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Purpose: To determine whether Macklin effect (a linear collection of air contiguous to the bronchovascular sheath) on baseline CT imaging is an accurate predictor for subsequent pneumomediastinum (PMD)/pneumothorax (PNX) development in invasively ventilated patients with COVID-19-related acute respiratory distress syndrome (ARDS). Materials and methods: This is an observational, case-control study. From a prospectively acquired database, all consecutive invasively ventilated COVID-19 ARDS patients who underwent at least one baseline chest CT scan during the study time period (February 25th, 2020–December 31st, 2020) were identified; those who had tracheal lesion or already had PMD/PNX at the time of the first available chest imaging were excluded. Results: 37/173 (21.4%) patients enrolled had PMD/PNX; specifically, 20 (11.5%) had PMD, 10 (5.8%) PNX, 7 (4%) both. 33/37 patients with subsequent PMD/PNX had Macklin effect on baseline CT (89.2%, true positives) 8.5 days [range, 1–18] before the first actual radiological evidence of PMD/PNX. Conversely, 6/136 patients without PMD/PNX (4.4%, false positives) demonstrated Macklin effect (p < 0.001). Macklin effect yielded a sensitivity of 89.2% (95% confidence interval [CI]: 74.6–96.9), a specificity of 95.6% (95% CI: 90.6–98.4), a positive predictive value (PV) of 84.5% (95% CI: 71.3–92.3), a negative PV of 97.1% (95% CI: 74.6–96.9) and an accuracy of 94.2% (95% CI: 89.6–97.2) in predicting PMD/PNX (AUC:0.924). Conclusions: Macklin effect accurately predicts, 8.5 days in advance, PMD/PNX development in COVID-19 ARDS patients.

Arterial hypertension represents a systemic burden, and it is responsible of various morphological, functional and tissue modifications affecting the heart and the cardiovascular system. Advanced imaging techniques, such as speckle tracking and three-dimensional echocardiography, cardiac magnetic resonance, computed tomography and PET-computed tomography, are able to identify cardiovascular injury at different stages of arterial hypertension, from subclinical alterations and overt organ damage to possible complications related to pressure overload, thus giving a precious contribution for guiding timely and appropriate management and therapy, in order to improve diagnostic accuracy and prevent disease progression. The present review focuses on the peculiarity of different advanced imaging tools to provide information about different and multiple morphological and functional aspects involved in hypertensive cardiovascular injury. This evaluation emphasizes the usefulness of the emerging multiimaging approach for a comprehensive overview of arterial hypertension induced cardiovascular damage.

Background The EXCEL trial reported similar five-year rates of the primary composite outcome of death, myocardial infarction (MI), or stroke after percutaneous coronary intervention (PCI) compared with coronary artery bypass grafting (CABG) for treatment of obstructive left main coronary artery disease (LMCAD). Aims We sought to determine whether these outcomes remained consistent regardless of geography of enrolment. Methods We performed a pre-specified subgroup analysis based on regional enrolment. Results Among 1,905 patients randomised to PCI (n=948) or CABG (n=957), 1,075 (56.4%) were recruited at 52 European Union (EU) centres, and 752 (39.5%) were recruited at 67 North American (NA) centres. EU versus NA patients varied according to numerous baseline demographics, anatomy, pharmacotherapy and procedural characteristics. Nonetheless, the relative rates of the primary endpoint after PCI versus CABG were consistent across EU versus NA centres at 30 days and 5 years. However, NA participants had substantially higher late rates of ischaemia-driven revascularisation (IDR) after PCI, driven predominantly by the need for greater target vessel and lesion revascularisation. This culminated in a significant difference in the relative risk of the secondary composite outcome of death, MI, stroke, or IDR at 5 years (pinteraction=0.02). Conclusions In the EXCEL trial, the relative risks for the 30-day and five-year primary composite outcome of death, MI or stroke after PCI versus CABG were consistent irrespective of geography. However, five-year rates of IDR after PCI were significantly higher in NA centres, a finding the Heart Team and patients should consider when making treatment decisions. ClinicalTrials.gov identifier: NCT01205776.

Background and Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial. Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics. Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26–115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack ( P 0 ( P P =0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS. Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.

Purpose: To determine the best treatment for dissociated vertical deviation (DVD). Methods: The authors investigated the postoperative results of unilateral surgery for DVD in 14 patients when the visual acuity difference between the two eyes did not result in a postoperative dominance switch. All patients underwent bilateral medial rectus recession for congenital esotropia. Results: With this unilateral surgical procedure, all patients showed a significant improvement of the DVD in the primary position. None of the patients developed hypotropia, anti-elevation syndrome, or inferior oblique overaction in the contralateral (dominant) eye, and no changes were observed in the contralateral eye. Conclusions: Unilateral surgery for DVD in the non-dominant eye in case of strong fixation preference does not create a postoperative manifest DVD in the unoperated dominant eye. [ J Pediatr Ophthalmol Strabismus . 2022;59(1):60–64.]

Psoriasis and psoriatic arthritis (PsA) are interrelated inflammatory diseases. Psoriasis usually precedes PsA onset and represents a well-established risk factor for PsA development. Bone erosion is a hallmark of PsA, and the contribution of cutaneous psoriatic inflammation in this process has been demonstrated. However, little is still known on the pathogenetic mechanisms that link psoriatic skin to joint damage. Clinical features of psoriatic disease, including specific body site involvement, seem to be important risk predictors of PsA. The aim of this pilot research study was to investigate if psoriatic cutaneous inflammation, affecting these anatomical predictive sites for PsA, could be linked to osteoclast differentiation and activity. Our results showed that psoriasis skin localizations were positively related to the osteoclastogenic profile in psoriatic patients. These results provide new insights into the fascinating skin-joint axis concept.

Objective: The objective of this study was to evaluate the performance of percutaneous femoral access with large-bore sheaths (>21F outer diameter) mainly employed for thoracic and thoracoabdominal aortic endovascular treatment and to stratify the outcomes on the basis of the introducer size. Methods: Between December 2015 and December 2018, all consecutive patients who received endovascular repair through a percutaneous approach with a suture-mediated vascular closure device (VCD) and the preclose technique were included in a retrospective single-center study called Totally Percutaneous Approach to Endovascular Treatment of Aortic Aneurysms (PEVAR-PRO). The morphologic characteristics of the access vessels and patients' demographics were recorded, and 30-day closure success was defined as the primary end point. Analysis of the closure success comparing large-bore sheaths vs small-bore sheaths (≤21F outer diameter) was performed after 1:1 propensity score matching of preoperative confounding variables. Results: The closure success rate of the entire study cohort was 94% (622 femoral accesses in 360 patients; median age, 74 years; 84% male). Univariate analysis identified eight different factors associated with failure, but only two remained significant on multivariate analysis: diabetes (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.3-6.2; P =.011) and common femoral artery stenosis >50% (OR, 4.5; 95% CI, 1.3-13.7; P =.019). After propensity score matching (1:1, 172 femoral accesses per group), closure success rate was not significantly different between large-bore and small-bore sheaths (90.7% vs 93.0%; P =.43). Multivariate analysis of the large-sheath group identified two factors associated with failure: small (

INTRODUCTION: This post hoc analysis evaluated the effect of prucalopride on abdominal bloating in participants with chronic idiopathic constipation (CIC) who had moderate to very severe bloating at baseline. Methods: Data from 6 phase 3/4 studies of prucalopride in participants with CIC were pooled. Abdominal bloating was assessed weekly using a 5-point scale (0–4). Results: The proportion of bloating responders (≥1-point improvement in abdominal bloating score at week 12) was higher in participants treated with prucalopride (62.1%) vs placebo (49.6%). DISCUSSION: The prucalopride arm had a higher proportion of bloating responders vs placebo in this study population.

Background: Delirium is a serious and common condition that needs an upgrade of the scientific and clinical attention. Aim: To assess the delirium prevalence in an Italian university hospital. Methods: The monocentric 1-day observational study cohort has been conducted on March 15, 2018; the population was composed of adult hospitalized patients. All the eligible patients have been evaluated for the presence of delirium with the 4AT. Results: We enrolled 596 patients. Twenty-nine Acute and 3 Rehabilitation Units were involved in the study. The median age of the sample was 60 (IQR 48–74) and 52% (n = 313) were male. Patients from medical units were 42% (n = 252), from surgery units 41% (n = 249), and from rehabilitation units 15% (n = 95). Results of 4AT showed that 5.4% (n = 32) had delirium (4AT = 4), 12% (n = 73) had cognitive impairment (4AT = 1–3), and 82% (n = 491) had no delirium or cognitive impairment (4AT = 0). We found association between delirium and age, BMI, mortality at 30days, and hospital mortality. Delirium was related with Barthel Index, dementia, and anticholinesterase inhibitors. About devices in use, we observed a correlation of delirium with central venous catheter, feeding tube, and urinary catheter. Physical restraints were also correlated to delirium. Conclusions: We confirmed the presence of delirium across the hospital units, more in medical than in surgical ones. We found associations of delirium with conditions that limit movement, such as dementia, physical restraints, or devices. The development of delirium initiates a cascade of events culminating in the loss of independence and increased morbidity.

Purpose Perioperative myocardial dysfunction occurs frequently in cardiac surgery, and is a risk factor for morbidity and mortality. Levosimendan has been suggested to reduce mortality of patients with perioperative myocardial dysfunction. However, long-term outcome data on its efficacy in cardiac surgery are lacking. Materials and methods Cardiac surgery patients with perioperative myocardial dysfunction were randomized to levosimendan or placebo, in addition to standard inotropic care. One-year mortality data were collected. Results We randomized 506 patients (248 to levosimendan 258 to placebo). At 1-year follow-up, 41 patients (16.5%) died in the levosimendan group, while 47 (18.3%) died in the placebo group (absolute risk difference −1.8; 95% CI −8.4 to 4.9; P = .60). Female sex, history of chronic obstructive pulmonary disease, previous myocardial infarction, serum creatinine, hematocrit, mean arterial pressure, and duration of cardiopulmonary bypass were independently associated with 1-year mortality. Conclusions Levosimendan administration does not improve 1-year survival in cardiac surgery patients with perioperative myocardial dysfunction. One-year mortality in these patients is 17%. Six predictive factors for long-term mortality were identified. Study registration number NCT00994825 ( ClinicalTrials.gov ).

Background Telemetry applied to aquatic organisms has recently developed greatly. Physiological sensors have been increasingly used as tools for fish welfare monitoring. However, for the technology to be used as a reliable welfare indicator, it is important that the tagging procedure does not disrupt fish physiology, behaviour and performance. In this communication, we share our medium-term data on stress physiological profile and growth performance after surgical tag implantation in two important marine fish species for European aquaculture, the sea bream (Sparus aurata) and the European sea bass (Dicentrarchus labrax). Results Blood samples after surgical tag implantation (46 days for the sea bream and 95 days for the sea bass) revealed no differences between tagged and untagged fish in cortisol, glucose and lactate levels, suggesting that the tag implantation does not induce prolonged stress in these species. Moreover, the specific growth rates were similar in the tagged and untagged fish of both species. Conclusion Surgical tag implantation does not have medium-term consequences for the stress physiology and growth performance of these two marine fish species in a controlled environment. These observations support the use of accelerometer tags as valuable tools for welfare monitoring in aquaculture conditions. This study also shows that tagged fish can be sampled during experiments and considered a representative portion of the population, as they display growth and physiological parameters comparable to those of untagged fish.

Objectives To evaluate the safety and effectiveness of a multistaged approach for elective thoraco-abdominal aneurysm (TAAAs) repair by means of endovascular fenestrated and/or branched (F/B-EVAR) grafts. Methods Between 2013 and 2018, 80 high risk surgical patients received elective F/B-EVAR for TAAAs with a protocolled multistaged approach (thoracic, visceral, and limb steps) and were enrolled in an ambispective single centre study called STEAR (STaged Endovascular Aortic Repair - NCT03342755 ). Data regarding all study participants, single step mortality and morbidity (systemic complications) rates were recorded and the overall results were considered for statistical analysis. Results Previous aortic interventions (61/80 cases, 76.3%) combined with the TAAA extents resulted in different staging strategies: 58 patients (73%) had a thoracic step and 33 (41%) a limb step. The median TAAA treatment time was 77 days (50–107). The overall mortality was six cases (8%) and 30 day clinical success rate 64 cases (80%). The overall rate of grade 2 or 3 (including death) systemic complications was 19 cases (24%) and 20 patients (25%) experienced grade 1 complications. Three patients with type II or III TAAAs (4%) had permanent and fatal spinal cord (SC) impairment. On multivariable analysis, SC ischaemia was associated with an aortic coverage ≥350 mm (OR: 9.15, p = .03, 95% CI: 1.3–66.4) and bovine arch (OR: 10.6, p = .01, 95% CI: 1.6–68.6). The overall short term (six month) clinical success was 72 cases (90%) and none experienced SC ischaemia after late endoleak resolution or treatment. At mid term (mean follow up: 13.3 ± 15.4 months), the overall freedom from conversions, re-interventions, late rupture, or type I and III endoleaks was 57 of 72 survivors (79%). Conclusions A multistaged approach with a third limb step in case of TAAAs is safe and technically feasible, with an acceptable rate of permanent spinal cord ischaemia. Different staging methods and protocols have been proposed and standardisation is required, especially for type I-II-III aneurysms.

Left ventricular (LV) global longitudinal strain (GLS) can detect an early dysfunction in arterial hypertension. We investigated regional LV patterns of longitudinal strain (LS) and base-to-apex behaviour in newly diagnosed, never-treated hypertensive patients (HTN) without LV hypertrophy.180 HTN and 115 healthy controls underwent standard echocardiography, including regional LS and GLS assessment (in absolute values). The average LS of six basal (BLS), six middle (MLS), and six apical (ALS) segments and relative regional strain ratio = [ALS/(BLS + MLS)] were also computed.The two groups were comparable for sex, age and heart rate. Body mass index (BMI), systolic, diastolic and mean blood pressure (BP) (all p 0.0001) were higher in HTN. Despite LV ejection fraction (EF) was comparable, GLS, BLS and MLS resulted lower in HTN (all p 0.0001), without difference in ALS. Relative regional strain ratio resulted higher in HTN (p 0.001). Dividing HTN group according to lower normal values derived from the controls, BLS was able to identify a higher rate of LV dysfunction than GLS. By a multiple linear regression analysis performed in the pooled population after adjusting for age, sex, BMI, end-systolic stress, relative wall thickness and LV mass index, the association between BLS and mean BP remained significant (β coefficient = -0.42, p 0.0001), despite the significant impact of male sex. In a similar model, MLS and mean BP resulted also independently associated (β = -0.21, p 0.002).Despite normal LV EF, LS dysfunction is detectable in HTN, mainly involving basal and middle segments, resulting in higher relative regional strain ratio.

BACKGROUND In hypertensive patients, an impairment of midwall myocardial mechanics was described in presence of left ventricular (LV) concentric geometry. Under these circumstances, also LV longitudinal dysfunction was found. PURPOSE Our aim was to evaluate longitudinal and circumferential systolic function and correlations between these two functional components in newly diagnosed hypertensive patients without clinically defined LV hypertrophy (LVH). One hundred and thirty-eight newly diagnosed, never-treated hypertensive patients without LVH and a control group of 105 healthy normotensive individuals underwent two-dimensional and speckle tracking echocardiography. Global longitudinal strain (GLS) was derived (in absolute value) and midwall fractional shortening (MFS) computed. In addition, the hypertensive population was divided into two groups according to GLS: normal GLS (≥20%, n = 94) and reduced GLS (

In 2016, an update of the 2009 recommendations for the evaluation of left ventricular (LV) diastolic function (DF) was released by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. The aims of this study were to assess the concordance between the 2016 and 2009 recommendations and to test the impact of the consideration of "myocardial disease" recommended in the 2016 update on the evaluation of diastolic dysfunction (DD) and LV filling pressures in patients with normal and reduced LV ejection fractions referred to a general echocardiography laboratory.A total of 1,508 outpatients referred to an echocardiography laboratory during a predefined 5-month period were prospectively enrolled. All patients underwent targeted clinical history and Doppler echocardiographic examination. DD and LV filling pressures were assessed according to 2009 and 2016 recommendations. Concordance was calculated using the κ coefficient and overall proportion of agreement.Overall proportion of agreement between the two recommendations was 64.7% (κ = 0.43). Comparing the 2009 and 2016 recommendations, 47.5% and 36.1% patients, respectively, had DD (P .0001), and 22.7% and 12.6% had elevated LV filling pressures (P .0001). This difference remained significant in the setting of patients with normal LV ejection fractions (21.6% vs 10.7%, P .0001). In the application of the 2016 recommendations, whether or not the presence of "myocardial disease" was considered, the prevalence of indeterminate diastolic function was, respectively, 7.3% versus 13.7%, while patients in whom the DD grade could not be determined were 8.1% versus 14.4% (P .0001 for all).Considering the presence of myocardial disease when applying the 2016 recommendations resulted in a lower prevalence of inconclusive diagnosis.

Aims: Hypoglycemia is a serious complication of bariatric surgery. The aim of the present meta-analysis was to evaluate the rate and the timing of post-bariatric hypoglycemia (PBH) with different bariatric procedures using reliable data from continuous glucose monitoring (CGM). Data synthesis: Studies were systematically searched in the Web of Science, Scopus and PubMed databases according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The prevalence of PBH was expressed as weighted mean prevalence (WMP) with pertinent 95% confidence intervals (95%CI). A total of 8 studies (16 datasets) enrolling 280 bariatric subjects were identified. The total WMP of PBH was 54.3% (95%CI: 44.5%–63.8%) while the WMP of nocturnal PBH was 16.4% (95%CI: 7.0%–34%). We found a comparable rate of PBH after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) (OR 1.62, 95%CI: 0.71–3.7; P = 0.248); likewise, the percent time spent in hypoglycemia was similar with the two procedures (mean difference 5.3%, 95%CI: −1.4%–12.0%; P = 0.122); however, RYGB was characterized by a higher glycemic variability than SG. Regression models showed that the time elapsed from surgical intervention was positively associated with a higher rate of both total PBH (Z-value: 3.32, P < 0.001) and nocturnal PBH (Z-value: 2.15, P = 0.013). Conclusions: PBH, both post-prandial and nocturnal, is more prevalent than currently believed. The rate of PBH increases at increasing time from surgery and is comparable after RYGB and SG with a higher glucose variability after RYGB.

BACKGROUND Dermographism is a condition characterized by a weal response to a combination of pressure and traction on skin surface, and its diagnosis is based on medical history, clinical criteria and provocation test. The Dermographic Tester® , a pen-sized tool containing a spring-loaded blunt tip, is the most widely used instrument for the provocation test, and it exerts increasing pressures on the skin surface according to an arbitrary units (AU) scale. Analysing the mechanism of function and trying to convert the AUs to SI units (g/mm2 ), we found that this instrument had some defects and limits that would compromise a true and repeatable quantification of the weal response threshold. Consequently, we decided to develop a new instrument, the Digital Dermographic Tester (DDT), which is engineered with an inside force sensor to implement features lacking in the current tools, in the hope of enhancing the precision of the provocation test. AIM To validate the effectiveness and accuracy of the DDT. METHODS We tested the DDT on 213 participants purposely sampled to obtain three groups, each with a different pattern of reaction to mechanical stimuli. Based on anamnestic, diagnostic and symptomatic criteria, patients were divided into dermographic urticaria (DU), spontaneous urticaria (SU) and healthy control (HC) groups. The DDT was used to apply 12 levels of pressure to the skin surface, and a frequency distribution of positive reactions was displayed for each group. RESULTS A force of 36-40 g/mm2 appropriately differentiated physiological from pathological conditions with high sensitivity and specificity. CONCLUSIONS The DDT was found to be capable of differentiating patients with DU patients from those with SU and from HCs, and was able to precisely identify the weal elicitation threshold.

Introduction Chronic idiopathic constipation (CIC) is a common and burdensome illness. We performed a cost-effectiveness analysis of the US Food and Drug Administration-approved CIC drugs to evaluate and quantify treatment preferences compared with usual care from insurer and patient perspectives. Methods We evaluated the subset of patients with CIC and documented failure of over-the-counter (OTC) osmotic or bulk-forming laxatives. A RAND/UCLA consensus panel of 8 neurogastroenterologists informed model design. Treatment outcomes and costs were defined using integrated analyses of registered clinical trials and the US Centers for Medicare and Medicaid Services-supported cost databases. Quality-adjusted life years (QALYs) were calculated using health utilities derived from clinical trials. A 12-week time horizon was used. Results With continued OTC laxatives, CIC-related costs were $569 from an insurer perspective compared with $3,154 from a patient perspective (considering lost wages and out-of-pocket expenses). CIC prescription drugs increased insurer costs by $618-$1,015 but decreased patient costs by $327-$1,117. Effectiveness of CIC drugs was similar (0.02 QALY gained/12 weeks or ∼7 healthy days gained/year). From an insurer perspective, prescription drugs (linaclotide, prucalopride, and plecanatide) seemed less cost-effective than continued OTC laxatives (incremental cost-effectiveness ratio >$150,000/QALY gained). From a patient perspective, the cost-effective algorithm started with plecanatide, followed by choosing between prucalopride and linaclotide starting at the 145-μg dose (favoring prucalopride among patients whose disease affects their work productivity). The patient perspective was driven by drug tolerability and treatment effects on quality of life. Discussion Addressing costs at a policy level has the potential to enable patients and clinicians to move from navigating barriers in treatment access toward truly optimizing treatment choice.

Introduction Peppermint oil is often used to treat irritable bowel syndrome (IBS); however, the overall quality of previous studies is low, and findings have been heterogeneous. This study aimed to compare the effects of peppermint oil vs placebo in relieving IBS symptoms. Methods In a 6-week, randomized, double-blind, placebo-controlled trial at a single academic center in the United States, individuals diagnosed with IBS (Rome IV criteria), with moderate to severe symptoms based on the IBS Severity Scoring System (IBS-SSS score ≥175), were randomized to enteric-coated peppermint oil 180 mg 3 times daily vs placebo in a 1:2 ratio. The primary outcome was mean change in IBS-SSS scores from baseline to 6-week endpoint. Results A modified intent-to-treat analysis revealed that there were substantial mean improvements from baseline to 6-week endpoint in the main outcome measure (IBS-SSS) for both peppermint oil (90.8, SD = 75.3) and placebo (100.3, SD = 99.6). Although the peppermint oil group reported numerically lower improvement than the placebo group, the effect size was small (d = -0.11), and the difference between the groups was not statistically significant (P = 0.97). Similarly, both groups reported substantial improvements on the secondary endpoints; but again, there were no statistically significant differences between the groups on any of the secondary measures. Sensitivity analyses using multiple imputation to replace missing data produced similar results and revealed no significant differences between peppermint oil and placebo on any outcome measure. Discussion Peppermint oil and placebo both showed clinically meaningful improvement in IBS symptoms. However, there were no significant differences between the groups. Further large, rigorous trials are needed to evaluate the role of peppermint oil for the treatment of IBS.

OBJECTIVES Tricyclic antidepressants (TCAs) are commonly used to treat disorders of gut-brain interaction (DGBI). However, these medications are often associated with side effects that lead to early treatment discontinuation. Research in other chronic medical conditions suggests that many TCA side effects may be caused by nocebo (negative placebo) effects. The current study tests a brief, verbal intervention aimed at improving tolerance of TCAs in DGBI by providing education about nocebo effects. MATERIALS AND METHODS This pilot randomized controlled trial was performed in a tertiary care gastroenterology clinic. Participants with DGBI were randomized "standard information," describing the benefits and risks of TCAs, or "augmented information," which included an additional

Purpose Therapeutic strategies for prostate cancer (PCa) have been evolving dramatically worldwide. The current article reports on the evolution of surgical management strategies for PCa in Italy. Methods The data from two independent Italian multicenter projects, the MIRROR-SIU/LUNA (started in 2007, holding data of 890 patients) and the Pros-IT-CNR project (started in 2014, with data of 692 patients), were compared. Differences in patients' characteristics were evaluated. Multivariable logistic regression models were used to identify characteristics associated with robot-assisted (RA) procedure, nerve sparing (NS) approach, and lymph node dissection (LND). Results The two cohorts did not differ in terms of age and prostate-specific antigen (PSA) levels at biopsy. Patients enrolled in the Pros-IT-CNR project more frequently were submitted to RA (58.8% vs 27.6%,p < 0.001) and NS prostatectomy (58.4% vs. 52.9%,p = 0.04), but received LND less frequently (47.7% vs. 76.7%,p < 0.001), as compared to the MIRROR-SIU/LUNA patients. At multivariate logistic models, Lower Gleason Scores (GS) and PSA levels were significantly associated with RA prostatectomy in both cohorts. As for the MIRROR-SIU/LUNA data, clinical T-stage was a predictor for NS (OR = 0.07 for T3, T4) and LND (OR = 2.41 for T2) procedures. As for Pros-IT CNR data, GS >= (4 + 3) and positive cancer cores >= 50% were decisive factors both for NS (OR 0.29 and 0.30) and LND (OR 7.53 and 2.31) strategies. Conclusions PCa management has changed over the last decade in Italian centers: RA and NS procedures without LND have become the methods of choice to treat newly medium-high risk diagnosed PCa.

Objective Meropenem is a β-lactam, carbapenem antibacterial agent with antimicrobial activity against gram-negative, gram-positive and anaerobic micro-organisms and is important in the empirical treatment of serious infections in Intensive Care Unit (ICU) patients. Multi-drug resistant gram-negative organisms, coupled with scarcity of new antibiotic classes, forced healthcare community to optimize the therapeutic potential of available antibiotics. Our aim is to investigate the effect of continuous infusion of meropenem against bolus administration, as indicated by a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens in a population of ICU patients. Design Double blind, double dummy, multicenter randomized controlled trial (1:1 allocation ratio). Setting Tertiary and University hospitals. Interventions 600 ICU patients with sepsis or septic shock, needing by clinical judgment antibiotic therapy with meropenem, will be randomized to receive a continuous infusion of meropenem 3 g/24 h or an equal dose divided into three daily boluses (i.e. 1g q8h). Measurements The primary endpoint will be a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens. Secondary endpoints will be death from any cause at day 90, antibiotic-free days at day 28, ICU-free days at day 28, cumulative SOFA-free (Sequential Organ Failure Assessment) score from randomization to day 28 and the two, separate, components of the primary endpoint. We expect a primary outcome reduction from 52 to 40% in the continuous infusion group. Conclusions The trial will provide evidence for choosing intermittent or continuous infusion of meropenem for critically ill patients with multi-drug resistant gram-negative infections.

Background: Dupilumab, a fully human monoclonal antibody targeting the alpha subunit of IL-4 was recently approved for the treatment of moderate-to-severe atopic dermatitis (AD) in adult patients. Objective: To assess dupilumab effectiveness and safety in adults with moderate-to-severe AD in a real-life Italian multicentre retrospective cohort. Methods: Adult moderate-to-severe AD patients, referring to 39 Italian centers, received dupilumab in the context of a national patient access program. Disease assessment was performed at baseline, after 4 and 16 weeks of treatment using Eczema-Area-and-Severity-Index (EASI) score, itch and sleep numerical-rating-score (itch-NRS, sleep-NRS) and Dermatology-Life-Quality-Index (DLQI). Results: A total of 109 (71 M/38F) patients was studied. There was a significant reduction in EASI score, itch-NRS, sleep-NRS and DLQI from baseline to week 4 and a further significant decline to week 16. EASI 50, EASI75 and EASI90 were achieved by 59.6%, 28.4% and 9.3% of patients at 4 weeks and by 87.2%, 60.6% and 32.4% of them at 16 weeks, respectively. Adverse events were experienced by 19.2% (21/109) of the patients and they were all mild in intensity, being conjunctivitis the most common side effect. Conclusions: Dupilumab significantly improved disease severity, pruritus, sleep loss and quality of life with an acceptable safety profile.

Introduction Patients with disorders of gut-brain interaction (DGBIs) are high users of health care. Past studies exploring predictors of utilization have lacked patient-level clinical data. The aim of the current study is to identify demographic, clinical, and psychological predictors of health care utilization in patients with irritable bowel syndrome (IBS), functional constipation (FC), and functional diarrhea (FDr). Methods Consecutive new patients diagnosed with IBS, FC, and FDr (using Rome IV criteria) completed questionnaires assessing health care utilization as well as clinical and psychological symptoms. Health care utilization was assessed using a 13-item measure inquiring about the previous 6 months. Patient-Reported Outcome Measures Information System (PROMIS) was used to assess severity of abdominal pain, constipation, diarrhea, anxiety, depression, and sleep disturbance. Results Of the 507 patients diagnosed with IBS, FC, or FDr, 434 completed the health care utilization questionnaire (mean age of 44 years, 79.5% female, and 73.5% IBS). In the final multivariable models, more severe abdominal pain and higher depression scores were significantly associated with increased utilization of (i) total outpatient visits, (ii) outpatient visits for gastrointestinal (GI) symptoms, and (iii) number of medications for GI symptoms. More severe abdominal pain was also significantly predictive of GI-related emergency department visits. Altered bowel habits were not consistent predictors of health care utilization. Discussion Severity of abdominal pain and depressive symptoms, but not bowel habits, is a primary driver of increased care-seeking behavior in patients with IBS, FC, and FDr.

Background: There is a paucity of data regarding the effect of inhibition of the renin-angiotensin system on outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). We sought to examine long-term outcomes of patients with left main coronary disease (LMCAD) randomized to PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents or CABG according to treatment at discharge with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in the large-scale, multicenter, randomized EXCEL trial. Methods: EXCEL randomized 1905 patients with LMCAD of low and intermediate anatomical complexity (visually-assessed SYNTAX score ≤32) to PCI (n = 948) versus CABG (n = 957). Patients were categorized according to whether they were treated with ACEI/ARB at discharge; their outcomes from discharge to 5 years were examined using multivariable logistic regression with an offset for follow-up time. Results: Among 1775 patients discharged alive with known ACEI/ARB treatment status, 896 (50.5%) were treated with one of these agents. Among those treated with ACEI/ARB, the 5-year rate of all-cause death was similar after PCI or CABG (10.7% versus 9.8% respectively, adjOR, 0.94; 95% CI, 0.56-1.57) in contrast to patients not treated with ACEI/ARB (15.0% versus 7.8%, respectively, adjOR, 2.20; 95% CI, 1.32-3.67) (Pinteraction = 0.02). Significant interactions between treatment arm (PCI versus CABG) and ACEI/ARB treatment status were also found for cardiovascular death (Pinteraction = 0.03), ischemia-driven revascularization (Pinteraction = 0.03), target vessel revascularization (Pinteraction = 0.007) and target vessel failure (Pinteraction = 0.0009). Conclusion: In the EXCEL trial, the postdischarge rates of death and revascularization after 5 years were similar after PCI and CABG in patients with LMCAD treated with ACEI/ARB at discharge. In contrast, event rates were higher after PCI versus CABG in those not so treated.

Accumulating evidence suggests that modifications of gut function and microbiota composition might play a pivotal role in the pathophysiology of several cardiovascular diseases, including heart failure (HF). In this study we systematically analysed gut microbiota composition, intestinal barrier integrity, intestinal and serum cytokines and serum endotoxin levels in C57BL/6 mice undergoing pressure overload by transverse aortic constriction (TAC) for 1 and 4 weeks. Compared to sham-operated animals, TAC induced prompt and strong weakening of intestinal barrier integrity, long-lasting decrease of colon anti-inflammatory cytokine levels, significant increases of serum levels of bacterial lipopolysaccharide and proinflammatory cytokines. TAC also exerted effects on microbiota composition, inducing significant differences in bacterial genera inside Actinobacteria, Firmicutes, Proteobacteria and TM7 phyla as shown by 16S rDNA sequencing of fecal samples from TAC or sham mice. These results suggest that gut modifications represent an important element to be considered in the development and progression of cardiac dysfunction in response to TAC and support this animal model as a valuable tool to establish the role and mechanisms of gut-heart crosstalk in HF. Evidence arising in this field might identify new treatment options targeting gut integrity and microbiota components to face adverse cardiac events.

Patients may experience long-term physical, psychological and cognitive impairment after intensive care unit (ICU) discharge, a condition commonly described as post-intensive care syndrome. The relative contribution of each of these components to long-term quality of life was never investigated.The aim of this studyis to identify the type and severity of disability and QoL at the discharge from ICU and up to following 6 months.Material and Methods. All patients (n=218) discharged from a university hospital ICU between April 2016 and July 2017 were eligible. Exclusion criteria included: age n=109) or patients requiring ICU treatment (IT, Intensive Treatment,n=109).Results. All dimensions of SF-36 and EQ-5D-5L parameters increased from ICU discharge to 180-days, except for the SF-36 Synthetic index linked to mental health (P=0.08). All EQ-5D-5L parameters improved significantly in the IT group, while only Visual Analog Scale Health Perception improved in the IM group.Conclusion. ICU survivors suffer long-term physical and psychological sequelae. The perception of Quality of Life is reduced after ICU discharge. The psychological and cognitive dimensions were more compromised than physical ones. Patients discharged from the ICU may benefit from specific intensive care follow-up clinics addressing their needs in term of psychological and cognitive support.

Prior studies in patients with noncomplex coronary artery disease have demonstrated the safety of percutaneous coronary intervention (PCI) in the outpatient setting. We sought to examine the outcomes of outpatient PCI in patients with unprotected left main coronary artery disease (LMCAD). In the EXCEL trial, 1905 patients with LMCAD and site-assessed low or intermediate SYNTAX scores were randomized to PCI with everolimus-eluting stents versus coronary artery bypass grafting. The primary end point was major adverse cardiovascular events (MACE; the composite of death, stroke, or myocardial infarction). In this sub-analysis, outcomes at 30 days and 5 years were analyzed according to whether PCI was performed in the outpatient versus inpatient setting. Among 948 patients with LMCAD assigned to PCI, 935 patients underwent PCI as their first procedure, including 100 (10.7%) performed in the outpatient setting. Patients who underwent outpatient compared with inpatient PCI were less likely to have experienced recent myocardial infarction. Distal left main bifurcation disease involvement and SYNTAX scores were similar between the groups. Comparing outpatient to inpatient PCI, there were no significant differences in MACE at 30 days (4.0% vs 5.0% respectively, adjusted OR 0.52 95% CI 0.12 to 2.22; p = 0.38) or 5 years (20.6% vs 22.1% respectively, adjusted OR 0.72, 95% CI 0.40 to 1.29; p = 0.27). Similar results were observed in patients with distal left main bifurcation lesions. In conclusion, in the EXCEL trial, outpatient PCI of patients with LMCAD was not associated with an excess early or late hazard of MACE. These data suggest that outpatient PCI may be safely performed in select patients with LMCAD.

We sought to summarize current recommendations for the diagnosis of diarrhea-predominant irritable bowel syndrome (IBS-D) and describe available management options, highlighting a newer US Food and Drug Administration (FDA)-approved agent, eluxadoline.Literature on IBS-D was assessed up to January 2020 using PubMed, with key search terms including "IBS-D diagnosis", "IBS-D management", and "eluxadoline".IBS is a common gastrointestinal disorder affecting up to 14% of US adults and is particularly prevalent in women and those aged under 50. Symptoms include abdominal pain associated with altered bowel habits (i.e. diarrhea and/or constipation subtyped based on the predominant stool pattern). As IBS-D is challenging to manage with varying symptom severity, effective treatment requires a personalized management approach. Evidence-based therapeutic options endorsed by the American Gastroenterological Association and the American College of Gastroenterology can be used to effectively guide treatment. Dietary and lifestyle modifications, including adequate hydration, reducing caffeine and alcohol intake, and increasing soluble fiber intake may lead to symptom improvement. Over-the-counter medications such as loperamide are frequently recommended and may improve stool frequency and rectal urgency; however, for the outcome of abdominal pain, mixed results have been observed. Several off-label prescription medications are useful in IBS-D management, including tricyclic antidepressants, bile acid sequestrants, and antispasmodics. Three prescription medications have been approved by the FDA for IBS-D: alosetron, eluxadoline, and rifaximin.IBS-D can be effectively managed in the primary care setting in the absence of alarm features. Benefits and risks of pharmacologic interventions should be weighed during treatment selection.

Aortic stenosis (AS) is a very common valve disease and is associated with high mortality once it becomes symptomatic. Arterial hypertension (HT) has a high prevalence among patients with AS leading to worse left ventricle remodeling and faster degeneration of the valve. HT also interferes with the assessment of the severity of AS, leading to an underestimation of the real degree of stenosis. Treatment of HT in AS has not historically been pursued due to the fear of excess reduction in afterload without a possibility of increasing stroke volume due to the fixed aortic valve, but most recent evidence shows that several drugs are safe and effective in reducing BP in patients with HT and AS. RAAS inhibitors and beta-blockers provide benefit in selected populations based on their profile of pharmacokinetics and pharmacodynamics. Different drugs, on the other hand, have proved to be unsafe, such as calcium channel blockers, or simply not easy enough to handle to be recommended in clinical practice, such as PDE5i, MRA or sodium nitroprusside. The present review highlights all available studies on HT and AS to guide antihypertensive treatment.

Both the conventional and organic aquaculture sectors have grown rapidly over the past few years. Moreover, welfare has attracted increased attention on the part of both consumers and governments. However, fish welfare assessment is complex and thus needs to adapt measurements that are easily applicable to aquaculture conditions. In this study, in addition to classical welfare indicator measurements (physiological stress indicators and growth performance), we recorded the swimming activity data using acoustic transmitters to evaluate the welfare of European sea bass (Dicentrarchus labrax) fed a conventional vs. an organic diet. Prior feeding trial, the swimming activity recorded by tag has been calibrated with water speed during critical swimming speed (Ucrit) tests. This calibration allowed us to increase the power of the recorded data, providing information on swimming activity with respect to the Ucrit value and on the metabolic cost of swimming. After a four-month experimental period, physiological stress indicators and growth performance did not differ significantly between the two diet groups. However, we observed a subtle difference in swimming activity: the fish in the organic diet group were more active during the feeding period in the morning. All indicators considered, our results suggest that an organic diet does not incur higher metabolic costs and does not affect the welfare of the European sea bass. Moreover, this study shows that the use of acoustic transmitters previously calibrated with physiological indicators, such as Ucrit, is a promising tool for welfare monitoring in aquaculture conditions.

Prescription drug costs exert profound effects on commercial insurance coverage and access to effective therapy. We aimed to assess threshold pricing to achieve budget neutrality of FDA-approved drugs treating irritable bowel syndrome from an insurance perspective, based on cost-savings resulting in decreased healthcare utilization through effective disease management. We constructed a decision-analytic model from an insurance perspective to assess the budget impact of IBS prescription drugs under usual insurance coverage levels in practice: (1) unrestricted drug access or (2) step therapy in a primary care population of middle-age, care-seeking IBS patients. Budget-neutral drug prices were then calculated which resulted in $0 budget impact to insurers with a short-term, one-year time horizon. If used according to FDA labeling, IBS-D drugs cost between $4778 and $16,844 per year and IBS-C drugs cost between $4319 and $4955 per year. These drug costs often exceed insurance expenditures of $6999 for IBS-D and $3929 for IBS-C if left untreated. Therefore, for drugs to have $0 budget impact to insurers, their prices would need to be discounted 36.7–74.2% for IBS-D drugs and 59.3–82.5% for IBS-C. IBS drugs are already priced to support step therapy “failing one of several common, inexpensive IBS treatments with a responder rate > 30–40%,” reflecting the subpopulation with more severe disease and greater healthcare costs. Broader prescription drug coverage for patients failing common, inexpensive IBS treatments to which at least 30–40% of patients would typically respond appears warranted to enable gastroenterologists to offer personalized approaches targeting specific mechanisms of this heterogeneous disease.

BackgroundEpidermolysis bullosa (EB) comprises a heterogeneous group of rare genetic diseases associated with skin blistering caused by minimal trauma. A major and common EB subtype, recessive dystrophic EB (RDEB), is characterized by altered wound healing, inflammatory dysbalance and fibrotic changes associated with reduced to absent collagen VII. Because of its exposed position and its continued use in daily activities, the hand is constantly at risk of microtrauma and is therefore one of the organs most affected by the disease with highly disabling deformities that represent a challenging field in hand surgery practice.MethodsThe authors present their experience in the microsurgical treatment of pseudosyndactylies comparing the classic dressing with vaseline gauze with an innovative “glove protocol” using Integra®dermal regeneration template. The endpoints analyzed were: healing times, hospital stay time, discomfort for the patient, free-recurrence interval, follow-up range and major complications.ResultsA total of 34 procedures were performed on 24 RDEB patients with hand deformities. Compared with the dressing with vaseline gauze, microsurgery followed by application of dermal regeneration template gloves allowed a significant reduction of hospital stay, healing time, and dressing pain as well as an increased recurrence-free interval.ConclusionsThe microsurgical approach followed by our new protocol described in the study has been beneficial in providing consistent and successful long-term results for these patients.

INTRODUCTION: Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the long-term efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). METHODS: In this randomized double-blind study (ClinicalTrials.gov identifier: NCT02686138), patients with IBS-C received tenapanor 50 mg b.i.d. or placebo b.i.d. for 26 weeks. The primary endpoint was the proportion of patients who had a reduction of ≥30.0% in average weekly worst abdominal pain and an increase of ≥1 weekly complete spontaneous bowel movement from baseline, both in the same week, for ≥6 of the first 12 treatment weeks (6/12-week combined responder). RESULTS: Of the 620 randomized patients with IBS-C, 593 (95.6%) were included in the intention-to-treat analysis set (tenapanor: n = 293; placebo: n = 300) and 481 patients (77.6%) completed the 26-week treatment period. In the intention-to-treat analysis set (mean age: 45.4 years; 82.1% women), a significantly greater proportion of patients treated with tenapanor were 6/12-week combined responders than those treated with placebo (36.5% vs 23.7%; P < 0.001). Abdominal symptoms and global symptoms of IBS were significantly improved with tenapanor compared with placebo. Diarrhea, the most common adverse event, was typically transient and mild to moderate in severity. Diarrhea led to study drug discontinuation for 19 (6.5%) and 2 patients (0.7%) receiving tenapanor and placebo, respectively. DISCUSSION: Tenapanor 50 mg b.i.d. improved IBS-C symptoms over 26 weeks and was generally well tolerated, offering a potential new long-term treatment option for patients with IBS-C (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B797).

Background The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. Methods We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient’s age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. Results The median age in the sample of 7487 consecutive patients was 84 years (IQR 81–87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p p Conclusion Knowledge about a patient’s frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

Simple Summary A novel challenge in cancer immunotherapy is the identification of the most potent combinations of immunomodulatory mAbs that are capable of maximizing therapeutic benefits while minimizing irAEs. We set up an in vitro system to quickly predict the efficacy and eventual cardiotoxic side effects of combinatorial treatments, thus allowing for the early screening of most potent and safe combinatorial therapeutic regimens for both validated and emerging immunomodulatory mAbs against different immune checkpoints (ICs). Furthermore, we provide for the first time evidence on cis-interactions of ICs in tumor cells. Abstract Antibodies targeting Immune Checkpoints (IC) on tumor infiltrating lymphocytes improve immune responses against cancer. Recently, the expression of some ICs has also been reported on cancer cells. We used the clinically validated Ipilimumab and Nivolumab and other novel human antibodies targeting Cytotoxic T- lymphocyte-antigen 4 (CTLA-4), Programmed Death receptor-1 (PD-1) and Programmed Death Ligand 1 (PD-L1) to shed light on the functions of these ICs in cancer cells. We show here for the first time that all these antagonistic mAbs are able to reduce Erk phosphorylation and, unexpectedly, to induce a significant increase of ICs expression on tumor cells, involving a hyperphosphorylation of NF-kB. On the contrary, agonistic PD-L1 and PD-1 recombinant proteins showed opposite effects by leading to a significant reduction of PD-1 and PD-L1, thus also suggesting the existence of a crosstalk in tumor cells between multiple ICs. Since the immunomodulatory mAbs show their higher anti-tumor efficacy by activating lymphocytes against cancer cells, we also investigated whether it was possible to identify the most efficient combinations of immunomodulatory mAbs for achieving potent anti-tumor efficacy associated with the lowest adverse side effects by setting up novel simple and predictive in vitro models based on co-cultures of tumor cells or human fetal cardiomyocytes with lymphocytes. We demonstrate here that novel combinations of immunomodulatory mAbs with more potent anti-cancer activity than Ipilimumab and Nivolumab combination can be identified with no or lower cardiotoxic side effects. Thus, we propose these co-cultures-based assays as useful tools to test also other combinatorial treatments of emerging immunomodulatory mAbs against different ICs for the early screening of most potent and safe combinatorial therapeutic regimens.

BackgroundThe number of intensive care patients aged ≥ 80 years (Very old Intensive Care Patients; VIPs) is growing. VIPs have high mortality and morbidity and the benefits of ICU admission are frequently questioned. Sepsis incidence has risen in recent years and identification of outcomes is of considerable public importance. We aimed to determine whether VIPs admitted for sepsis had different outcomes than those admitted for other acute reasons and identify potential prognostic factors for 30-day survival.ResultsThis prospective study included VIPs with Sequential Organ Failure Assessment (SOFA) scores ≥ 2 acutely admitted to 307 ICUs in 21 European countries. Of 3869 acutely admitted VIPs, 493 (12.7%) [53.8% male, median age 83 (81–86) years] were admitted for sepsis. Sepsis was defined according to clinical criteria; suspected or demonstrated focus of infection and SOFA score ≥ 2 points. Compared to VIPs admitted for other acute reasons, VIPs admitted for sepsis were younger, had a higher SOFA score (9 vs. 7,p p p p = 0.02]. Frailty was similar in both groups. Unadjusted 30-day survival was not significantly different between the two groups. After adjustment for age, gender, frailty, and SOFA score, sepsis had no impact on 30-day survival [HR 0.99 (95% CI 0.86–1.15),p = 0.917]. Inverse-probability weight (IPW)-adjusted survival curves for the first 30 days after ICU admission were similar for acute septic and non-septic patients [HR: 1.00 (95% CI 0.87–1.17),p = 0.95]. A matched-pair analysis in which patients with sepsis were matched with two control patients of the same gender with the same age, SOFA score, and level of frailty was also performed. A Cox proportional hazard regression model stratified on the matched pairs showed that 30-day survival was similar in both groups [57.2% (95% CI 52.7–60.7) vs. 57.1% (95% CI 53.7–60.1),p = 0.85].ConclusionsAfter adjusting for organ dysfunction, sepsis at admission was not independently associated with decreased 30-day survival in this multinational study of 3869 VIPs. Age, frailty, and SOFA score were independently associated with survival.

The long-term efficacy and safety of dupilumab has been demonstrated in clinical trials and only in few real-world studies. We conducted an extension analysis from a previous 16-week study on 109 adult patients affected by moderate-to-severe atopic dermatitis treated with dupilumab. Eczema-Area-and-Severity-Index (EASI), itch numerical-rating-score (itch-NRS), Dermatology-Life-Quality-Index (DLQI) scores, drug survival rate and occurrence of adverse events after 24 and 48 weeks of dupilumab treatment were retrospectively collected. Dupilumab demonstrated sustained improvement of disease severity, pruritus, and quality of life in our series with an increasing percentage of patients gaining EASI75 and EASI90 response during the study period. Few patients interrupted treatment resulting in a very high drug survival rate. We also confirmed the favorable safety profile of the drug with absence of serious adverse events and serious infections throughout the 48-week period. The prevalence of conjunctivitis was low and mainly occurred in the mid-term with resolution of the majority of cases at 48 weeks.

Background The search for reliable cardiac functional parameters is crucial in patients with mitral regurgitation (MR). In the Italian arm of the European Registry of MR, we compared the ability of global longitudinal strain (GLS) and left ventricular (LV) ejection fraction (LVEF) to detect cardiac damage in MR. Methods Five hundred four consecutive patients with MR underwent a complete echo-Doppler exam. A total of 431, 53 and 20 patients had degenerative, secondary and mixed MR, respectively. The main echocardiographic parameters, including LV and left atrial (LA) size measurements, pulmonary artery systolic pressure (PASP) and GLS were compared between patients with mild MR (n = 392) vs. moderate to severe MR (n = 112). Results LVEF and GLS were related one another in the pooled population, and separately in patients with mild and moderate/severe MR (all p Conclusions Both LVEF and GLS are independently associated with LV and LA size, but only GLS is related to pulmonary arterial pressure. GLS is a powerful hallmark of cardiac damage in MR.

BACKGROUND In hypertensive patients, high left ventricular (LV) mass/end-diastolic volume ratio (LVM/EDV) is related to LV dysfunction and myocardial fibrosis. PURPOSE We examined the ability of 3D-echo-derived LVM/EDV ratio in identifying early systolic and diastolic dysfunction in relation with LV concentric geometry in native hypertensive patients. METHODS One-hundred and forty-four newly diagnosed, never treated hypertensive patients underwent 2D-echo, including computation of 2D-derived global longitudinal strain (GLS), and 3D-echo. The study population was divided into two groups: elevated 3D-LVM/EDV (≥1.23 in women and ≥1.22 in men), corresponding to LV concentric geometry (n = 50), and normal ratio (

Aims This study assessed the impact of the strain-guided therapeutic approach on cancer therapy-related cardiac dysfunction (CTRCD) and rate of cancer therapy (CT) interruption in breast cancer. Methods and results We enrolled 116 consecutive female patients with HER2-positive breast cancer undergoing a standard protocol by EC (epirubicine + cyclophosphamide) followed by paclitaxel + trastuzumab (TRZ). Coronary artery, valvular and congenital heart disease, heart failure, primary cardiomyopathies, permanent or persistent atrial fibrillation, and inadequate echo-imaging were exclusion criteria. Patients underwent an echo-Doppler exam with determination of ejection fraction (EF) and global longitudinal strain (GLS) at baseline and every 3 months during CT. All patients developing subclinical (GLS drop >15%) or overt CTRCD (EF reduction Conclusion These findings highlight the usefulness of ‘strain oriented’ approach in reducing the rate of overt CTRCD and CT interruption by a timely cardioprotective treatment initiation.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies, vascular thrombosis (venous, arterial, or small vessels), and/or pregnancy morbidity. Diagnosis of APS is based on the presence of at least one clinical criterion (thrombotic events or pregnancy morbidity) and at least one of the laboratory criteria (persistently medium/high titer immunoglobulin G [IgG]/immunoglobulin M [IgM] anticardiolipin antibodies, and/or medium/high titer IgG/IgM anti-β2-glycoprotein I antibodies, and/or a positive lupus anticoagulant test), confirmed after repetition at least 12 weeks apart. The clinical spectrum of APS encompasses additional (extracriteria) clinical manifestations, including cardiac diseases. Heart involvement may become evident as a consequence of direct (autoimmune-mediated) or indirect (thrombosis) mechanisms, and include valve heart disease (vegetations and/or thickening associated with functional abnormalities) and intracardiac thrombosis, coronary, and vascular accelerated atherosclerosis, along with ischemic heart disease. APS can also cause pulmonary arterial hypertension, left ventricular dysfunction, and heart failure. This review describes the major cardiac manifestations of APS and illustrates the role of cardiac imaging for diagnosing subclinical and overt heart involvement and addressing management of these patients. The possible role of therapeutic strategies in cardiac manifestations of APS is also discussed.

Infants are at risk of vitamin K deficiency that may lead to vitamin K deficiency bleeding (VKDB). Although many vitamin K prophylactic regimens have been developed throughout the years, still cases of late form VKBD may occur. The introduction of combined prophylactic strategy with prolonged oral prophylaxes after the intramuscular dose at birth has showed a decrease of the late severe VKDB incidence. Nevertheless, there is still lack of consensus about the administration scheme after the first dose at birth. CONCLUSION: Late form VKBD is not eradicated, and the best prophylactic regimen in term and preterm infants is still an open debate.

Background A number of Australian hospitals are piloting outpatient rapid access chest pain clinics (RACC) as a new clinical pathway. These clinics aim to provide an alternative to inpatient care for timely access to specialist cardiology assessment whilst improving quality of care and experience. An understanding of overall patient satisfaction can be considered a marker of overall clinical success, contributes to cost-effectiveness, and is needed to develop improvement strategies. We aimed to evaluate uncertainty, satisfaction and experience among patients treated in a RACC. Methods All consecutive patients presenting with troponin negative intermediate risk chest pain treated in a new RACC in a public quaternary teaching hospital over a 12-month period, were invited to participate in two core components: A paper-based questionnaire, and a one-month follow-up telephone structured interview. Patient satisfaction and uncertainty were assessed by the short form of the Mishel Uncertainty in Illness Scale (MUIS) and Picker Dimensions of care. Results There was a 51.2% response rate (190/371). Patients ranged in age from 20 to 89 years (56.4±13.6 years) and 47% were female. Findings illustrated a global high level of satisfaction in all areas: care, comfort, communication and engagement, with low levels of uncertainty in illness experienced by patients. Conclusion There were high levels of satisfaction and minimal uncertainty for patients related to their management and care in the RACC during the study period. These results have formed part of the formal cost-effectiveness assessment of the RACC used to support its transition from a pilot implementation to standard of care at the study centre.

Radical ablative surgery is the gold standard treatment of head skin cancer. The authors expose their experience with a new artificial dermis (Pelnac®), analyzing retrospectively the overall morbidity and aesthetic outcomes. 16 consecutive patients underwent two surgical procedures under local anesthesia. The first involved the tumor removal and application of the ADM. In the second, the exposed tissue was covered with a split-thickness skin graft. On follow-up (6 months), tumor recurrences, quality of scars (using the Vancouver Scar Scale), and patient reported outcomes (using FACE-Q Skin Cancer Module) were evaluated. 10 were males and 6 females, with a mean age of 73 years (61–89). The follow-up ranged from 12 to 48 months (mean: 30). The sites of skin tumor were scalp (12 cases), forehead (2), cheek (1), and zygomatic area (1). Nine patients underwent previous local surgery; two received radiotherapy. The average length of hospital stay was 3.2 days. The mean surface area of the defect was 59.15 cm2 (16.9–89.5). In three cases, the surgical bed was bone without periosteum. The malignant tumors excised were basal cell carcinoma (68.75%), squamous cell carcinoma (18.75%), malignant melanoma (6.25%), and sarcoma (6.25%). The mean operating time was 41 minutes for the first operation (25–55) and 34 for the second (25–48). No significant problems were observed and 15 patients (93.75%) had 100 percent intake of graft. The mean time of healing was 39 days (32–45). At 6 months post-op, no tumor recurrence. Satisfactory cosmetic and functional results were obtained in all patients as shown by the VSS Scale and FACEQ skin cancer module mean scores. We believe that the artificial dermis is a reliable alternative to flaps and should be considered an excellent option in head reconstruction for skin cancer, especially in critical patients (old, with large and deep defects, with recurrent tumors, required radiotherapy).

Background We examined guidewire and microcatheter utilization during chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Methods We examined device utilization in 2,968 CTO PCIs performed in 2,936 patients at 19 US and two international center between January 2016 and January 2019. Results The median number of antegrade guidewires used per case declined (5 in 2016 vs 3 in 2019) and was higher in higher complexity lesions (2 in J-CTO 0 vs. 8 in J-CTO 4 or 5 score). In antegrade-only procedures, the most frequently used guidewires were the Pilot 200 (Abbott Vascular, 37%), Fielder XT (Asahi Intecc, 25%) and Gaia third (Asahi Intecc, 18%), while the most commonly used microcatheters were the Turnpike Spiral (Vascular Solutions, 18%) and Turnpike (Vascular Solutions, 16%). Compared with 2012-2015, during 2016-2019 use of novel equipment such as the Gaia guidewires and the Turnpike microcatheters led to decreased use of Confianza Pro 12 (Asahi Intecc) wire and Corsair (Asahi Intecc) family of microcatheters. In retrograde cases, the guidewires most commonly used were the Sion (44%), Pilot 200 (27%) and Fielder FC (26%), while the Corsair/Corsair Pro, Turnpike LP (Vascular Solutions) and Caravel (Asahi Intecc) were the most frequently used microcatheters for collateral crossing (29%, 26% and 22%, respectively). Conclusions The most commonly used guidewires during CTO PCI are polymer-jacketed guidewires and the most commonly used microcatheters are torquable microcatheters.

Twin obstructive megaureters associated with duplex renal system is a rare malformation, particularly when a giant ureter dilation is present. We report an original case, initially misinterpreted, of a right incomplete duplex renal system with huge disproportion between the upper pole giant megaureter and the lower pole moderate megaureter, with severe obstruction at the uretero-ureteral junction and minor obstruction at the uretero-vesical junction. Uromagnetic resonance imaging allowed conclusive diagnosis and the laparoscopic approach was effective for definitive, successful treatment.

Purpose: To describe the unusual presentation, diagnosis, and clinical course of an early-onset X-linked infantile retinoschisis Case report: A 6-month-old infant presented with strabismus and poor fixation. After the detection of bilateral intraretinal hemorrhage and diffuse dystrophic retinal pattern at indirect ophthalmoscopy, the patient received a complete evaluation under anesthesia. Retinal wide-field imaging, spectral domain optical coherence tomography, and electroretinogram were performed and revealed a retinoschisis involving the posterior pole and the inferior periphery in the right eye. In the left eye, an inferior retinal detachment extending to the macula was detected. Blood sample and genetic counseling were required in the strong suspicion of an inherited retinal dystrophy. Genetic tests confirmed the diagnosis of X-linked retinoschisis (RS1 gene mutation). After consultation with a pediatric vitreoretinal surgeon, a wait and see strategy was chosen. The follow up visits showed a surprisingly good natural course of the disease. Conclusion: X-linked retinoschisis is a well-known inherited retinal disease potentially affecting young children as early as 3 months old. In this case, the stunning presentation (diffuse retinal pigment epithelium dystrophic changes resembling a macular dystrophy) and the positive course of the disease (resolution of macular retinal detachment in the left eye and stability of schisis in the right eye) arise some interesting considerations about the necessity of an early surgical treatment.

Summary Background Relamorelin, a pentapeptide ghrelin receptor agonist, accelerated gastric emptying significantly and improved symptoms in adults with diabetic gastroparesis in phase 2 trials. Aim To assess the safety and tolerability of relamorelin across phase 2 trials. Methods Safety assessments in patients aged 18‐75 years (weight, adverse events [AEs] and laboratory tests) from two randomised, double‐blind phase 2 trials (NCT01571297, NCT02357420; results published previously) were reviewed descriptively. Analysis of covariance assessed treatment effect on glycated haemoglobin (HbA1c) and blood glucose post hoc. Phase 2a and 2b trial durations were, respectively, 4 weeks (relamorelin 10 µg once or twice daily [b.d.] or placebo b.d.) and 12 weeks (relamorelin 10, 30 or 100 µg or placebo b.d.) with 1‐ and 2‐week, single‐blind placebo run‐ins. Results Among 204 phase 2a and 393 phase 2b patients, respectively, 67% and 62% were female, and 88% and 89% had type 2 diabetes. Proportions of patients reporting serious AEs were similar across treatment groups, as were those with ≥1 treatment‐emergent AE (TEAE). TEAE‐related discontinuations were proportionally higher in relamorelin groups than placebo. Of 12 serious TEAEs in phase 2a, none occurred in >1 patient. In phase 2b, five serious TEAEs were reported in >1 patient, and one (100 µg) died (urosepsis), all unrelated to relamorelin. In phase 2b, increased HbA1c and fasting blood glucose levels were dose‐related (P

Up to 60% of patients with irritable bowel syndrome (IBS) report fatigue and 50% meet criteria for clinical insomnia. Recent studies have demonstrated a relationship between poor sleep and next-day IBS symptoms. However, no study to-date has evaluated behavioral therapy to treat poor sleep in IBS. The aim of the current pilot study is to test feasibility of behavioral therapy for insomnia among patients with IBS and poor sleep. This randomized controlled pilot study tested the feasibility of administering brief behavioral therapy for insomnia (BBT-I) to patients with IBS who report poor sleep. Participants were randomized to BBT-I or self-monitoring control. Exploratory analyses evaluated group differences after 4 weeks of treatment. A total of 25 participants were randomized to the study, 13 to BBT-I and 12 to the control group. Three participants dropped out of the treatment group. Satisfaction with treatment was high. At follow-up, there were significant differences between groups in measures of sleep quality and insomnia severity. There were trends toward significance in IBS severity score, with 40% of the BBT-I sample reporting clinically meaningful drop in symptoms compared to 17% of the control group. Similar trends were observed with belly pain and global improvement scores. This pilot study demonstrates feasibility/acceptability of a brief behavioral therapy for patients with IBS and poor sleep. Additionally, this study provides preliminary evidence to suggest that treatment of sleep difficulties in patients with IBS may improve IBS symptom outcomes. Future, larger randomized controlled studies are needed.