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In these last 25 years, the Neonatal Emergency Transport (NET) service has been widely improved in Italy. To date, all National areas are covered by a NET service; 53 NET centers have been activated in all the Italian territory. Herein, the authors present an observational study to evaluate the rate of infantile mortality after introduction of NET in Sicily, and to study the efficiency of this service in reducing these rates of mortality in vulnerable neonates, transported from primary care birth centers to tertiary facilities to undergo to specialized NICU assistance. All neonates who required an emergency transport by NETS were included. No exclusions criteria were applied. Demographic and regional infantile mortality data, expressed as infant mortality rate, were selected by the official government database (ISTAT- National Statistic Institute—http://www.istat.it). All data were respectively divided into three groups: data concerning transport, clinical condition, and mortality of the transported patients. We transported by NET 325 neonates. The analysis of the infant mortality rate (per 1.000 live births) in Catania from 2016 to 2018 was reduced compared to the same rate calculated before NETS activation (4.41 index before 2016 vs 4.17 index after 2016). These data showed an increase in other provinces (Enna, Caltanissetta, and Agrigento). 61% of neonates showed a respiratory disease. During the study period the proportion of neonates with a Mortality Index for Neonatal Transportation—MINT

Introduction Drug repurposing represented an important contribution in the management of COVID-19, becoming the first line of defense to mitigate the effects of the new coronavirus. In a brief time, drug repurposing (DR) provided potentially effective and already available drugs for COVID-19, while specific therapies against SARS-CoV-2 and/or vaccines were developing. Identifying repurposed drugs requires a multidisciplinary approach, where clinical pharmacology represents the missing piece of the puzzle. Areas covered Nowadays, clinical pharmacology is recognized as a discipline at the core of translational science, whose activities lead to the identification of the right drug for the right patient. In the context of the COVID-19 pandemic, its role in drug development and therapy choice has been decisive and itself repositioned. In this review, we tried to highlight the important role of clinical pharmacology in the identification and evaluation of possible repurposed drugs for COVID-19. Expert opinion We believe that clinical pharmacology had an important role in identifying patient-oriented therapy during the COVID-19 pandemic. In this context, DR was just one of the challenges for clinical pharmacology, which proved that this discipline is ready to respond to future threats.

BACKGROUND Educators agree that clinical experiences are vital to the development of a graduate nurse; however, there is little research on student learning outcomes related to these experiences. PURPOSE The purpose of this systematic review was to examine qualitative studies of student learning in traditional clinical models. METHODS A systematic review was conducted following the Joanna Briggs Institute and Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Nine electronic databases were searched using 43 search terms. Full-text review was completed on 109 articles, with 26 undergoing critical appraisal. RESULTS Only 6 qualitative studies reported learning outcomes attributed to clinical education models, focusing on experiences in foreign clinical placements, nurse-run clinics, the night shift, transition to professional identity, practicing as a clinical dyad, and development of caring skills. CONCLUSIONS The results of the systematic review of qualitative research that studied outcomes of prelicensure clinical education were insufficient to provide recommendations for traditional clinical education that are supported by evidence.

Lessons Learned Background The objectives of this study were to compare the safety profiles of sodium levofolinate (Na-Lev) and calcium levofolinate (Ca-Lev) in combination with 5-fluorouracil (5-FU) in the FOLFIRI regimen and to measure the organizational impact of the introduction of Na-Lev on drug production and administration. Methods The study opened in November 2015 and closed in August 2019. Patients with gastrointestinal cancers who were candidates for treatment with the FOLFIRI regimen were included in this nonrandomized study. Age ≥18 years, life expectancy Results Sixty patients were enrolled, 30 in each arm. Patient characteristics were balanced. Grade (G)1–2 adverse events occurred in 18 (60.0%) and 19 (63.4%) patients of Na-Lev and Ca-Lev cohorts, respectively, whereas G3–4 adverse events occurred in 12 (40.0%) and 11 (36.6%) patients, respectively. The use of Na-Lev enabled us to save approximately 13 minutes for drug preparation and 2 hours for treatment administration, per patient per cycle. Conclusion Na-Lev showed a reassuring toxicity profile and a favorable impact on drug preparation and administration.

Background: Effectiveness of traditional apprenticeship models used in undergraduate nursing education has been questioned in the literature for over 50 years. This systematic review aimed to examine best evidence available upon which to base decisions regarding use of traditional clinical experience with prelicensure nursing students. Method: A systematic review was conducted following Joanna Briggs Institute and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Nine electronic databases were searched. Full-text review was completed for 118 articles meeting inclusion criteria. Results: No studies reported learning outcomes attributed to clinical education models, resulting in an empty review. Studies were commonly self-reports of perceptions and confidence, lacking quantitative outcomes. Conclusion: No sufficient evidence was found to support traditional clinical models. The scope of nursing practice and patient complexity requires higher order thinking skills, ability to prioritize, and leadership in interdisciplinary care environments. This review raises serious concerns about how nurse educators assess learning in traditional clinical environments. [ J Nurs Educ . 2021;60(3):136–142.]

The Meckel's diverticulum is usually asymptomatic but in sometimes it presents severe complications, such as bleeding or perforation. The presence of enterolith inside a Meckel diverticulum is rare. In this report, we present a case of a 56- years- old man, with an abdominal pain and small bowel obstruction for a enterolith. Preoperative radiologic studies in Emergency Room (ER) didn't reveal this stone, but realeved a small bowel obstruction. Initially, we tried a conservative management, however after about 48 hours, due to worsening symptoms, the patient undergoes an exploratory laparotomy and a intestinal resection. Key words: Enteriith, Meckel's diverticulum, Small bowel obstruction.Descriviamo un caso non frequente di occlusione intestinale dovuta ad enterolita di un diverticolo di Meckel. Il diverticolo di Meckel è l’anomalia congenita più comune del tratto gastrointestinale. L’incidenza è di circa il 2% della popolazione. La maggior parte dei pazienti è asintomatica, solo il 4-16% presenta complicanze, tra cui sanguinamento, ostruzione e diverticolite. L’enterolitasi altresì rappresenta una complicanza rara ma da tener conto in diagnosi differenziale. L’esecuzione di una TAC addome può nella maggior parte dei casi, conoscendo anche l’esistenza di tale complicanza, fare una diagnosi precoce e precisa del quadro clinico, evitando di giungere a quadri avanzati e scompensati di occlusione intestinale. Pertanto auspichiamo che tale complicanza venga annoverata nelle complicanze classiche del diverticolo di Meckel così da permettere un più semplice e precoce riconoscimento.

In locally advanced pancreatic cancer (LAPC), the combination of chemotherapy and radiotherapy is a widely used treatment option. We performed a pooled analysis, including an exploratory analysis for prognostic and predictive factors, of two phase 2 trials including 73 patients with LAPC, treated with gemcitabine and oxaliplatin (GEMOX) and hypofractionated tomotherapy. With a median follow-up of 36 months (range 1–65), median progression-free (PFS) and overall survival (OS) were 10.2 (95% confidence interval [CI] 7.8–13.2) and 14.3 (95% CI 12.0–18.1) months, respectively. The overall resectability rate was 23.3% (95% CI 13.6–33.0), and the R0 resection rate was 13.7% (95% CI 5.8–21.6). In the multivariate analysis, ECOG performance status (PS) 0 and low levels of CA 19–9 were associated with improved OS and PFS. Concerning OS, log(CA19–9) resulted in a hazard ratio (HR) of 1.20 (95% CI 1.02–1.42), p = 0.027. For ECOG PS 0, HR was 1.00, for PS 1, HR was 2.69 (95% CI 1.46–4.96), for PS 2, HR was 4.18 (95% CI 0.90–19.46), p = 0.003. Low CA19–9 levels were also predictive for resection, with an odds ratio of 0.71 (95% CI 0.52–0.97), p = 0.034. In conclusion, GEMOX and hypofractionated radiotherapy is a treatment option in LAPC. Further studies are needed to identify differences in tumor biology, which may help to predict resectability and prognosis.

Highlights • This scoping review provides an up-to-date overview of published evidence regarding the frequency and severity of acute viral respiratory AEs related to antirheumatic disease therapies. • Glucocorticoid use was associated with a higher frequency of acute upper and lower respiratory viral events. • Mild viral respiratory infections occurred more frequently in several studies in which patients were treated with JAKi, most notably at higher doses. • TNFi and IL-17 inhibitors seemed to be associated with higher frequency of mild viral respiratory infections such as URTI and nasopharyngitis. • Our review identifies a knowledge gap for most antirheumatic medications and their acute respiratory viral complications; in the context of the COVID-19 pandemic, increased widespread respiratory viral PCR testing offers immediate research opportunities to clarify the safety of antirheumatic therapies in terms of viral respiratory complications., Introduction COVID-19 is an acute respiratory viral infection that threatens people worldwide, including people with rheumatic disease, although it remains unclear to what extent various antirheumatic disease therapies increase susceptibility to complications of viral respiratory infections. Objective The present study undertakes a scoping review of available evidence regarding the frequency and severity of acute respiratory viral adverse events related to antirheumatic disease therapies. Methods Online databases were used to identify, since database inception, studies reporting primary data on acute respiratory viral infections in patients utilizing antirheumatic disease therapies. Independent reviewer pairs charted data from eligible studies using a standardized data abstraction tool. Results A total of 180 studies were eligible for qualitative analysis. While acknowledging that the extant literature has a lack of specificity in reporting of acute viral infections or complications thereof, the data suggest that use of glucocorticoids, JAK inhibitors (especially high-dose), TNF inhibitors, and anti-IL-17 agents may be associated with an increased frequency of respiratory viral events. Available data suggest no increased frequency or risk of respiratory viral events with NSAIDs, hydroxychloroquine, sulfasalazine, methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, or apremilast. One large cohort study demonstrated an association with leflunomide use and increased risk of acute viral respiratory events compared to non-use. Conclusion This scoping review identified that some medication classes may confer increased risk of acute respiratory viral infections. However, definitive data are lacking and future studies should address this knowledge gap.

The objective of this systematic review is to synthesize the relevant literature published after 2016 to ascertain the current landscape of science that relates mild traumatic brain injury (mTBI) to the onset of Alzheimer's disease and related dementias (ADRD) and identify areas of need for future research. We conducted database searches and retrieved articles that were published after 2016 that utilized cognitive assessments to understand the relationship between mTBI and ADRD. We identified eight relevant articles in the review process, four of which presented a significant relationship between mTBI and disease or cognitive impairment outcomes. The studies included in this systematic review underscore the need for future research investigating a possible causal relationship between mTBI and ADRDs given the high prevalence of mTBI among brain injury patients and the lack of literature specifically addressing this issue. Future research should standardize the definitions of mTBI, AD, and ADRDs to create reliable and reproducible results that more comprehensively capture the nuances of this relationship.

IntroductionONCO-TreC platform consists of a mobile application delivered to patients as electronic diary and a web-based dashboard managed by healthcare professionals. We aim to compare the effectiveness of ONCO-TreC electronic diary with a standard paper diary, in improving adherence to oral cancer therapy in patients with solid and haematological tumours.Methods and analysisThis is an open label, superiority, randomised controlled trial conducted in two Italian oncology units. Patients will be randomised with a 1:1 ratio to electronic or paper diary. For both groups a counsellor will be responsible for drug and diary delivery. The evaluation period will end after six cycles of therapy. The primary aim is to compare the proportion of non-adherent patients in the two arms. Adherence will be measured through pill count; anyone who takes less than 90% of the total prescribed drug dose will be considered non-adherent. Assuming a percentage of non-adherent patients to oral therapy of 40% in arm B, and a 60% reduction in this percentage in arm A, a sample of 124 patients will provide 80% power to identify an absolute difference greater than 24 percentage points using a bilateral Fisher’s exact test with a significance level of 0.05. Considering a dropout rate of 10%, approximately 136 patients will have to be enrolled. The primary analysis will be performed on the intention-to-treat population. Secondary aims are to describe the reasons for non-adherence, the level of satisfaction of patients and healthcare professionals with the paper and electronic diary, and the impact of non-adherence in terms of healthcare costs.Ethics and disseminationEthical approval was obtained from Romagna Ethics Committee (CEROM), study ID 2108, prot. n. IRST 100.28 of 10/04/2020. Informed consent will be obtained from all study participants. Findings will be disseminated through peer-reviewed journals, conferences and event presentations.Protocol versionVersion 2, 6 April 2021.Trial registration numberNCT04826458.

Objective: The purpose of this scoping review is to evaluate the extent of library or librarian involvement in informatics education in the health domain. Methods: We searched eight databases from their inception to 2019 for reports of informatics educational activities for health professionals or health professions students that involved library staff or resources. Two reviewers independently screened all titles/abstracts (n=2,247) and resolved inclusion decisions by consensus. From the full text of the 36 papers that met the inclusion criteria, we extracted data on 41 educational activities. Results: The most frequent coded purposes of activities were “teaching clinical tools” (n=19, 46.3%) and “technology” (n=17; 41.5%). Medical students were the most frequent primary audience (34.1%), though 41.5% of activities had multiple audiences. Evaluation was reported for 24 activities (58.5%), only a few of which assessed short or post-activity impact on attitudes, knowledge, or skills. The most common long-term outcome was applying skills in other courses or clinical experiences. Thematic analysis yielded three areas of outcomes and issues for the library and organizational partners: expanded opportunities, technology and resource issues, and value demonstration. Conclusions: Limited published examples of health informatics educational activities provide models for library roles in informatics education. More librarians should report on their informatics educational activities and provide sufficient details on the interventions and their evaluation. This would strengthen the evidence base about the potential impact of libraries within informatics education.

Immune checkpoint inhibition induced a great step forward in the treatment of non-small cell lung cancer patients. In cancer immune microenvironment many checkpoints were studied and their involvement could represent a mechanism of resistance to cancer immunotherapy. For this reason, the inhibition of multiple immune checkpoints is under development. However, myeloid-derived suppressor cells (MDSC) and exhausted immune cells could limit the efficacy of cancer immunotherapy. We analyzed the variation of circulating immune suppressive-like cell subsets and exhausted immune cells in three non-small cell lung cancer patients treated with the combination of anti-CTLA-4 plus anti-PD-1 plus anti-LAG-3 at T0 (baseline), T1 (after 2 months) and T2 (after 4 months). We also describe the clinical and radiological course of the disease during this treatment in all three patients. We observed both clinical differences and changes in the composition of immune suppressive-like cell subsets and exhausted immune cells between the patients receiving the same schedule of treatment with immune checkpoint inhibitors. The study on a wider patient population and experimental model design could help to clarify the kinetics of these cell subpopulations with the perspective to find new targets for treatment or new biomarkers for resistance to cancer immunotherapy.

Evidence-based standardization of the perioperative management of patients undergoing complex spine surgery can improve outcomes such as enhanced patient satisfaction, reduced intensive care and hospital length of stay, and reduced costs. The Society for Neuroscience in Anesthesiology and Critical Care (SNACC) tasked an expert group to review existing evidence and generate recommendations for the perioperative management of patients undergoing complex spine surgery, defined as surgery on 2 or more thoracic and/or lumbar spine levels. Institutional clinical management protocols can be constructed based on the elements included in these clinical practice guidelines, and the evidence presented.

Introduction While survival for pediatric bladder rhabdomyosarcoma (RMS) has recently improved with risk-based multimodality treatment protocols, survival for adult bladder RMS remains to be poor. Survival is poor likely because adult bladder RMS is rare, understudied, and consequently lacking in high-level evidence to inform standardization of treatment. In addition, adult bladder RMS exhibits high rates of recurrence. The purpose of this systematic review is to determine associations between patient clinicopathologic factors and recurrence for adult primary bladder RMS, as well as to provide an updated survey of the various treatments employed for this disease in adults. Material and Methods Studies involving adult primary bladder RMS were acquired from MEDLINE (OVID), Scopus, and Cochrane Central Register of Controlled Trials from 1947 to 2018. Cases with no metastatic disease at diagnosis and at least 6 months follow-up were included. Multivariable Cox-regression hazard analysis was utilized to determine associations of age, sex, histology, and TNM stage with recurrence. Kaplan-Meier analysis and log-rank testing was used to calculate overall survival (OS) for patients who underwent surgical treatment only, and to evaluate differences in survival between radical cystectomy and partial cystectomy. Results 20 articles were selected for the review, and 22 cases were obtained. The mean age of the patients was 55.7 ± 18.4 (range = 28–83). With a mean follow-up time of 21.4 ± 18.6 months, 36.4% of the patients experienced disease recurrence. Recurrence was not associated with age, sex, histology, or stage (p = 0.366, p = 0.754, p = 0.889, and p = 0.590, respectively). Most patients underwent surgery only as their initial therapy (n = 12), while the remaining had chemotherapy, radiation, or some combination of these therapies (including surgery). The median OS of patients who underwent surgery only was 21.0 months (95% CI: 0.0–44.6 months). Among these patients, no difference in OS between radical cystectomy and partial cystectomy was found (p = 0.841). Conclusion Adult bladder RMS is a rare, lethal tumor with a high proclivity for recurrence. No association between age, sex, histology, or stage and recurrence was found. Radical cystectomy is not superior to partial cystectomy in terms of survival, suggesting a role for bladder preservation in select patients. Our study is the first to provide a comprehensive summary of the various treatments employed with clinical outcomes for adult primary bladder RMS.

Vitamin B12 is a water-soluble vitamin that plays a fundamental role as an essential cofactor for two enzymes responsible for the production of succinyl-CoA and methionine. Vitamin B12 deficiency can occur in infants and may be related to the breastfeeding mother's adherence to a vegan diet or somatic diseases in the mother. It should be differentiated from inborn errors of vitamin B12 metabolism. Herein, we report the cases of three infants with West syndrome; all three were breastfed by mothers who followed a strict vegan diet. In one of the three infants, West syndrome developed during treatment with vitamin B12 and normalization of the vitamin B12 level. Early treatment and replacement therapy are worthwhile to prevent serious neurological problems and to improve the patient's clinical course.

In March 2020, the Dean of the George Washington (GW) University School of Medicine and Health Sciences (SMHS) and the GW COVID-19 Incident Management Team asked the Senior Associate Dean for Clinical Public Health to initiate a daily report that surveyed COVID-19 literature/resources. This COVID-19 Intelligence Report would serve as a concise, authoritative source of COVID-19 information for clinicians, the Incident Management Team, and operational leaders. The Senior Associate Dean established an Intelligence Gathering Team comprised of clinicians and librarians. Himmelfarb librarians facilitated the collection, distribution, and archiving of COVID-19 resources and Intelligence Reports.

Background A platform designed to support the home management of oral anticancer treatments and provide a secure web-based patient–health care professional communication modality, ONCO-TreC, was tested in 3 cancer centers in Italy. Objective The overall aims of the trial are to customize the platform; assess the system’s ability to facilitate the shared management of oral anticancer therapies by patients and health professionals; and evaluate system usability and acceptability by patients, caregivers, and health care professionals. Methods Patients aged ≥18 years who were candidates for oral anticancer treatment as monotherapy with an Eastern Cooperative Oncology Group performance status score of 0 to 1 and a sufficient level of familiarity with mobile devices were eligible. ONCO-TreC consisted of a mobile app for patients and a web-based dashboard for health care professionals. Adherence to treatment (pill count) and toxicities reported by patients through the app were compared with those reported by physicians in medical records. Usability and acceptability were evaluated using questionnaires. Results A total of 40 patients were enrolled, 38 (95%) of whom were evaluable for adherence to treatment. The ability of the system to measure adherence to treatment was high, with a concordance of 97.3% (95% CI 86.1%-99.9%) between the investigator and system pill count. Only 60% (3/5) of grade 3, 54% (13/24) of grade 2, and 19% (7/36) of grade 1 adverse events reported by physicians in the case report forms were also reported in the app directly by patients. In total, 94% (33/35) of patients had ≥1 app launch each week, and the median number of daily accesses per patient was 2. Approximately 71% (27/38) and 68% (26/38) of patients used the app for messages and vital sign entering, respectively, at least once during the study period. Conclusions ONCO-TreC is an important tool for measuring and monitoring adherence to oral anticancer drugs. System usability and acceptability were very high, whereas its reliability in registering toxicity could be improved. Trial Registration ClinicalTrials.gov NCT02921724; https://www.clinicaltrials.gov/ct2/show/NCT02921724

Background Non-Epileptic Paroxysmal Events (NEPE) are common clinical manifestations in pediatric age presenting with dysfunction of motor and behavioral activity mimicking features of epileptic seizures. Objective To present and analyze number and clinical characteristic of a group of children/adolescents presenting with various types of NEPE; to compare clinical data of this group of NEPE affected children/adolescents with a group of children/adolescents affected by Epileptic Seizures (ES). Methods The retrospective study was conducted at the Pediatric Clinic of University of Catania, Catania, Italy, in a period ranging from January 2005 and January 2018. Two groups of children/adolescents, aged from 1 month to 15 years, were selected: 312 affected by NEPE and 192 by ES. Number and percentage of the single type of NEPE were reported. Then, demographic characteristics, clinical manifestations, duration of the events, time of diagnosis, and age of onset of each type of NEPE and ES affected children/adolescents were analyzed and compared. Results of statistical analysis of the data were carried out between ES and some type of NEPEs including Sandifer syndrome, breath-holding spells, paroxysmal tremors, vertigo, and syncope. Results Among the group of NEPE, vertigo, type of paroxysmal event clinically not classifiable, syncope, and Sandifer syndrome were the most common events; In the comparative analyzed samples, variability between NEPE and ES was found in the duration of the paroxysmal events, in number of episodes, in lag-time between the onset of symptoms and the diagnosis, and in age of onset. Analyzing clinical data of ES with some type of NEPE, statistical significant results were obtained in vertigo as regards the duration and average duration event, in paroxysmal tremors as number of events, in Sandifer syndrome as lag-time of diagnosis, and finally in all the types of NEPE as regards the age of onset, and loss of consciousness. Conclusions Analyzing the clinical features of each type of NEPE differences with ES are found. However, globally considered diagnostic differences between NEPE and ES remain difficult, questionable, and unrealizable without the support of correct parental report, direct clinical observations, and video-EEG monitoring.

Primary headache disorders in children are one of the most prominent topics in the pediatric neurology literature. However, there are many unsolved aspects, including the conditions associated with migraine. The present study aims to report on the frequency of behavioral comorbidities in the setting of primary headache in childhood.In this study, we enlisted 475 children (290 males and 185 females; ratio 1.6:1), aged 4 to 14 years, who were affected by primary headache. In direct interviews, children and parents gave information on the association of their headache with, attention-deficit/hyperactivity disorder, learning disabilities, tics, anxiety, depression, and obsessive-compulsive disorder. Other 475 children with no history of headache or recognized neurological conditions were matched for age, sex, race, and socioeconomic status and were used as controls.A significant association of primary headache was found with anxiety and depression (p-value0.001); overall, behavioral disorders were more common in children who experienced headache than in controls (p-value0.001).Primary headache in children is not associated with most of the common behavioral conditions. On the contrary, there was a significant association with anxiety and depression, as reported in adults.

Objective: Gap in knowledge on benefit/risk ratio of second generation antipsychotics (SGA) in the paediatric population represents a challenge for the scientific community. This study aims to analyse all suspected adverse drug reactions (ADRs) to SGA observed during the study period; compare the safety profiles of risperidone and aripiprazole; evaluate the effect of switching from risperidone to aripiprazole or to a first generation antipsychotic (FGA). Methods: Prospective analysis of spontaneously reported ADRs concerning 184 paediatric outpatients between 2012 and 2014.; clinical outcomes of drug switch were evaluated. Results: Out of the 184 patients, 130 experienced at least one ADR; ADRs were usually not serious and more frequently associated with aripiprazole. Switching to aripiprazole was associated with better results than switching to FGAs in the Clinical Global Impression scale- Efficacy (CGI-E) scores (p = 0.018), Disturbed behaviour checklist-parents (DBC-P) self-absorption subscale (p = 0.010); only a trend for difference between changing to aripiprazole vs FGAs in the DBC-P total score (p = 0.054) and social relating subscale (p = 0.053) was observed. Conclusions: SGAs safety data were consistent with the ones already known; however, there is still a need to improve the knowledge in pharmacovigilance field among clinicians. Switching to aripiprazole may be a valid alternative to risperidone.

Background: Today, there is a poor knowledge about gender differences in adverse drug reactions (ADRs) to cardiovascular drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Therefore, the aim of this study was to analyze spontaneous reports of suspected ADRs induced by ACE-inhibitors and ARBs, between January 2001 and June 2015, recorded in a Region of Southern Italy (Campania Region). Methods: We performed a descriptive gender-related analysis of regional safety data, obtained from the spontaneous reporting system. Results: In the considered period, 772 suspected ADRs to ACE inhibitors and ARBs (in monotherapy or in combination) were reported with a slightly higher frequency in men compared with women. In both genders, the most involved category was ARBs in combination, whereas the most prescribed active substance was ramipril. General and administration site conditions, vascular disorders and modification of laboratory parameters were more common in men, while respiratory disorders were most common in women. In 88.2% of cases, not serious ADRs were described more by men than women. Conclusions: This analysis suggested no substantial gender differences. Further studies such as randomized population studies or meta-analysis of ACE inhibitors and ARBs randomized studies are needed to clarify whether gender differences exist in the safety profile of these drugs.

Background The gut-brain axis plays a potential role in numerous physiological and pathological conditions. Several substances link stomach with central nervous system. In particular, hypothalamo-pituitary-adrenocortical axis, thyrotropin-releasing factor-containing nerve fibers and capsaicin-sensitive nerves are principal mediators of the harmful and protective central nervous system-mediated effects on gastric mucosa. Also, existing evidence indicates that nitric oxide, prostaglandins and calcitonin gene-related peptide play a role as final effectors of gastric protection. Methods We undertook a structured search of bibliographic databases for peer-reviewed research literature with the aim of focusing on the role of gut-brain axis in gastric damage and protection. In particular, we examined manuscripts dealing with the role of steroids, thyrotropin-releasing hormone, prostaglandins, melatonin, hydrogen sulfide and peptides influencing food intake (i.e. leptin, cholecystokinin, peptide YY, central glucagon–like peptide-1, and ghrelin). Also, the role of GABAergic and glutamatergic pathways in gastric mucosal protection have been examined. Results We found and reviewed 61 peer-reviewed papers dealing with the major aspects related to the role of gut brain axis in gastric mucosal damage and protection. Conclusions A dense neuronal network links stomach with central nervous system and a number of neurotransmitters and peptides functionally and anatomically related to central nervous system play a major role in contributing to gastric mucosal integrity. Exploiting the mechanisms underlying the connection between brain and gut may lead to a better understanding of the pathophysiology of gastric mucosal injury and to an improvement in the prevention and, eventually, management of gastric damage.

Gastrointestinal (GI) complications are one of the most limiting cause of use of NSAIDs. Beyond others well defined factors, history of peptic ulcer, older age, Helicobacter pylori infection and use of gastrotoxic drugs may affect their GI safety profile. In particular, the risk of GI complications associated to the use of antiplatelet drugs, especially low-dose acetylsalicylic acid (LDA) should deserve much attention. However, only few studies have focused on the effect of combination LDA/NSAIDs on the GI tract compared with the monotherapy and much less studies assessed this effect with multiple NSAIDs use. We aimed to characterize the GI safety profile of NSAIDs and LDA as monotherapy or their combinations in real-life conditions by analysing spontaneous adverse drug reactions (ADRs) reporting system in a Southern Italy. We used the case/non-case method in the Italian Pharmacovigilance Network (RNF). Cases were reports of GI events in the RNF between January 2007 and December 2011. Non-cases were all other reports during the same period. The association between NSAID and suspected GI ADRs was calculated using the reporting odds ratio (ROR) with 95% confidence intervals as a measure of disproportionality while adjusting for age, and concomitant use of antineoplastic agents or drugs for cardiovascular diseases. Sub-analysis were performed within the NSAID class. Among the 2816 adverse drug reactions recorded, we identified 374 (13.3%) cases of GI complications. Upper GI complications were the most frequently reported type of events. The highest associations were found for the combined use of NSAIDs and/or LDA, whilst the lowest associations were for their respective monotherapy. Looking at individual NSAIDs the highest association with GI events was observed for ketorolac exposure followed by nimesulide, diclofenac, aspirin, ketoprofen, and ibuprofen. This study highlights the primary role of the national spontaneous reporting system to bring out potential signals, such as the inappropriate drug use pattern, which however, have to be furtherly studied in-depth with ad hoc population-based studies.

Background Experimental studies suggest that mechanical cell washing to remove pro-inflammatory components that accumulate in the supernatant of stored donor red blood cells (RBCs) might reduce inflammation and organ injury in transfused patients. Methods Cardiac surgery patients at increased risk of large-volume RBC transfusion were eligible. Participants were randomized to receive either mechanically washed allogenic RBCs or standard care RBCs. The primary outcome was serum interleukin-8 measured at baseline and at four postsurgery time points. A mechanism substudy evaluated the effects of washing on stored RBCs in vitro and on markers of platelet, leucocyte, and endothelial activation in trial subjects. Results Sixty adult cardiac surgery patients at three UK cardiac centres were enrolled between September 2013 and March 2015. Subjects received a median of 3.5 (interquartile range 2–5.5) RBC units, stored for a mean of 21 (sd 5.2) days, within 48 h of surgery. Mechanical washing reduced concentrations of RBC-derived microvesicles but increased cell-free haemoglobin concentrations in RBC supernatant relative to standard care RBC supernatant. There was no difference between groups with respect to perioperative serum interleukin-8 values [adjusted mean difference 0.239 (95% confidence intervals −0.231, 0.709), P=0.318] or concentrations of plasma RBC microvesicles, platelet and leucocyte activation, plasma cell-free haemoglobin, endothelial activation, or biomarkers of heart, lung, or kidney injury. Conclusions These results do not support a hypothesis that allogenic red blood cell washing has clinical benefits in cardiac surgery. Clinical trial registration ISRCTN 27076315.

Objectives Extracorporeal membrane oxygenation is a treatment for Persistent Pulmonary Hypertension of the Newborn with high mortality. Hypothesis the extracorporeal membrane oxygenation circuit results in inflammatory responses that mitigate against successful weaning. Design Single-center prospective observational feasibility study. Setting PICU. Patients Twenty-four neonates requiring extracorporeal membrane oxygenation support for Persistent Pulmonary Hypertension of the Newborn. Interventions None. Measurements and main results The reference outcome was death or more than 7 days of extracorporeal membrane oxygenation support. Other outcomes included serial measures of plasma-free hemoglobin and markers of its metabolism, leucocyte, platelet and endothelial activation, and biomarkers of inflammation. Of 24 participants recruited between February 2016 and June 2017, 10 died or required prolonged extracorporeal membrane oxygenation support. These patients were sicker at baseline with higher levels of plasma-free hemoglobin within 12 hours of cannulation (geometric mean ratio, 1.92; 95% CIs, 1.00-3.67; p = 0.050) but not thereafter, versus those requiring less than 7 days extracorporeal membrane oxygenation. Serum haptoglobin concentrations were significantly elevated in both groups. Patients who died or required prolonged extracorporeal membrane oxygenation support demonstrated elevated levels of platelet-leucocyte aggregation, but decreased concentrations of mediators of the inflammatory response: interleukin-8, C-reactive protein, and tumor necrosis factor α. Conclusions Clinical status at baseline and not levels of plasma-free hemoglobin or the systemic inflammatory response may determine the requirement for prolonged extracorporeal membrane oxygenation support in neonates.

Food allergy (FA) is a serious health problem, and its incidence has been increasing especially in children. Wheat is one of the five most common foods that trigger allergic reactions in children. It is an increasingly recognised trigger for immune-mediated FAs, both Immunoglobulin E (IgE) and non-IgE mediated. We describe the case of a 4-year-old boy with a combination of symptoms due to IgE-mediated asthma worsened by IgE-non-dependent hypersensitivity to wheat demonstrated by a positive patch test. With the avoidance of wheat oral intake, we observed a progressive clinical improvement. To the best of our knowledge, this is the first report of a patient with IgE-non-dependent allergy to wheat presenting with chronic symptoms in one body system outside of the gastrointestinal tract and with negative skin prick test.

A new paradigm for Niemann-Pick C disease is presented where lysosomal storage leads to a deficit in cytoplasmic glucosylceramide (GlcCer) where it performs important functions. Previously it had been reported that Gaucher cells have defective endolysosomal pH. GlcCer also accumulates in Niemann-Pick C disease and also shows this defect. Niemann-Pick C cells were found to have reduced cytoplasmic glucosylceramide (GlcCer) transport. Inhibiting cytoplasmic glucocerebrosidase (GBA2), increased GlcCer, decreased endolysosomal pH in normal cells, reversed increases in endolysosomal pH and restored disrupted BODIPY-LacCer trafficking and increased expression of vATPase a subunit in Niemann-Pick C fibroblasts. The results are consistent with a model where both endolysosomal pH and Golgi targeting of BODIPY-LacCer are dependent on adequate levels of cytosolic GlcCer which are reduced in NPC disease. This work consequently suggests GBA2 and vATPase as new therapeutic targets in Niemann-Pick C and related neurodegenerative diseases. The work was in collaboration with colleagues in the Netherlands and Leicester University. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Niemann-Pick type C disease (NPCD) is a neurodegenerative disease associated with increases in cellular cholesterol and glycolipids and most commonly caused by defective NPC1, a late endosomal protein. Using ratiometric probes we find that NPCD cells show increased endolysosomal pH. In addition U18666A, an inhibitor of NPC1, was found to increase endolysosomal pH, and the number, size and heterogeneity of endolysosomal vesicles. NPCD fibroblasts and cells treated with U18666A also show disrupted targeting of fluorescent lipid BODIPY-LacCer to high pH vesicles. Inhibiting non-lysosomal glucocerebrosidase (GBA2) reversed increases in endolysosomal pH and restored disrupted BODIPY-LacCer trafficking in NPCD fibroblasts. GBA2 KO cells also show decreased endolysosomal pH. NPCD fibroblasts also show increased expression of a key subunit of the lysosomal proton pump vATPase on GBA2 inhibition. The results are consistent with a model where both endolysosomal pH and Golgi targeting of BODIPY-LacCer are dependent on adequate levels of cytosolic-facing GlcCer, which are reduced in NPC disease.

BACKGROUND AND PURPOSE: There is evidence supporting a role for the nociceptin/orphanin FQ (N/OFQ; NOP) receptor and its endogenous ligand N/OFQ in the modulation of neurogenic inflammation, airway tone and calibre. We hypothesized that NOP receptor activation has beneficial effects upon asthma immunopathology and airway hyperresponsiveness. Therefore, the expression and function of N/OFQ and the NOP receptor were examined in healthy and asthmatic human airway tissues. The concept was further addressed in an animal model of allergic asthma. EXPERIMENTAL APPROACH: NOP receptor expression was investigated by quantitative real-time PCR. Sputum N/OFQ was determined by RIA. N/OFQ function was tested using several assays including proliferation, migration, collagen gel contraction and wound healing. The effects of N/OFQ administration in vivo were studied in ovalbumin (OVA)-sensitized and challenged mice. KEY RESULTS: NOP receptors were expressed on a wide range of human and mouse immune and airway cells. Eosinophils expressed N/OFQ-precursor mRNA and their number correlated with N/OFQ concentration. N/OFQ was found in human sputum and increased in asthma. Additionally, in asthmatic human lungs N/OFQ immunoreactivity was elevated. NOP receptor activation inhibited migration of immunocytes and increased wound healing in airway structural cells. Furthermore, N/OFQ relaxed spasmogen-stimulated gel contraction. Remarkably, these findings were mirrored in OVA-mice where N/OFQ treatment before or during sensitization substantially reduced airway constriction and immunocyte trafficking to the lung, in particular eosinophils. N/OFQ also reduced inflammatory mediators and mucin production. CONCLUSIONS AND IMPLICATIONS: We demonstrated a novel dual airway immunomodulator/bronchodilator role for N/OFQ and suggest targeting this system as an innovative treatment for asthma.

Objective: To gain information on safety of drugs used in pediatrics through a 4-year post-marketing active pharmacovigilance program. The program sampled the Italian population and was termed 'Monitoring of the Adverse Effects in Pediatric population' (MEAP).Research design and methods: Adverse drug reactions (ADRs) were collected for individuals aged 0-17 years treated in hospitals and territorial health services in Lombardy, Tuscany, Apulia and Campania; located to gain an appropriate sampling of the population. ADRs were evaluated using the Adverse Drug Reaction Probability Scale (Naranjo) and analyzed with respect to time, age, sex, category of ADR, seriousness, suspected medicines, type of reporter and off-label use.Results: We collected and analyzed reports from 3539 ADRs. Vaccines, antineoplastic and psychotropic drugs were the most frequently pharmacotherapeutic subgroups involved. Seventeen percent of reported ADRs were serious; of them fever, vomiting and angioedema were the most frequently reported. Eight percent of ADRs were associated with off-label use, and 10% were unknown ADRs. Analysis of these revealed possible strategies of therapy optimization.Conclusions: The MEAP project demonstrated that active post-marketing pharmacovigilance programs are a valid strategy to increase awareness on pediatric pharmacology, reduce underreporting and provide information on drug actions in pediatrics. This information enhances drug therapy optimization in the pediatric patients. © Informa UK, Ltd.

Reference librarians, specifically those working in academic health sciences environments, have expanded their roles and taken on new and unique responsibilities. While librarians at The George Washington University's Himmelfarb Health Sciences Library continue to provide traditional reference services, they have gone beyond their comfort zone in many cases to become involved in activities that are outside of the librarian's established role. This article describes the current roles of Himmelfarb's reference librarians, as well as the way these librarians prepared for these roles and addressed the associated challenges.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Objectives: Micro-RNA, small noncoding RNA fragments involved in gene regulation, and microvesicles, membrane-bound particles less than 1 μm known to regulate cellular processes including responses to injury, may serve as disease-specific biomarkers of acute kidney injury. We evaluated the feasibility of measuring these signals as well as other known acute kidney injury biomarkers in a mixed pediatric cardiac surgery population. Design: Single center prospective cohort feasibility study. Setting: PICU. Patients: Twenty-four children (≤ 17 yr) undergoing cardiac surgery with cardiopulmonary bypass without preexisting inflammatory state, acute kidney injury, or extracorporeal life support. Interventions: None. Measurements and Main Results: Acute kidney injury was defined according to modified Kidney Diseases Improving Global Outcomes criteria. Blood and urine samples were collected preoperatively and at 6–12 and 24 hours. Microvesicles derivation was assessed using flow cytometry and NanoSight analysis. Micro-RNAs were isolated from plasma and analyzed by microarray and quantitative real-time polymerase chain reaction. Data completeness for the primary outcomes was 100%. Patients with acute kidney injury (n = 14/24) were younger, underwent longer cardiopulmonary bypass, and required greater inotrope support. Acute kidney injury subjects had different fractional content of platelets and endothelial-derived microvesicles before surgery. Platelets and endothelial microvesicles levels were higher in acute kidney injury patients. A number of micro-RNA species were differentially expressed in acute kidney injury patients. Pathway analysis of candidate target genes in the kidney suggested that the most often affected pathways were phosphatase and tensin homolog and signal transducer and activator of transcription 3 signaling. Conclusions: Microvesicles and micro-RNAs expression patterns in pediatric cardiac surgery patients can be measured in children and potentially serve as tools for stratification of patients at risk of acute kidney injury.

Objective To investigate the relationship between awareness of memory loss and psychological well-being in a nonclinically depressed sample of participants with mild to moderate Alzheimer disease (AD). Methods Study participants (N = 104) enrolled through Columbia University Medical Center and the University of Pennsylvania completed clinical and cognitive assessments. Participants were rated with regard to their degree of awareness of memory deficits and completed questionnaires relating to their psychological well-being, including mood and quality of life (QOL). Mediating models were used to establish the relationship between awareness, depression, and QOL and to examine potential mediators of awareness and depression, including psychological distress, objective memory deficits, and negative self-ratings. Results There was a direct association between awareness of memory deficits and depressed mood but not awareness and QOL. However, there was an indirect association between awareness and QOL through depression. Neither psychological distress, memory deficits, nor negative self-ratings mediated the relationship between awareness and depression. Conclusion Awareness is associated with depressed mood in nonclinically depressed participants with mild to moderate AD. However, depressed mood does not appear to reflect the direct psychological reaction to awareness of memory loss. Moreover, awareness has only an indirect association with QOL via depressed mood. These results suggest that preserved awareness does not have a direct negative impact on overall psychological well-being in AD.

Increases in newly licensed nurses and experienced nurses changing specialties create a challenge for nursing professional development specialists (NPDS). The NPDS must use the best available evidence in designing programs. A systematic review of interventions for developing preceptors is needed to inform the NPDS in best practice. A search was conducted for full-text, quantitative, and mixed-methods articles published after the year 2000. Over 4000 titles were initially identified, which yielded 12 research studies for evaluation and syntheses. Results identified a limited body of evidence reflecting a need for NPDS to increase efforts in measuring the effectiveness of preceptor development initiatives.(See CE Video, Supplemental Digital Content 1, http://links.lww.com/JNPD/A9).

Background Many asthmatic women complain of symptom exacerbations in particular periods, i.e. during pregnancy and menstrual cycles (perimenstrual asthma: PMA)". The goal of this study was to study the effect of the luteal and follicular phases of the menstrual cycle on bronchial reactivity (BR) in a group of asthmatic women. Methods For this purpose, 36 pre-menopausal women were enrolled and underwent testing for resting pulmonary function, measurement of the diffusing capacity of the lung for carbon monoxide (DLCO), and airway responsiveness to methacholine in the follicular and luteal phases of their menstrual cycles. We also measured plasma hormone levels and levels of cyclic adenosine monophosphate (cAMP; a mediator of bronchial smooth muscle contraction) and testosterone in induced sputum samples. Results Our study showed that about 30% of the asthmatic women had decreased PC20FEV1.0 in the follicular phase of menstrual cycle with a significant correlation between PC20FEV1.0 and serum testosterone levels. Moreover, marked increases in sputum testosterone levels (mean = 2.6-fold increase) together with significant increases in sputum cAMP concentrations (mean = 3.6-fold increases) were observed during the luteal phase of asthmatic patients, suggesting that testosterone contributes to the pathophysiology of PMA. We excluded the possibility that testosterone directly inhibits phosphodiesterase (PDE) activity as incubating PDE with testosterone in vitro did not reduce PDE catalytic activity. Conclusions In conclusion, our data show that PC20FEV1.0 was decreased in the follicular phase of the menstrual cycle in about 30% of women and was associated with lower cAMP levels in sputum samples, which may contribute to bronchoconstriction. Our results also suggest a link between PMA and testosterone levels. However, whether these findings are of clinical significance in terms of the management of asthma or asthma worsening during the menstrual cycle needs further investigation.

Background: Sodium oxybate is used in the treatment of narcolepsy. Currently no published literature supports its safety during breastfeeding, although it has a favorable pharmacokinetic profile for minimizing exposure. Materials and Methods: We report a case of a 27-year-old primigravida with narcolepsy who was taking sodium oxybate for symptom control and contacted our Lactation Study Center for advice. Based on our current pharmacokinetic knowledge, she was advised to avoid breastfeeding 4 hours after a dose. Results: Follow-up phone interviews were done and the patient reported that the feeding schedule was manageable, and she was able to exclusively breastfeed for 6 months of her infant's life. Based on pediatric records, her infant's growth and development were excellent. There were no noted side effects of the medication for the infant. Conclusions: This is the first report to our knowledge of breastfeeding during maternal therapy with sodium oxybate, which appears to be compatible with sa...

T-lineage ALL is an aggressive disease that needs to be treated with intensive treatment schedules. A late relapse rarely occurs and a clear choice for second-line treatment is on debate. We report on a young adult with a very late isolated extramedullary relapse of PICALM-MLLT10 positive T-ALL, successfully treated with a chemotherapy-based and radiotherapy-based pediatric protocol. We demonstrate that relapse can occur in T-ALL although a SR-MRD behavior treated with a high-risk protocol; specific molecular diagnostic aberrations, as PICALM-MLLT10, are still conserved at very late relapse; a second-line treatment based on pediatric protocol can be effective.

Background We evaluated the effects of two interventions that modify the red cell storage lesion on kidney and lung injury in experimental models of transfusion. Methods White–landrace pigs (n = 32) were allocated to receive sham transfusion (crystalloid), 14-day stored allogeneic red cells, 14-day red cells washed using the red cells washing/salvage system (CATS; Fresenius, Germany), or 14-day red cells rejuvenated using the inosine solution (Rejuvesol solution; Zimmer Biomet, USA) and washed using the CATS device. Functional, biochemical, and histologic markers of organ injury were assessed for up to 24 h posttransfusion. Results Transfusion of 14 day red cells resulted in lung injury (lung injury score vs. sham, mean difference −0.3 (95% CI, −0.6 to −0.1; P = 0.02), pulmonary endothelial dysfunction, and tissue leukocyte sequestration. Mechanical washing reduced red cell–derived microvesicles but increased cell-free hemoglobin in 14-day red cell units. Transfusion of washed red cells reduced leukocyte sequestration but did not reduce the lung injury score (mean difference −0.2; 95% CI, −0.5 to 0.1; P = 0.19) relative to 14-day cells. Transfusion of washed red cells also increased endothelial activation and kidney injury. Rejuvenation restored adenosine triphosphate to that of fresh red cells and reduced microvesicle concentrations without increasing cell-free hemoglobin release. Transfusion of rejuvenated red cells reduced plasma cell-free hemoglobin, leukocyte sequestration, and endothelial dysfunction in recipients and reduced lung and kidney injury relative to 14-day or washed 14-day cells. Conclusions Reversal of the red cell storage lesion by rejuvenation reduces transfusion-associated organ injury in swine.

OBJECTIVE Metamemory, or knowledge of one's memory abilities, is often impaired in individuals with Alzheimer's disease (AD), although the basis of this metacognitive deficit has not been fully articulated. Behavioral and imaging studies have produced conflicting evidence regarding the extent to which specific cognitive domains (i.e., executive function; memory) and brain regions contribute to memory awareness. The primary aim of this study was to disentangle the cognitive correlates of metamemory in AD by examining the relatedness of objective metamemory performance to cognitive tasks grouped by domain (executive function or memory) as well as by preferential hemispheric reliance defined by task modality (verbal or nonverbal). METHOD Eighty-nine participants with mild AD recruited at Columbia University Medical Center and the University of Pennsylvania underwent objective metamemory and cognitive testing. Partial correlations were used to assess the relationship between metamemory and four cognitive variables, adjusted for recruitment site. RESULTS The significant correlates of metamemory included nonverbal fluency (r = .27, p = .02) and nonverbal memory (r = .24, p = .04). CONCLUSIONS Our findings suggest that objectively measured metamemory in a large sample of individuals with mild AD is selectively related to a set of interdomain nonverbal tasks. The association between metamemory and the nonverbal tasks may implicate a shared reliance on a right-sided cognitive network that spans frontal and temporal regions.

To assess the prescribing pattern of antidiabetic drugs (AD) in a general practice of Southern Italy from 2009 to 2012, with focus on behaviour prescribing changes.This retrospective, drug utilization study was conducted using administrative databases of the Local Health Unit of Caserta (Southern Italy) including about 1 million citizens. The standardized prevalence of AD use was calculated within each study year. A sample cohort of 78,789 subjects with at least one prescription of AD was identified during the study period.There was an overall increase of the proportion of the patients treated with monotherapy, which was significant for insulin monotherapy (from 11.2 to 14.6%, p0.001). The proportion of patients treated with metformin remained stable (from 68.3% to 67.8%, p=0.076), while those receiving sulfonylurea dropped from 18.4% to 12.5% (p0.001); GLP-1 analogues and DPP-4 inhibitors showed the greatest increase (from 1.2% to 6.6%, p0.001). In the whole sample of 25,148 new AD users, metformin was the most commonly prescribed drug in monotherapy (41.9%), while insulin ranked second (13.3%).This study shows a rising trend of AD monotherapy, with sulfonylureas and incretins showing the more negative and positive trend, respectively.

S1P (sphingosine 1-phosphate) represents one of the key latest additions to the list of vasoactive substances that modulate vascular tone. PAR-2 (proteinase activated receptor-2) has been shown to be involved in cardiovascular function. In the present study, we investigated the involvement of PAR-2 in S1P-induced effect on vascular tone. The present study has been performed by using isolated mouse aortas. Both S1P and PAR-2 agonists induced endothelium-dependent vasorelaxation. L-NAME (NG-nitro-L-arginine methyl ester) and wortmannin abrogated the S1P-induced vasorelaxatioin, while significantly inhibiting the PAR-2-mediated effect. Either ENMD1068, a PAR-2 antagonist, or gabexate, a serine protease inhibitor, significantly inhibited S1P-induced vasorelaxation. Aortic tissues harvested from mice overexpressing PAR-2 displayed a significant increase in vascular response to S1P as opposed to PAR-2-null mice. Immunoprecipitation and immunofluorescence studies demonstrated that S1P1 interacted with PAR-2 and co-localized with PAR-2 on the vascular endothelial surface. Furthermore, S1P administration to vascular tissues triggered PAR-2 mobilization from the plasma membrane to the perinuclear area; S1P-induced translocation of PAR-2 was abrogated when aortic rings were pre-treated with ENMD1068 or when caveolae dysfunction occurred. Similarly, experiments performed in cultured endothelial cells (human umbilical vein endothelial cells) showed a co-localization of S1P1 and PAR2, as well as the ability of S1P to induce PAR-2 trafficking. Our results suggest that S1P induces endothelium-dependent vasorelaxation mainly through S1P1 and involves PAR-2 transactivation.

Objective: To examine how cognitive impairment affects Parkinson disease (PD) patients9 research consent capacity. Methods: A cross-sectional study of 90 patients with PD, divided using Mattis Dementia Rating Scale–2 scores into 3 groups of 30 (normal, borderline, and impaired), and 30 neurologically normal older adults completed 2 capacity interviews (an early-phase randomized and controlled drug trial and a sham-controlled surgical implantation of genetic tissue) using the MacArthur Competence Assessment Tool for Clinical Research. Expert clinicians used the interviews to classify the patients as either capable or not capable of providing their own informed consent. These judgments were compared with performance on the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Results: Cognitively normal PD patients typically scored well on the capacity measures. In contrast, patients with impaired cognition were not capable of providing their own informed consent: 17% (5/30) on the drug trial and 3% (1/30) on the surgery trial were judged capable. Patients with borderline impairment showed adequate performance on measures of appreciation and reasoning, but impaired performance on understanding the drug trial compared with normal controls and normal PD patients, and on understanding the surgery trial compared with normal controls. Sixty-seven percent (20/30) on the drug trial and 57% (17/30) on the surgery trial were judged capable of consent. Receiver operating characteristic analyses showed that the MMSE and MoCA could detect the likelihood of impaired capacity, with the MoCA demonstrating greater sensitivity. Conclusions: PD patients with borderline cognitive impairment have impairments in their decisional capacity. The MoCA may be useful to identify the patients at risk of impaired capacity.

The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide (NOP) receptor. It is cleaved from a larger precursor identified as prepronociceptin (ppN/OFQ). NOP is a member of the seven transmembrane-spanning G-protein coupled receptor (GPCR) family. ppN/OFQ and NOP receptors are widely distributed in different human tissues. Asthma is a complex heterogeneous disease characterized by variable airflow obstruction, bronchial hyper-responsiveness and chronic airway inflammation. Limited therapeutic effectiveness of currently available asthma therapies warrants identification of new drug compounds. Evidence from animal studies suggests that N/OFQ modulates airway contraction and inflammation. Interestingly up regulation of the N/OFQ-NOP system reduces airway hyper-responsiveness. In contrast, inflammatory cells central to the inflammatory response in asthma may be both sources of N/OFQ and respond to NOP activation. Hence paradoxical dysregulation of the N/OFQ-NOP system may potentially play an important role in regulating airway inflammation and airway tone. To date there is no data on N/OFQ-NOP expression in the human airways. Therefore, the potential role of N/OFQ-NOP system in asthma is unknown. This review focuses on its physiological effects within airways and potential value as a novel asthma therapy.

SummarySkeletal muscle dysfunction (SMD) often occurs in patients with COPD, affecting their quality of life and mitochondrion is one of the cellular organelles involved in the pathogenesis of SMD in COPD.The aim of this study was to investigate exercise capacity and mitochondria skeletal muscle oxidative processes using a pilot study, with 20 COPD patients and 10 healthy subjects, prior to and following LABA treatment.The two groups were similar for BODE (2–7) and GOLD stages (2–3), and no one was cachectic or more symptomatic. The patients were randomized according to a distribution list.The Cycle Ergometry test with tau evaluation was used to determine exercise capacity, while a skeletal muscle biopsy for cytochrome oxidase (CytOX) activity evaluation was used to determine mitochondria skeletal muscle oxidative processes.In six of the COPD treated patients the individual values of tau and CytOX activity showed inversely parallel changes with a significant relationship between the tau values and the CytOX activity. No significant differences in tau values were observed in healthy subjects.In conclusion, LABA treatment may improve skeletal muscle oxidative processes, enhancing the CytOX activity and, at least in some COPD patients, such effects could be strictly linked to the kinetic exchanges occurring at skeletal muscle level, implying an important link between the regulation of oxygen uptake, energy production and the exercise capacity of these patients.Nevertheless, further studies are required and a better understanding of the mechanism(s) underlying LABA effects might allow us to identify or unmask new therapeutic target(s) in such patients.

Allergen exposure may induce changes in the brainstem secondary neurons, with neural sensitization of the nucleus solitary tract (NTS), which in turn can be considered one of the causes of the airway hyperresponsiveness, a characteristic feature of asthma. We evaluated neurofunctional, morphological, and biochemical changes in the NTS of naive or sensitized rats. To evaluate the cell firing activity of NTS, in vivo electrophysiological experiments were performed before and after capsaicin challenge in sensitized or naive rats. Immunohistochemical studies, endocannabinoid, and palmitoylethanolamide quantification in the NTS were also performed. This study provides evidence that allergen sensitization in the NTS induced: (1) increase in the neural firing response to intratracheal capsaicin application, (2) increase of endocannabinoid anandamide and palmitoylethanolamide, a reduction of 2-arachidonoylglycerol levels in the NTS, (3) glial cell activation, and (4) prevention by a Group III metabotropic glutamate receptor activation of neural firing response to intratracheal application of capsaicin in both naïve and sensitized rats. Therefore, normalization of ovalbumin-induced NTS neural sensitization could open up the prospect of new treatments based on the recovery of specific brain nuclei function and for extensive studies on acute or long-term efficacy of selective mGlu ligand, in models of bronchial hyperreactivity. © 2015 Giuseppe Spaziano et al.

Aims Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre-clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. Methods We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. Results Thirty-six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml−1, Cmax 189.4 ng ml−1 and t1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post-surgery nitric oxide bioavailability. Conclusions Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery.

According to World Health Organization, medication adherence refers not only to pharmacological treatment, but also extends to all behaviors which guarantee patient's health. Poor medication adherence is the main cause of low efficacy of pharmacological therapy and it is more common in chronic diseases. For example, among hypothyroid patients, it was estimated that after 5 years of levothyroxine therapy 21.5% of patients still have a TSH level5.0 mU/L due to poor medication adherence. Moreover, it was found that almost 40% of pediatric patients had at least one episode of non-compliance following thyroidectomia. Several strategies can be adopted in order to improve medication adherence. These include self-monitoring drug therapy and self-management programs, simplified dosing regimens, directly involving pharmacists in drug therapy management, use of pharmaceutical formulations more attractive to the patient and through the therapeutic drug monitoring. The effects mediated by the thyroid gland, the clinical symptoms of hypothyroidism and the main characteristics of levothyroxine therapy have been discussed. In order to give an overview of interactions with food and drinks, pharmacokinetic characteristics, efficacy/safety profile, as well as the impact on medication adherence of levothyroxine in oral solution and soft gel capsule formulations, a literature search was performed. The results of 21 clinical studies were reviewed. Levothyroxine oral solution and soft gel capsule formulations showed irrelevant interactions with food and drinks, with a dissolution profile minimally influenced by pH variations. According to pharmacokinetic study results, bioequivalence between these formulations and levothyroxine tablets was confirmed. Regarding the efficacy/safety profile, while some studies did not detect any difference between levothyroxine formulations, other studies suggested that oral solution and soft gel capsule were associated to a higher efficacy compared to levothyroxine tablet. It was also demonstrated that removing the demand for fasting, patients would prefer to take the medication at breakfast. Therefore, most of the patients treated with levothyroxine oral solution preferred to continue this therapy instead of treatment with tablets. An increase in patient's compliance was observed. All the characteristics of new levothyroxine oral liquid formulations allow to administer the drug also in patients with gastrointestinal comorbidities or patients who are already treated with other drugs. The availability of different dosages let the clinician to adapt the treatment for each individual patient. These benefits contribute to a better medication adherence and to the maintenance of normal TSH levels. In conclusion, the use of different pharmaceutical formulations represents a therapeutic approach innovative, effective and inexpensive in the treatment of the hypothyroid patient.

We examined the association between cognitive domains and research consent capacity in PD. Our hypothesis was that research consent capacity is best predicted by executive function.A cohort of 90 PD patients and 30 healthy older adults were administered the MacArthur Competence Assessment Tool for Clinical Research, Dementia Rating Scale-2, and the MoCA. Experts classified patients as either "capable" or "not capable" of providing informed consent to participate in two clinical trials.MacArthur Competence Assessment Tool for Clinical Research Reasoning scores for both clinical trial types were most associated with executive functions and delayed recall. As scores on these domains improved, the odds of an expert rating of "capable of consent" increased.These results extend our previous findings by demonstrating that memory and executive abilities appear closely associated with capacity when evaluated using either a structured interview or expert judgment of that interview.

Design fluency tests, commonly used in both clinical and research contexts to evaluate nonverbal concept generation, have the potential to offer useful information in the differentiation of healthy versus pathological aging. Although normative data for older adults (OAs) are available for multiple timed versions of this test, similar data have been unavailable for a previously published untimed test, the Graphic Pattern Generation Test (GPG). Time constraints common to almost all of the available design fluency tests may cloud interpretation of higher-level executive abilities-for example, in individuals with slow processing speed. The current study examined the psychometric properties of the GPG and presents normative data in a sample of 167 healthy OAs and 110 individuals diagnosed with Alzheimer's disease (AD). Results suggest that a brief version of the GPG can be administered reliably and that this short form has high test-retest and interrater reliability. Number of perseverations was higher in individuals with AD as compared with OAs. A cutoff score of 4 or more perseverations showed a moderate degree of sensitivity (76%) and specificity (37%) in distinguishing individuals with AD and OAs. Finally, perseverations were associated with nonmemory indexes, thereby underscoring the nonverbal nature of this error in OAs and individuals with AD.

Pharmacologic coronary vasodilation with adenosine, combined with myocardial scintigraphy, is a useful test for the diagnosis of coronary artery disease (CAD) in patients unable to exercise. It has been demonstrated recently that exercise 99mTc-labeled tetrofosmin cardiac imaging can be used for the detection of CAD. However, no data are available comparing 99mTc-labeled tetrofosmin adenosine and exercise tests in the same patients.The results of adenosine and exercise 99mTc-labeled tetrofosmin myocardial tomography were compared in 41 patients (37 men and four women; mean age 53 +/- 8 years) with suspected or known CAD who underwent coronary angiography. All patients were submitted, on separate days, to three injections of 99mTc-labeled tetrofosmin (740 MBq intravenously): one at rest, one during bicycle exercise, and one during adenosine infusion (140 micrograms/kg/min for 6 minutes with injection of 99mTc-labeled tetrofosmin at 4 minutes). A total of 902 myocardial segments were analyzed quantitatively. One patient had normal coronary vessels, 19 patients had single-vessel CAD, 12 patients had two-vessel CAD, and nine patients had three-vessel CAD (50% coronary stenosis) on coronary angiography. Adenosine induced a significant increase in heart rate (88 +/- 16 beats/min at peak vs 72 +/- 11 beats/min at rest; p0.01). Systolic and diastolic blood pressure was not significantly different after adenosine infusion compared with rest. Double product was 22931 +/- 7039 at peak exercise and 11229 +/- 3413 after adenosine (p0.01). Agreement on the presence of abnormal single-photon emission computed tomography by adenosine and exercise was 100% by quantitative analysis. In all segments a significant relationship between exercise and adenosine 99mTc-99m-labeled tetrofosmin uptake was observed (r = 0.90; p0.001). Segmental agreement for regional 99mTc-labeled tetrofosmin uptake score between exercise and adenosine was observed in 737 (82%) of the 902 segments (kappa value of 0.66). Concordance between the two studies for identification of perfusion status was observed in 809 (90%) of the segments (kappa value of 0.80). Sensitivity and specificity for detection of stenosed vessels were not different for dynamic exercise stress testing and adenosine 99mTc-labeled tetrofosmin cardiac tomography.Despite different hemodynamic effects, adenosine and dynamic exercise 99mTc-labeled tetrofosmin single-photon emission computed tomographic imaging provides similar information in the diagnosis and localization of CAD.