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Introduction : Treatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50–100 × 109/L) are reported. Patients and Methods : Patients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 109/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety. Results : Of 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were −20.5% (−55.8% to 38.5%, n=51) and −39.8% (−98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3). Conclusion : A starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.

Background: No evidence currently exists characterising global outcomes following major cancer surgery, including esophageal cancer. Therefore, this study aimed to characterise impact of high income countries (HIC) versus low and middle income countries (LMIC) on the outcomes following esophagectomy for esophageal cancer.Method: This international multi-center prospective study across 137 hospitals in 41 countries included patients who underwent an esophagectomy for esophageal cancer, with 90-day follow-up. The main explanatory variable was country income, defined according to the World Bank Data classification. The primary outcome was 90-day postoperative mortality, and secondary outcomes were composite leaks (anastomotic leak or conduit necrosis) and major complications (Clavien-Dindo Grade III - V). Multivariable generalized estimating equation models were used to produce adjusted odds ratios (ORs) and 95% confidence intervals (CI95%).Results: Between April 2018 to December 2018, 2247 patients were included. Patients from HIC were more significantly older, with higher ASA grade, and more advanced tumors. Patients from LMIC had almost three-fold increase in 90-day mortality, compared to HIC (9.4% vs 3.7%, p < 0.001). On adjusted analysis, LMIC were independently associated with higher 90-day mortality (OR: 2.31, CI95%: 1.17-4.55, p = 0.015). However, LMIC were not independently associated with higher rates of anastomotic leaks (OR: 1.06, CI95%: 0.57-1.99, p = 0.9) or major complications (OR: 0.85, CI95%: 0.54-1.32, p = 0.5), compared to HIC.Conclusion: Resections in LMIC were independently associated with higher 90-day postoperative mortality, likely reflecting a failure to rescue of these patients following esophagectomy, despite similar composite anastomotic leaks and major complication rates to HIC. These findings warrant further research, to identify potential issues and solutions to improve global outcomes following esophagectomy for cancer.

Background and Aims: Several studies have found Golimumab (GOL) effective and safe in the short-term treatment of ulcerative colitis (UC), but few long-term data are currently available from real world. Our aim was to assess the long-term real-life efficacy and safety of GOL in managing UC outpatients in Italy. Methods: A retrospective multicenter study assessing consecutive UC outpatients treated with GOL for at least 3-month of follow-up was made. Primary endpoints were the induction and maintenance of remission in UC, defined as Mayo score ≤2. Several secondary endpoints, including clinical response, colectomy rate, steroid free remission and mucosal healing, were also assessed during the follow-up. Results: One hundred and seventy-eight patients were enrolled and followed up for a median (IQR) time of 9 (3-18) months (mean time follow-up: 33.1±13 months). Clinical remission was achieved in 57 (32.1%) patients: these patients continued with GOL, but only 6 patients (3.4%) were still under clinical remission with GOL at the 42nd month of follow-up. Clinical response occurred in 64 (36.4%) patients; colectomy was performed in 8 (7.8%) patients, all of them having primary failure. Steroid-free remission occurred in 23 (12.9%) patients, and mucosal healing was achieved in 29/89 (32.6%) patients. Adverse events occurred in 14 (7.9%) patients. Conclusions: Golimumab does not seem able to maintain long-term remission in UC in real life. The safety profile was good.

Background Polycythemia vera (PV) is a myeloproliferative neoplasm affecting >100,000 people in the United States annually. Patients (pts) with PV are at risk for thromboembolic events (TEs), premature death, and high symptom burden. Hydroxyurea (HU) is recommended for high-risk pts with PV; however, up to 40% of pts become resistant and/or intolerant to the drug (Demuynck T, et al. Ann Hematol. 2019;98:1421-1426). Ruxolitinib (RUX), a Janus kinase (JAK) 1/JAK2 inhibitor, is currently the only FDA-approved treatment option for pts with PV who are resistant to or intolerant of HU. We conducted a retrospective chart review to characterize the reasons pts were switched from HU to RUX and to describe the real-world dosing patterns of RUX in pts with PV. Methods This retrospective medical chart review was conducted at US community hematology/oncology practices in the Cardinal Health Oncology Provider Extended Network. Eligible pts were ≥18 y old, initiated RUX therapy during the index period (January 1, 2015, to December 31, 2016), were previously treated with HU for ≥3 mo, and were seen at least twice during the 6 mo following RUX initiation. Data were collected for the 12 mo prior to RUX initiation (including near the time of HU discontinuation), near the time of RUX initiation (index), and up to the last provider visit. Pt and clinical characteristics were collected, including blood counts, symptoms, TEs, cardiovascular disease risk factors, phlebotomy, and HU and RUX treatment patterns. Target enrollment was 250 pts; interim results are presented here. Results Providers identified 99 pts for inclusion; mean (SD) age was 64 (9.9) y, 56% were male, and 68% had high-risk PV (ie, age ≥60 y and/or history of TE). All pts had been tested for the JAK2V617F mutation, and 99% were positive. At the time of HU discontinuation, 28% of pts had reached an HU dose of ≥2 g/d; median (range) HU treatment duration was 9.7 (3.6-182.4) mo. Causes of HU discontinuation were resistance (63%), intolerance (17%), resistance and intolerance (11%), and other reasons (9%; Table). The most frequent reasons for HU discontinuation due to resistance were hematocrit (Hct) ≥45% (79%), symptoms (45%), leukocytosis (32%), thrombocytosis (31%), and splenomegaly (22%). The most frequent intolerance signs and symptoms were nausea (43%), stomatitis (25%), fever (18%), and skin ulcers (14%). With respect to the RUX starting dose, 44 pts (44%) initiated RUX at the US package insert-recommended dose of 10 mg twice daily (BID); median (range) treatment duration for these pts was 26.4 (3.2-52.0) mo (Table). During the first 6 mo of RUX treatment, dose modification was noted in 19 pts (43%) who initiated at 10 mg BID (dose increase, n=13 [30%]; dose decrease, n=5 [11%]; dose interruption, n=1 [2%]). The most common reasons for dose increase were continued need for phlebotomy (39%) and symptoms (39%). Five pts required a dose reduction; the most common reason was low hemoglobin levels (n=3). Overall, pts starting at 10 mg BID had more dose modifications in the first 6 mo of RUX treatment (43%), with fewer dose modifications needed after 6 mo (25%). Hct control (Hct Conclusions In this interim analysis of real-world data pertaining to pts with PV who discontinued HU and were subsequently treated with RUX, the most common resistance events leading to HU discontinuation were Hct ≥45%, uncontrolled symptoms, leukocytosis, thrombocytosis, and splenomegaly. Discontinuations due to intolerance were most commonly attributed to nausea, stomatitis, fever, and skin ulcers. Of pts who were switched from HU to RUX, the duration of HU treatment was shorter and the proportion of pts treated with HU doses of ≥2 g/d was higher than has been reported for all pts discontinuing HU, irrespective of their next line of therapy (Grunwald MR, et al. ASH Annual Meeting 2017. Poster 1633). Less than half of pts initiated RUX at the recommended dose of 10 mg BID; 41% of pts dosed in accordance with the recommended starting dose experienced dosing modifications (primarily dose increases); however, the majority of pts who discontinued RUX had no dosing modifications during their treatment. Results from the entire cohort of 250 pts will be presented. Disclosures Altomare: Amgen: Consultancy; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy; Rigel: Consultancy. Nguyen:Incyte: Employment, Equity Ownership. Parasuraman:Incyte: Employment, Equity Ownership. Paranagama:Incyte: Employment, Equity Ownership. Kish:Cardinal Health: Employment. Lord:Cardinal Health: Employment, Equity Ownership. Colucci:Incyte: Employment, Equity Ownership.

The therapeutic efficacy of B cell–depleting anti-CD20 treatment in both pediatric and adult steroid-sensitive nephrotic syndromes (SSNS) suggests that B cells play a pathogenic role in the disease. In adults with minimal change disease (MCD), only circulating plasmablasts are increased during the active phase of the disease, among B cell subsets. These cells have not been studied yet in children with SSNS. We retrospectively quantified by flow cytometry analysis circulating plasmablasts in 107 pediatric patients with SSNS (51 at disease onset, 27 during relapse, and 29 in remission). Data were compared with an equal number of age- and sex-matched healthy donors (HD). Circulating plasmablast levels, expressed as percentage of total CD19+ B cells or as percentage of total lymphocytes, were normal in all SSNS subgroups, compared to HD. Patients in remission had significantly fewer circulating plasmablasts compared to patients at disease onset. No significant correlation was observed between plasmablast levels and proteinuria or serum proteins, at onset. Treatment with prednisone and mycophenolate mofetil significantly reduced circulating levels of plasmablasts, unlike treatment with prednisone and calcineurin inhibitors. The B cell phenotype of children with SSNS differs from that of adults with MCD. This may justify different therapeutic approaches.

The arteriovenous fistula (AVF) has long been considered the optimal vascular access. However, the evolving characteristics of the ageing dialysis population limit the creation of an AVF in all patients. Thus, more patients start hemodialysis (HD) with a central venous catheter (CVC) rather than an AVF, and the supremacy of the AVF has recently been questioned. The aim of this study was to analyze the incidence and rate of access complications in 100 patients between 2010 and 2015. A total of 63 patients started HD with an AVF, while 37 began HD with a CVC. We found no differences in patient survival according to the vascular access in use at the beginning of dialysis, but patients were more likely to die while undergoing dialysis by means of a CVC than an AVF. Patients started on dialysis with a CVC had more cardiovascular disease, while patients who began dialysis with an AVF presented more hypertension. Fistulas presented a longer survival time despite more hospital admissions, but CVCs bore a higher risk of infections. Our results suggest that starting dialysis with a CVC does not confer a greater risk of death.

Objective Although a relationship between schizophrenia (SCZ), antipsychotic (AP) medication, and metabolic dysregulation is now well established, the effect of adiposity is less well understood. By synthesizing findings from imaging techniques that measure adiposity, our systematic review and meta-analysis (PROSPERO CRD42020192977) aims to determine the adiposity-related effects of illness and treatment in this patient population. Methods We searched MEDLINE, EMBASE, PsychINFO and Scopus for all relevant case-control and prospective longitudinal studies from inception until February 2021. Measures of adiposity including percent body fat (%BF), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were analyzed as primary outcomes. Results Our search identified 29 articles that used imaging methods to quantify adiposity among patients with SCZ spectrum disorders. Analyses revealed that patients have greater %BF (mean difference (MD) = 3.09%; 95%CI: 0.75 to 5.44), SAT (MD = 24.29 cm2 ; 95%CI: 2.97 to 45.61) and VAT (MD = 33.73 cm2 , 95%CI: 4.19 to 63.27) compared to healthy controls. AP treatment was found to increase SAT (MD = 31.98 cm2 ; 95%CI: 11.33 to 52.64) and VAT (MD = 16.30 cm2 ; 95%CI: 8.17 to 24.44) with no effect on %BF. However, change in %BF was higher for AP-free/AP-naive patients compared to treated patients. Conclusion Our findings indicate that patients with SCZ spectrum disorders have greater adiposity than healthy controls, which is increased by AP treatment. Young, AP-naive patients may be particularly susceptible to this effect. Future studies should explore the effect of specific APs on adiposity and its relation to overall metabolic health.

Many maternal immune cells populate the decidua, which is the mucosal lining of the uterus transformed during pregnancy. Here, abundant natural killer (NK) cells and macrophages help the uterine vasculature adapt to fetal demands for gas and nutrients, thereby supporting fetal growth. Fetal trophoblast cells budding off the forming placenta and invading deep into maternal tissues come into contact with these and other immune cells. Besides their homeostatic functions, decidual NK cells can respond to pathogens during infection, but in doing so, they may become conflicted between destroying the invader and sustaining fetoplacental growth. We review how maternal NK cells balance their double duty both in the local microenvironment of the uterus and systemically, during toxoplasmosis, influenza, cytomegalovirus, malaria and other infections that threat pregnancy. We also discuss recent developments in the understanding of NK-cell responses to SARS-Cov-2 infection and the possible dangers of COVID-19 during pregnancy.

NO abstract available- Case report

ObjectiveTo investigate the predictive value of the Diverticular Inflammation and Complication Assessment (DICA) classification and to develop and validate a combined endoscopic-clinical score predicting clinical outcomes of diverticulosis, named Combined Overview on Diverticular Assessment (CODA).DesignA multicentre, prospective, international cohort study.Setting43 gastroenterology and endoscopy centres located in Europe and South America.Participants2215 patients (2198 completing the study) at the first diagnosis of diverticulosis/diverticular disease were enrolled. Patients were scored according to DICA classifications.InterventionsA 3-year follow-up was performed.Main outcome measuresTo predict the acute diverticulitis and the surgery according to DICA classification. Survival methods for censored observation were used to develop and validate a novel combined endoscopic-clinical score for predicting diverticulitis and surgery (CODA score).ResultsThe 3-year cumulative probability of diverticulitis and surgery was of 3.3% (95% CI 2.5% to 4.5%) in DICA 1, 11.6% (95% CI 9.2% to 14.5%) in DICA 2 and 22.0% (95% CI 17.2% to 28.0%) in DICA 3 (p10% and >2.5% in CODA C, respectively. The CODA score showed optimal discrimination capacity in predicting the risk of surgery in the development (c-statistic: 0.829; 95% CI 0.811 to 0.846) and validation cohort (c-statistic: 0.943; 95% CI 0.905 to 0.981).ConclusionsDICA classification has a significant role in predicting the risk of diverticulitis and surgery in patients with diverticulosis, which is significantly enhanced by the CODA score.Trial registration numberNCT02758860.

Background Congenital malformations of the central nervous system (CNS) consist of a wide range of birth defects of multifactorial origin. Methods Concentrations of 44 metals were determined by Inductively Coupled Plasma Mass Spectrometry in serum of 111 mothers in the second trimester of pregnancy who carried a malformed fetus and compared them with serum concentrations of the same metals in 90 mothers with a normally developed fetus at the same week of pregnancy. Data are reported as means ± standard deviations. Results We found a direct relationship between congenital defects of the CNS and maternal serum concentration of aluminum: it was statistically higher in women carrying a fetus with this class of malformation, compared both to mothers carrying a fetus with another class of malformation (6.45 ± 15.15 μg/L Vs 1.44 ± 4.21 μg/L, p Conclusion CAluminum may play a role in the onset of central nervous system malformations, although the exact Aluminum species and related specific type of malformation needs further elucidation.

Background: Although FD may affect up to 10% of the general population, the therapy for FD is not standard. Recently, ginger-based food supplements have been proposed in order to restore FD symptoms. Our aim was to assess the efficacy of a new nutraceutical formulation containing extract of gingerol and thymus as a possible natural treatment in managing the symptoms of functional dyspepsia (FD). Methods: We retrospectively analyzed the efficacy and safety profiles of a nutraceutical formulation containing Zingiber officinalis root extract and a standardized Thymus extract. It was administered as 1 ml/day twice a day for 90 days. Patients were assessed at baseline and after 1, 2 and 3 months of treatment, following a month of pharmacological washout by completing a questionnaire reporting the trend of the following symptoms: epigastric pain, epigastric heaviness, early satiety, belching, and regurgitation. Every symptom was assessed by a Visual Analogic Scale (VAS), ranging from 0= absence to 10= maximal severity. Results: We enrolled 272 patients (99 males and 173 females; median IQR age 49.5, 36-64 yrs). Obesity (BMI>30) was present in 28 (12.5%) patients; smokers were 83 (30.5%); and comorbidities were present in 107 (39.3%) patients. Improvement of symptom scores during treatment and one month after its suspension was extremely significant (p Conclusion: This large study found that nutraceutical formulation could be one of the tools for an empirical approach to treat patients with FD, especially when a non-conventional drug treatment is preferable for the patient and considered suitable by the physician.

Background Surgical strategies are being adapted to face the COVID‐19 pandemic. Recommendations on the management of acute appendicitis have been based on expert opinion, but very little evidence is available. This study addressed that dearth with a snapshot of worldwide approaches to appendicitis. Methods The Association of Italian Surgeons in Europe designed an online survey to assess the current attitude of surgeons globally regarding the management of patients with acute appendicitis during the pandemic. Questions were divided into baseline information, hospital organization and screening, personal protective equipment, management and surgical approach, and patient presentation before versus during the pandemic. Results Of 744 answers, 709 (from 66 countries) were complete and were included in the analysis. Most hospitals were treating both patients with and those without COVID. There was variation in screening indications and modality used, with chest X‐ray plus molecular testing (PCR) being the commonest (19·8 per cent). Conservative management of complicated and uncomplicated appendicitis was used by 6·6 and 2·4 per cent respectively before, but 23·7 and 5·3 per cent, during the pandemic (both P, The COVID‐19 pandemic required reorganization of surgical services, affecting patients with common surgical diseases including acute appendicitis. No evidence is available on the topic. This study found global variation in screening policies, use of personal protective equipment and intraoperative directives. There has been increased adoption of non‐operative management and open appendicectomy. Hands off

Background Infliximab and adalimumab are widely used for the treatment of Crohn's disease and ulcerative colitis. Aim To compare the long-term efficacy and safety of infliximab and adalimumab in a large cohort of Crohn's disease and ulcerative colitis patients reflecting real-life clinical practice. Methods Seven hundred twelve patients were retrospectively reviewed, 410 with Crohn's disease (268 treated with adalimumab and 142 with infliximab; median follow-up 60 months, range, 36-72) and 302 with ulcerative colitis (118 treated with adalimumab and 184 with infliximab; median follow-up 48 months, range, 36-84). Results In Crohn's disease, clinical remission was maintained in 75.0% of adalimumab vs. in 72.5% of infliximab patients (P = 0.699); mucosal healing and steroid-free remission were maintained in 49.5% of adalimumab vs. 63.9% of infliximab patients (P = 0.077) and in 77.7% of adalimumab vs. 77.3% in infliximab group (P = 0.957), respectively. In ulcerative colitis, clinical remission was maintained in 50.0% of adalimumab vs. 65.8% of infliximab patients (P 10 were predictors of failure in Crohn's disease; treatment with adalimumab, BMI ≥30 and Mayo score >10 were predictors of failure in ulcerative colitis. infliximab was more likely to cause adverse events than adalimumab (16.6 vs. 6.2%, P Conclusion Both adalimumab and infliximab are effective in long-term outpatients management of inflammatory bowel diseases. Adalimumab had a lower rate of adverse events.

Patients with Autism Spectrum Disorder (ASD) need to be provided with behavioral, psychological, educational, or skill-building interventions as early as possible. Cognitive Behavior Therapy has proven useful to manage such problems. There is also growing evidence on the usefulness of Virtual Reality Therapy (VRT) in treating various functional deficits in ASD. This exploratory study is aimed at assessing the changes in cognitive functions in children with ASD, and the putative subtending neurophysiological mechanisms, following the provision of rehab training using an innovative VRT system. Twenty patients with ASD, aged 6-15 years, were provided with 24 sessions of VRT by using the pediatric module of the BTS NIRVANA System. Neuropsychological and EEG evaluations were carried out before and at the end of the training. After VRT, all patients showed a significant improvement in their cognitive-behavioral problems concerning attention processes, visuospatial cognition, and anxiety. These findings were paralleled by an evident reshape of frontoparietal connectivity in the alpha and theta frequency range. Our study suggests that VRT could be a useful and promising tool to improve ASD neurorehabilitation outcomes. This improvement is likely to occur through changes in frontoparietal network connectivity following VRT.

Described here is a simple method to isolate and phenotype mouse group 1 uterine innate lymphoid cells (g1 uILCs) from individual pregnant uterus by flow cytometry. The protocol describes how to set up time mating to obtain multiple synchronous dams, the mechanical and enzymatic digestion of the pregnant uterus, the staining of single-cell suspensions, and a FACS strategy to phenotype and discriminate g1 uILCs. Although this method inevitably loses the spatial information of cellular distribution within the tissue, the protocol has been successfully applied to determine uILC heterogeneity, their response to maternal and foetal factors affecting pregnancy, their gene expression profile, and their functions.

A apneia obstrutiva do sono (AOS) é caracterizada pelo colapso das vias aéreas superiores, causando obstrução total ou parcial durante o sono. A melhor forma de diagnóstico é através da polissonografia, a aplicação de questionários também pode ser útil no diagnóstico, um dos melhores é o Epworth. O objetivo desse artigo é analisar por meio do questionário Epworth a frequência de apneia obstrutiva do sono em adultos jovens. Todos os indivíduos participantes responderam a três questionários, o primeiro tem a finalidade de coletar os dados antropométricos e de hábitos de vida, e estilo de vida, o segundo questionário é o questionário de Berlin que tem por finalidade saber se o participante tem indicativo para apneia do sono, e o terceiro questionário é o de Epworth que tem por finalidade avaliar a sonolência diurna e índice de apneia do sono. Foram coletados dados de 108 participantes, sendo que foram excluídos um total de 22 questionários. A frequência de SAS foi maior entre as mulheres do que para os homens, também aqueles com peso maior do 100kg e IMC maior do 25 teve alta frequência de SAS, assim como entre aqueles com alimentação não saudável. Existe a possibilidade de indivíduos com SAS de dormirem durante estiverem dirigindo um automóvel. A frequência de apneia do sono vista pelo questionário de Berlin foi de 15%, sendo maior entre as mulheres, indivíduos com IMC maior do que 25 kg/m2.

During the last decade, the advent of modern sequencing methods (next generation techniques, NGS) has helped describe the composition of the human gut microbiome, enabling us to understand the main characteristics of a healthy gut microbiome and, conversely, the magnitude of its disease-related changes. This new knowledge has revealed that healthy gut microbiota allow the maintenance of several crucial physiological functions, such as the ability to regulate the innate and adaptive immune systems. Increasing evidence has pointed out a condition of dysbiosis in several autoimmune/immune mediated dermatological conditions and specific gut microbial signatures have also been reported to correlate with clinical and prognostic parameters of such diseases. Based on a literature search of relevant published articles, this review debates the current knowledge and the possible pathogenic implications of bacterial gut microbiota composition assessed through NGS techniques in systemic lupus erythematosus, atopic dermatitis, psoriasis, and alopecia areata. Evidence of a potential role of specific gut microbiota signatures in modulating the clinical course of such diseases and their main comorbidities has been also reviewed., Plain Language Summary The gut microbiota is defined as the collection of microbes (bacteria, fungi, archaea, and viruses) inhabiting the human gut. If healthy, it allows the maintenance of several crucial physiological functions, such as the ability to regulate the immune system. Accordingly, increasing evidence has pointed out a condition of imbalance in the gut microbial community (dysbiosis) in several autoimmune/immune mediated dermatological conditions. Specific gut dysbioses have also been reported to correlate with clinical and prognostic parameters of such diseases. In this review, the current knowledge and the possible pathogenic implications of bacterial gut microbiota composition assessed through advanced techniques in systemic lupus erythematosus, atopic dermatitis, psoriasis, and alopecia areata are discussed. Furthermore, evidence of a potential role of specific gut microbiota signatures affecting the clinical course and main associated diseases is also reviewed. In this scenario, an increased knowledge of gut microbiota composition and functions in autoimmune/immune mediated dermatological diseases might suggest additional treatments besides conventional therapies, and predict clinical evolution and comorbidities association.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder whose pathogenesis relies on a maladaptive expression of the memory for a life-threatening experience, characterized by over-consolidation, generalization, and impaired extinction, which are responsible of dramatic changes in arousal, mood, anxiety, and social behavior. Even if subjects experiencing a traumatic event during lifetime all show an acute response to the trauma, only a subset of them (susceptible) ultimately develops PTSD, meanwhile the others (resilient) fully recover after the first acute response. However, the dynamic relationships between the interacting brain circuits that might potentially link trauma-related experiences to the emergence of susceptible and resilient PTSD phenotypes in individuals is not well understood. Toward the first step to reach this goal, we have implemented our experimental PTSD model previously developed, making it suitable to differentiate between susceptible (high responders, HR) and resilient (low responders, LR) rats in terms of over-consolidation, impaired extinction, and social impairment long after trauma. Rats were exposed to five footshocks paired with social isolation. One week after trauma but before extinction, animals were tested in the Open Field and Social Interaction tasks for the identification of a predictive variable to identify susceptible and resilient animals before the possible appearance of a PTSD-like phenotype. Our findings show that exploratory activity after trauma in a novel environment is a very robust variable to predict susceptibility towards a PTSD-like phenotype. This experimental model is thus able to screen and differentiate, before extinction learning and potential therapeutic intervention, susceptible and resilient PTSD-like rats.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) can promote lower gastrointestinal detrimental effects. Proteinase-activated receptors 1 (PAR1) and PAR2 are involved in the pathophysiology of several digestive disorders. This study examines the contribution of PAR1 and PAR2 in NSAID-induced small intestinal injury, and to investigate the underlying mechanisms. Male Wistar rats (40 weeks old) were treated with indomethacin (1.5 mg/kg BID) for 14 days. Subgroups of animals were treated intraperitoneally with TFFLR-NH2 (PAR1 agonist), AC55541 (PAR2 agonist), SCH79797 (PAR1 antagonist) or ENMD-1068 (PAR2 antagonist). After treatments, blood and feces were collected for the assessment of hemoglobin and calprotectin, respectively. The ileum was processed for the evaluation of myeloperoxidase (MPO), malondialdehyde (MDA), and the protein expression of occludin and activated caspase-3. Indomethacin elicited a significant intestinal damage, associated with a decrease in blood hemoglobin and an increase in tissue MPO, MDA and fecal calprotectin. In this setting, either the PAR1 agonist or PAR2 antagonist counteracted these changes, with the exception of MDA, which was unaffected. By contrast, the PAR1 antagonist or PAR2 agonist did not exert any effect on all the parameters. Indomethacin also decreased occludin and increased activated caspase-3 expression in ileal tissues. The PAR1 agonist or PAR2 antagonist prevented the reduced occludin expression, while the PAR2 antagonist also decreased the levels of activated caspase-3. PAR2 is involved in the pathogenesis of indomethacin enteropathy, through pro-inflammatory mechanisms and an impairment of the intestinal epithelial barrier. PAR1 activation and PAR2 inhibition could represent suitable strategies for the prevention of NSAID enteropathy.

Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIRs and HLAs in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIRs and HLAs associated with immunity to malaria thus far.

Sodium-glucose cotransporter (SGLT2) inhibitors have demonstrated cardiovascular (CV) benefits in large-scale clinical trials of people who have type 2 diabetes and either established CV disease or multiple CV risk factors. These studies also indicated early signals in benefiting heart failure (HF) patients and those with chronic kidney diseases. This article reviews recent and future clinical studies that focus on evaluation of the use of SGLT2 inhibitors in HF management and renal protection.

In this review we aim to summarize the latest findings on the network of molecules produced by muscle and bone under physiological and pathological conditions. The concomitant onset of osteoporosis and sarcopenia is currently one of the main threats that can increase the risk of falling fractures during aging, generating high health care costs due to hospitalization for bone fracture surgery. With the growing emergence of developing innovative therapies to treat these two age-related conditions that often have common onset, a broader understanding of molecular messengers regulating the communication between muscle and bone tissue became imperative. Recently it has been highlighted that two muscle-derived signals, such as the myokines Irisin and L-BAIBA, positively affect bone tissue. In parallel, there are signals derived from bone that affect either positively the skeletal muscle, such as osteocalcin, or negatively, such as RANKL.

Background. The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC. Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. Results. Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1–98). ORR was 56.7% (95% CI, 44.1–68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3–4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. Conclusions. Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment., Highlights • Combination of chemotherapy plus anti HER-2 agents is the standard treatment of HER-2 positive breast cancer. • Combination of trastuzumab and metronomic chemotherapy is an alternative therapeutic approach. • Metronomic therapy allows long-term administration of drugs. • Mild toxicity in advanced breast cancer is desirable.

Abstract. Reduced serum 25(OH)D levels have been largely reported in vitiligo, which is an autoimmune skin disorder characterized by the appearance of achromic macules. Since vitamin D can positively modulate immune function and stimulate melanogenesis in vitro, a possible role of sufficient vitamin D levels in promoting the stability of the disease and repigmentation process might be hypothesized in vitiligo. Hence, we conducted an observational study on medical records related to 101 vitiligo patients, in order to correlate baseline 25(OH)D levels with the baseline vitiligo activity and repigmentation of vitiligo macules on a 6-month follow-up. According to our results, at baseline we found that active vitiligo was significantly associated with 25(OH)D deficiency (≤20 ng/mL) (P = 0.036) or insufficiency (21–29 ng/mL) (P = 0.041), while stable disease was significantly associated with sufficient 25(OH)D levels (30–100 ng/mL) (P = 0.043). After 6 months, vitiligo patients with sufficient 25(OH)D levels (30–100 ng/mL) achieved a significantly higher degree of repigmentation. In conclusion, our study provides a novel evidence of a significant positive association of sufficient 25(OH)D levels with the stability of the disease and a satisfactory repigmentation process in Caucasian adult vitiligo patients and strengthen the need to assess vitamin D status in vitiligo. The correlation between sufficient vitamin D levels and a satisfactory course of the disease opens the way for future randomized controlled trials assessing a possible beneficial role of vitamin D supplementation on vitiligo.

Clinical thrombophilia is the consequence of multiple gene and/or environment interactions. Thrombophilia screening requires a targeted patient with specific indication, in which a finding would have implications. Carrying out a thrombophilia examination in the physician’s practice is often a cause of uncertainty and concern. The concerns begin in choosing the right patient to be examined, are associated with the time of investigation, with the choice of analysis, the test-material and with the correct interpretation of the results. Difficulties, which can influence the results, can occur with both organization and blood sampling. As common for any analysis, pre-analytical, analytical and post-analytical factors should be considered, as well as the possibility of false positive or false negative results. Finally, recommendation of correct therapeutic and prophylactic measures for the patient and his relatives is an additional focus. In this article we want to provide—on the basis of the evidence and personal experience—the theory of thrombophilia-investigation, the indications for testing, as well as practical recommendations for treatment options.

Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non-bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti-LIGHT or RANK-fragment crystallizable region (RANK-Fc) in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model this observation in mice, we used the mouse lung cancer cell line LLC-1. After intratibial implantation, wild-type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, Tnfsf14-/- mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT is a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. © 2019 American Society for Bone and Mineral Research.

OBJECTIVE This study aimed to characterize rates and management of anastomotic leak (AL) and conduit necrosis (CN) after esophagectomy in an international cohort. BACKGROUND Outcomes in patients with anastomotic complications of esophagectomy are currently uncertain. Optimum strategies to manage AL/CN are unknown, and have not been assessed in an international cohort. METHODS This prospective multicenter cohort study included patients undergoing esophagectomy for esophageal cancer between April 2018 and December 2018 (with 90 days of follow-up). The primary outcomes were AL and CN, as defined by the Esophageal Complications Consensus Group. The secondary outcomes included 90 day mortality and successful AL/CN management, defined as patients being alive at 90 day post-operatively, and requiring no further AL/CN treatment. RESULTS This study included 2247 esophagectomies across 137 hospitals in 41 countries. The AL rate was 14.2% (n = 319) and CN rate was 2.7% (n = 60). The overall 90-day mortality rate for patients with AL was 11.3%, and increased significantly with severity of AL (Type 1: 3.2% vs. Type 2: 13.2% vs. Type 3: 24.7%, p < 0.001); a similar trend was observed for CN. Of the 329 patients with AL/CN, primary management was successful in 69.6% of cases. Subsequent rounds of management lead to an increase in the rate of successful treatment, with cumulative success rates of 85.4% and 88.1% after secondary and tertiary management, respectively. CONCLUSION Patient outcomes worsen significantly with increasing AL and CN severity. Re-intervention after failed primary anastomotic complication management can be successful, hence surgeons should not be deterred from trying alternative management strategies.

Summary Background The microbiome is emerging as a crucial player of the immune checkpoint in cancer. Melanoma is a highly immunogenic tumour, and the composition of the gut microbiome has been correlated to prognosis and evolution of advanced melanoma and proposed as a biomarker for immune checkpoint therapy. Objectives We investigated the gut fungal and bacterial compositions in early-stage melanoma and correlated microbial profiles with histopathological features. Methods Sequencing of bacterial 16S rRNA and the fungal internal transcribed spacer region was performed on faecal samples of patients with stage I and II melanoma, and healthy controls. A meta-analysis with gut microbiota data from patients with metastatic melanoma was also carried out. Results We found a combination of gut fungal and bacterial profiles significantly discriminating patients with melanoma from controls. In patients with melanoma, we observed an abundance of Prevotella copri and yeasts belonging to the order Saccharomycetales. We found that the bacterial and fungal community correlated to melanoma invasiveness, whereas the specific fungal profile correlated to melanoma regression. Bacteroides was identified as general marker of immunogenicity, being shared by regressive and invasive melanoma. In addition, the bacterial communities in patients with stage I and II melanoma were different in structure and richer than those from patients with metastatic melanoma. Conclusions The composition of the gut microbiota in early-stage melanoma changes along the gradient from in situ to invasive (and metastatic) melanoma. Changes in the microbiota and mycobiota are correlated to the histological features of early-stage melanoma, and to the clinical course and response to immune therapies of advanced-stage melanoma, through direct or indirect immunomodulation.

Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others. Current therapy with cysteamine only partially reverts some of these changes, highlighting the need to develop additional treatments. Among compounds that were identified in a previous drug-repositioning study, disulfiram (DSF) was selected for in vivo studies. The cystine depleting and anti-apoptotic properties of DSF were confirmed by secondary in vitro assays and after treating Ctns-/- mice with 200 mg/kg/day of DSF for 3 months. However, at this dosage, growth impairment was observed. Long-term treatment with a lower dose (100 mg/kg/day) did not inhibit growth, but failed to reduce cystine accumulation, caused premature death, and did not prevent the development of renal lesions. In addition, DSF also caused adverse effects in cystinotic zebrafish larvae. DSF toxicity was significantly more pronounced in Ctns-/- mice and zebrafish compared to wild-type animals, suggesting higher cell toxicity of DSF in cystinotic cells. ispartof: CELLS vol:10 issue:12 ispartof: location:Switzerland status: published

Non-Alcoholic Fatty Liver Disease encompasses a spectrum of diseases ranging from simple steatosis to steatohepatitis (or NASH), up to cirrhosis and hepatocellular carcinoma (HCC). The challenge is to recognize the more severe and/or progressive pathology. A reliable non-invasive method does not exist. Untargeted metabolomics is a novel method to discover biomarkers and give insights on diseases pathophysiology.We applied metabolomics to understand if simple steatosis, steatohepatitis and cirrhosis in NAFLD patients have peculiar metabolites profiles that can differentiate them among each-others and from controls.Metabolomics signatures were obtained from 307 subjects from two separated enrollments. The first collected samples from 69 controls and 144 patients (78 steatosis, 23 NASH, 15 NASH-cirrhosis, 8 HCV-cirrhosis, 20 cryptogenic cirrhosis). The second, used as validation-set, enrolled 44 controls and 50 patients (34 steatosis, 10 NASH and 6 NASH-cirrhosis).The "Partial-Least-Square Discriminant-Analysis"(PLS-DA) was used to reveal class separation in metabolomics profiles between patients and controls and among each class of patients, and to reveal the metabolites contributing to class differentiation.Several metabolites were selected as relevant, in particular:Glycocholic acid, Taurocholic acid, Phenylalanine, branched-chain amino-acids increased at the increase of the severity of the disease from steatosis to NASH, NASH-cirrhosis, while glutathione decreased (p0.001 for each). Moreover, an ensemble machine learning (EML) model was built (comprehending 10 different mathematical models) to verify diagnostic performance, showing an accuracy80% in NAFLD clinical stages prediction.Metabolomics profiles of NAFLD patients could be a useful tool to non-invasively diagnose NAFLD and discriminate among the various stages of the disease, giving insights into its pathophysiology.

Objective Heart anomalies represent nearly one-third of all congenital anomalies. They are currently diagnosed using ultrasound. However, there is a strong need for a more accurate and less operator-dependent screening method. Here we report a metabolomics characterization of maternal serum in order to describe a metabolomic fingerprint representative of heart congenital anomalies. Methods Metabolomic profiles were obtained from serum of 350 mothers (280 controls and 70 cases). Nine classification models were built and optimized. An ensemble model was built based on the results from the individual models. Results The ensemble machine learning model correctly classified all cases and controls. Malonic, 3-hydroxybutyric and methyl glutaric acid, urea, androstenedione, fructose, tocopherol, leucine and putrescine were determined as the most relevant metabolites in class separation. Conclusion The metabolomic signature of second trimester maternal serum from pregnancies affected by a fetal heart anomaly is quantifiably different from that of a normal pregnancy. Maternal serum metabolomics is a promising tool for the accurate and sensitive screening of such congenital defects. Moreover, the revelation of the associated metabolites and their respective biochemical pathways allows a better understanding of the overall pathophysiology of affected pregnancies. This article is protected by copyright. All rights reserved.

Background Sexually transmitted infections (STIs) are prevalent throughout the world and impose a significant burden on individual health and public health systems. Missed diagnosis and late treatment of STIs can lead to serious complications such as infertility and cervical cancer. Although sexually transmitted co-infections are common, most commercial assays target one or a few STIs. The HPV-STI ChapterDx Next Generation Sequencing (NGS) assay detects and quantifies 29 HPVs and 14 other STIs in a single-tube and single-step PCR reaction and can be applied to tens to thousands of samples in a single sequencing run. Methods A cohort of 274 samples, previously analyzed by conventional cytology/histology and Roche cobas HPV Test, were analyzed by ChapterDx HPV-STI NGS assay for detection of 43 HPV and STI. A set of 43 synthetic control DNA fragments for 43 HPV and STI were developed to evaluate the limit of detection, specificity, and sensitivity of ChapterDx HPV-STI NGS assay. Results The assay was evaluated in this study, and the limit of detection was 100% at 50 copies for all targets, and 100%, 96%, 88% at 20 copies for 34, 8, and 1 target, respectively. The performance of this assay has been compared to Roche cobas HPV test, showing an overall agreement of 97.5% for hr-HPV, and 98.5% for both, HPV16 and HPV18. The assay also detected all HPV-infected CIN2/3 with 100% agreement with Roche cobas HPV results. Moreover, several co-infections with non-HPV STIs, such as C. trachomatis, T. vaginalis, M. genitalium, and HSV2 were identified. Conclusions The ChapterDx HPV-STI NGS assay is a user-friendly, easy to automate and cost-efficient assay, which provides accurate and comprehensive results for a wide spectrum of HPVs and STIs.

There is heterogeneity across studies and a lack of knowledge about recovery of EFs over time following traumatic brain injury (TBI). Also, EFs are associated with functional outcome, but there is still a gap in knowledge concerning the association between EFs and social participation following TBI. For this reason, we aim to (1) measure the recovery of the three executive function subcomponents of Miyake's model, namely flexibility, updating and inhibition between the acute phase (T1) and 6 months post TBI (T2) and (2) measure the relationship between EFs and social participation after TBI. Thus, a prospective longitudinal study that included 75 patients with TBI (mild and moderate-severe) and 50 patients with orthopedic injuries (controls) without brain damage was carried out. An extensive EFs test battery was administered at T1 and T2 whereas the Mayo-Portland Adaptability Inventory-4 (MPAI-4) was administered only at T2. In contrast with the controls, both TBI groups improved significantly between T1 and T2 on WMS-III Mental Control test (MC) and the D-KEFS Category Switching Condition of the Verbal Fluency task (SVF). Results also showed a simple time effect for the WAIS-IV Digit span and the Hayling tests. Moreover, there was an association between the SVF test and social participation (MPAI-4) at T2. In conclusion, the MC and SVF tests were found to be the best tools for measuring recovery of EFs following TBI. The SVF test was the most likely measure of EFs to give the neuropsychologist an idea of the patient's social participation.

A 57-year-old man presented to the emergency department with severe abdominal pain. Three months prior to presentation, he had sustained blunt trauma to his right side whilst cycling but had not sought medical attention. On admission, a CT scan showed small bowel obstruction and he underwent an emergency laparotomy. Intraoperatively, a subcapsular liver haematoma was identified, with incarcerated, necrotic small bowel within the liver capsule. The patient underwent deroofing of the haematoma with an omental patch and a small bowel resection with primary anastomosis. Small bowel obstruction is a common presentation in A&E and is responsible for half of emergency laparotomies in the UK each year. Although hepatic haematomas are also a relatively common complication of blunt trauma to the abdomen, associated bowel herniation into the liver capsule is very unusual. We believe this is the first time such a case of small bowel obstruction has been reported in the literature and we discuss details of operative management and highlight key learning points.

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p

In his Origin, Charles Darwin led the foundations to debunk the long-held belief that man and animals derive from separate lineages, landing the final blow in The Descent of Man. The discovery in the mid-1980's that fertilized mammal eggs must have male components to generate healthy offspring had similarly dramatic consequences on other religious beliefs, as discussed in “Genetics: immaculate misconception” (1). In the Catholic calendar, the 8th of December is dedicated to the Virgin Mary. The occasion was celebrated with loud fireworks cracking during the second night of the 25th course of the EFIS-EJI Ruggero Ceppellini Advanced School of Immunology, held at Castellammare di Stabia, near Naples, 7th−9th December 2014. A faculty of 13 gathered together with 60 attendants from 19 countries to discuss the theme Maternal Immune System in Pregnancy. While the conclusions of the course were not quite as dramatic as Darwin's and Surani's, new exciting concepts were discussed that had already emerged at a previous meeting held in Cambridge in 2013 to celebrate the 60th anniversary of Peter Medawar's famous article on the “immunological paradox” of pregnancy (2). I had the honor of directing both events, together with Ashley Moffett, and learned a great deal. This brief article is a report on the activities during that 25th course, as well as an opportunity to celebrate the importance of the Ceppellini School to connect young immunologists with leader scientists in their fields, as well as to spur new collaborations. With the generous support of the EFIS-EJI, the Bill and Melinda Gates Foundation, and the International Union of Immunological Societies, a record number of travel fellowships was offered to 13 participants from African countries, including South Africa, Kenya, Nigeria, Gabon, and Cameroon. This was appropriate because it is in Sub-Saharan Africa (SSA) that maternal morbidity and mortality is highest due to pregnancy complications, such as the hypertensive disorder of pregnancy pre-eclampsia, still birth or intrauterine growth restriction (3).

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is very complex and heterogeneous. If not adequately treated, RA patients are likely to manifest excess of morbidity and disability with an important impact on the quality of life. Pharmacological treatment is based on the administration of the disease-modifying antirheumatic drugs (DMARDs), subdivided into conventional synthetic (csDMARDs), targeted synthetic (tsDMARDs), and biological (bDMARDs). bDMARDs are now frequently administered in patients, both as alternative treatment and together with csDMARDs. Unfortunately, there is a therapeutic response variability both to old and new drugs. Therefore, to identify pre-therapeutic and on-treatment predictors of response is a priority. This review aims to summarize recent advances in understanding the causes of the variability in treatment response in RA, with particular attention to predictive potential of autoantibodies and DMARD pharmacogenetics. In recent years, several biomarkers have been proposed to personalize the therapy. Unfortunately, a magic bullet does not exist, as many factors concur to disease susceptibility and treatment outcomes, acting around the patient’s congenital background. Models integrating demographic, clinical, biochemical, and genetic data are needed to enhance the predictive capacity of specific factors singularly considered to optimize RA treatment in light of multidisciplinary patient management.

Polyunsaturated long-chain omega-3 fatty acids (n3-PUFAs) are crucially involved in brain development and function. Inadequate n3-PUFA intake in rats during the perinatal period leads to behavioral deficits in adulthood, but early behavioral changes have not yet been investigated. The present study aimed to investigate potential behavioral alterations in neonatal rats exposed to a perinatal n3-PUFA imbalance. Female Sprague Dawley rats were fed an n3-PUFA-enriched or an n3-PUFA-deficient diet throughout mating, pregnancy, and lactation. Controls were fed an n6/n3-PUFA-balanced diet. We observed maternal behavior from postnatal day (PND) 2 to PND 13 and tested pups in the isolation-induced ultrasonic vocalization (USV) emission task at PNDs 3, 5, 9 and 13 to evaluate the impact of perinatal n3-PUFA on early emotional traits. Both the n3-PUFA-enriched and n3-PUFA-deficient diets profoundly decreased maternal behavior. At PNDs 3 and PND 5, pups of the n3-PUFA-deficient or -enriched diet groups emitted significantly fewer USVs compared with control pups. Further, the sonographic pattern of the USVs was altered in the test pups compared with the control pups at PND 9 and PND 13. The present findings indicate that both n3-PUFA deficiency and supplementation induce alterations in mother-infant interaction and early behavioral disturbances in the offspring.

Many studies have demonstrated the usefulness of some optical coherence tomography (OCT) parameters, like total macular volume (TMV) and retinal nerve fiber layer thickness (RNFL-T), for monitoring patients with multiple sclerosis (MS). However, there are no real-world, long-term studies on patients with relapsing-remitting MS (RR-MS) treated with fingolimod. Therefore, the purpose of this study was to describe retinal changes associated with fingolimod therapy during a two-year follow-up while considering previous episodes of optic neuritis (ON). Patients diagnosed with RR-MS and treated with fingolimod (46 in total) underwent a two-year follow-up. Based on previous ON history, we identified 16 ON+ and 30 ON&minus, patients. The ophthalmological evaluations, including visual field (VF) examination and OCT, were performed at a baseline at 3&ndash, 6, 12 and 24 months to evaluate the progression rate for each parameter. When analyzing the whole sample, OCT showed no cases of macular edema. Instead, we observed a significant reduction rate in the central retinal thickness (CRT) (p &lt, 0.001), TMV (p &lt, 0.001) and RNFL (p &lt, 0.05). Moreover, we observed a significant difference in the progression rate between ON+ and ON&minus, patients, relative to the VF and RNFL (p &lt, 0.05) examinations. OCT highlighted a significant progression rate of retinal damage in MS patients despite fingolimod therapy, especially in MS ON+ patients.

Despite recent advances, the causes of and effective therapies for pediatric chronic cholestatic diseases remain elusive, and many patients progress to liver failure and need liver transplantation. Malnutrition is a common complication in these patients and is a well-recognized, tremendous challenge for the clinician. We undertook a narrative review of both recent and relevant older literature, published during the last 20 years, for studies linking nutrition to pediatric chronic cholestasis. The collected data confirm that malnutrition and failure to thrive are associated with increased risks of morbidity and mortality, and they also affect the outcomes of liver transplantation, including long-term survival. Malnutrition in children with chronic liver disease is multifactorial and with multiple potential nutritional deficiencies. To improve life expectancy and the quality of life, patients require careful assessments and appropriate management of their nutritional statuses by multidisciplinary teams, which can identify and/or prevent specific deficiencies and initiate appropriate interventions. Solutions available for the clinical management of these children in general, as well as those directed to specific etiologies, are summarized. We particularly focus on fat-soluble vitamin deficiency and malnutrition due to fat malabsorption. Supplemental feeding, including medium-chain triglycerides, essential fatty acids, branched-chain amino acids, and the extra calories needed to overcome the consequences of anorexia and high energy requirements, is reviewed. Future studies should address the need for further improving commercially available and nutritionally complete infant milk formulae for the dietary management of this fragile category of patients. The aid of a specialist dietitian, educational training regarding nutritional guidelines for stakeholders, and improving family nutritional health literacy appear essential.

Severe coronavirus disease-2019 (COVID-19) is frequently associated with microvascular thrombosis, especially in the lung, or macrovascular thrombosis, mainly venous thromboembolism, that significantly contribute to the mortality burden of the disease. COVID-19 patients also exhibit distinctive laboratory abnormalities that are compatible with a prothrombotic state. The key event underlying COVID-19-associated thrombotic complications is an excessive host inflammatory response to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection generating multiple inflammatory mediators, mainly cytokines and complement activation products. The latter, along with the virus itself, the increased levels of angiotensin II and hypoxia, drive the major cellular changes promoting thrombosis, which include: (1) aberrant expression of tissue factor by activated alveolar epithelial cells, monocytes-macrophages and neutrophils, and production of other prothrombotic factors by activated endothelial cells (ECs) and platelets; (2) reduced expression of physiological anticoagulants by dysfunctional ECs, and (3) suppression of fibrinolysis by the endothelial overproduction of plasminogen activator inhibitor-1 and, likely, by heightened thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Moreover, neutrophils and other cells, upon activation or death, release nuclear materials which are endowed with potent prothrombotic properties. The ensuing thrombosis significantly contributes to lung injury and, in most severe COVID-19 patients, to multiple organ dysfunction. Insights into the pathogenesis of COVID-19-associated thrombosis may have implications for the development of new diagnostic and therapeutic tools.

Innate lymphoid cells (ILCs) are the most abundant immune cells in the uterine mucosa both before and during pregnancy. Circumstantial evidence suggests they play important roles in regulating placental development but exactly how they contribute to the successful outcome of pregnancy is still unclear. Uterine ILCs (uILCs) include subsets of tissue-resident natural killer (NK) cells and ILCs, and until recently the phenotype and functions of uILCs were poorly defined. Determining the specific roles of each subset is intrinsically challenging because of the rapidly changing nature of the tissue both during the menstrual cycle and pregnancy. Single-cell RNA sequencing (scRNAseq) and high dimensional flow and mass cytometry approaches have recently been used to analyse uILC populations in the uterus in both humans and mice. This detailed characterisation has significantly changed our understanding of the heterogeneity within the uILC compartment. It will also enable key clinical questions to be addressed including whether specific uILC subsets are altered in infertility, miscarriage and pregnancy disorders such as foetal growth restriction and pre-eclampsia. Here, we summarise recent advances in our understanding of the phenotypic and functional diversity of uILCs in non-pregnant endometrium and first trimester decidua, and review how these cells may contribute to successful placental development.

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.

Background Inhibitors of the sodium‐glucose linked transporter 2 improve cardiovascular outcomes in patients with or without type 2 diabetes mellitus, but the effects on cardiac energetics and mitochondrial function are unknown. We assessed the effects of sodium‐glucose linked transporter 2 inhibition on mitochondrial function, high‐energy phosphates, and genes encoding mitochondrial proteins in hearts of mice with and without diet‐induced diabetic cardiomyopathy. Methods and Results Mice fed a control diet or a high‐fat, high‐sucrose diet received ertugliflozin mixed with the diet (0.5 mg/g of diet) for 4 months. Isolated mitochondria were assessed for functional capacity. High‐energy phosphates were assessed by 31 P nuclear magnetic resonance spectroscopy concurrently with contractile performance in isolated beating hearts. The high‐fat, high‐sucrose diet caused myocardial hypertrophy, diastolic dysfunction, mitochondrial dysfunction, and impaired energetic response, all of which were prevented by ertugliflozin. With both diets, ertugliflozin caused supernormalization of contractile reserve, as measured by rate×pressure product at high work demand. Likewise, the myocardial gene sets most enriched by ertugliflozin were for oxidative phosphorylation and fatty acid metabolism, both of which were enriched independent of diet. Conclusions Ertugliflozin not only prevented high‐fat, high‐sucrose–induced pathological cardiac remodeling, but improved contractile reserve and induced the expression of oxidative phosphorylation and fatty acid metabolism gene sets independent of diabetic status. These effects of sodium‐glucose linked transporter 2 inhibition on cardiac energetics and metabolism may contribute to improved structure and function in cardiac diseases associated with mitochondrial dysfunction, such as heart failure.