention and/or correction of signs, symptoms and complications of chronic renal failure and, possibly, the delay in starting of dialysis. The DNT includes modulation of protein intake, adequacy of caloric intake, control of sodium and potassium intake, and reduction of phosphorus intake. For all dietary-nutritional therapies, and in particular those aimed at the patient with chronic renal failure, the problem of patient adherence to the dietetic-nutritional scheme is a key element for the success and safety of the DNT and it can be favored by an interdisciplinary and multi-professional approach of information, education, dietary prescription and follow-up. This consensus document, which defines twenty essential points of the nutritional approach to patients with advanced chronic renal failure, has been written, discussed and shared by the Italian nephrologists together with representatives of dietitians (ANDID) and patients (ANED).

The mechanism of interaction of an intrinsically disordered protein (IDP) with its physiological partner is characterized by a disorder-to-order transition in which a recognition and a binding step take place. Even if the mechanism is quite complex, IDPs tend to bind their partner in a cooperative manner such that it is generally possible to detect experimentally only the disordered unbound state and the structured complex. The interaction between the disordered C-terminal domain of the measles virus nucleoprotein (NTAIL) and the X domain (XD) of the viral phosphoprotein allows us to detect and quantify the two distinct steps of the overall reaction. Here, we analyze the robustness of the folding of NTAILupon binding to XD by measuring the effect on both the folding and binding steps of NTAILwhen the structure of XD is modified. Because it has been shown that wild-type XD is structurally heterogeneous, populating an on-pathway intermediate under native conditions, we investigated the binding to 11 different site-directed variants of NTAILof one particular variant of XD (I504A XD) that populates only the native state. Data reveal that the recognition and the folding steps are both affected by the structure of XD, indicating a highly malleable pathway. The experimental results are briefly discussed in the light of previous experiments on other IDPs.

The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.

Introduction.Type I Gaucher disease (GD1) has been associated with increased cancer risk in the International Collaborative Gaucher Group (ICGG) Registry. Particularly, it is well recognized that the risk for multiple myeloma (MM) in affected individuals may be about 9 times higher than expected in the general US populations (Rosenbloom et al, 2022). Pathogenetic relationship between GD1 and MM is still unclear. It was hypothesized that accumulation of glucosylceramide in the macrophages leads to their activation and chronic immune stimulation favouring polyclonal gammopathies. In this scenario plasma cell clone selection could be promoted and subsequent MGUS/MM could derive from it. Diagnosis of GD1 is often inaccurate or delayed since symptoms and signs of disease are nonspecific or underhand. We designed a prospective study to investigate the prevalence of GD1 in a large MM patient population to provide substantial evidences to consider GD1 in the pathogenesis and management of MM.

Introduction The epidemiology of lung cancer is changing worldwide, with smoking being the key driver of lung cancer incidence and mortality. Our aim is to analyze the incidence, survival and mortality trends in Italy in the framework of the 2017 survey on smoking behavior in Italy.Methods AIRTUM 2017 reports on cancer survival and incidence; 2017 survey on smoking behavior in Italy.Results Men achieved progress in lung cancer control characterized by a decrease in incidence and mortality and an increase in survival. The decreasing use of tobacco in men (from 60% in the 1960s to 24% in 2017) was most likely responsible for the decreasing incidence and mortality. Women showed no progress: although survival improved slightly, the incidence and mortality were both on the rise. This was most likely due to the increasing smoking rates in women in the 1970s and 80s. Of major concern is the accelerated rise in the number of smoking women from 4.6 million in 2016 to 5.7 million in 2017 compared to the decrease observed in men (from 6.9 to 6 million).Conclusions The incidence and mortality trends in males clearly demonstrate that primary prevention is the most effective way to reduce lung cancer mortality. By contrast, a 24% increase in the prevalence of smoking among women in just 1 year is extremely worrying for the future, and calls for immediate action by targeted strategies to reduce tobacco consumption in women and avert the dreadful prospect of a lung cancer epidemic in Italy.

Objectives:To evaluate the results of active surveillance beyond 5 years in patients with branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) without worrisome features (WF) and high-risk stigmata (HRS) undergoing non-operative management.Methods:Patients with a minimum follow-up of 5 years who underwent surveillance with at least yearly magnetic resonance imaging were included. New onset of and predictors of WF/HRS during follow-up as well as long-term survival were analyzed.Results:In all, 144 patients were followed for a median of 84 months. At diagnosis multifocal BD-IPMNs were found in 53% of cases and mean size of the largest cyst was 15.5 mm. Changes during follow-up were observed in 69 patients (48%). New onset of WF/HRS were observed in 26 patients (18%) but the rate of HRS was only 4%. WF and HRS developed after a median follow-up of 71 and 77.5 months from diagnosis, respectively, and without previous changes in 19/26 patients. Independent predictors of WF/HRS development were size at diagnosis>15 mm, increase in number of lesions, main pancreatic duct growth rate ≥0.2 mm/year, cyst growth rate >1 mm/year. Overall, the rate of pancreatic invasive malignancy was 2% and the 12-year disease-specific survival was 98.6%.Conclusions:Long-term nonoperative management is safe for BD-IPMNs without WF and HRS. Discontinuation of surveillance cannot be recommended since one out of six patients developed WF/HRS far beyond 5 years of surveillance and without previous relevant modifications. An intensification of follow-up should be considered after 5 years.