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Congenital omphalocele is among the most common antenatally diagnosed anomalies. As additional abnormalities are found in majority of cases, antenatal investigations target the search for additional structural anomalies and genetic disorders, including aneuploidy. Antenatal management focuses on the assessment of fetal well-being. Unfortunately, antenatal prediction of postnatal and long-term outcomes represents 2 less well-documented but crucial facets of this pathology. A large part of the prognosis relies on aspects that are difficult to predict such as quality of life, neurological development, and autonomy, which cause significant anxiety in expectant parents.This article offers a comprehensive review of antenatal management of omphalocele with a specific focus on predictive factors and long-term outcomes.We conducted an extensive literature review targeting management of fetal omphalocele. We had a specific interest in factors predictive of fetal and neonatal outcome as well as long-term consequences of omphalocele. Fetuses with large defects and those containing the liver are at higher risk of having a complicated postnatal course. Neonates may experience pulmonary hypoplasia, pulmonary hypertension, and gastroesophageal reflux. In selected cases, motor and cognitive delay may be present, but the overall life-long prognosis and quality of life is good.A multidisciplinary approach should be encouraged after the diagnosis of fetal omphalocele. In addition to clinical team experience, antenatal counseling should be based on objective and gestational age-dependent criteria and should include long-term outcomes.

Novel treatments targeting in baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS) heart failure (HF) are grounded on small prognostic studies, partly performed in the pre-beta-blockade era.This study assesses the clinical/prognostic significance of BRS and CRS in a large cohort of patients with chronic HF on modern treatments.Outpatients with chronic HF with either reduced (≤40%) or mildly reduced left ventricular ejection fraction (LVEF) (41% to 49%) underwent BRS (SD method) and CRS to hypoxia and hypercapnia (rebreathing technique) assessment and were followed up for a composite endpoint of cardiac death, implantable cardioverter-defibrillator shock, or HF hospitalization.A total of 425 patients were enrolled (65 ± 12 years of age, LVEF 32% [IQR: 25%-38%], 94% on beta blockers). Patients with decreased BRS (n = 96 of 267, 36%) had lower exercise tolerance and heart rate variability (P 0.05), whereas those with increased CRS to both hypoxia and hypercapnia (n = 74 of 369, 20%) had higher plasma norepinephrine and central apneas across the 24-hour period (P 0.01). During a median 50-month follow-up (IQR: 24-94 months), the primary endpoint occurred more often in patients with decreased BRS (log-rank: 11.64; P = 0.001), mainly for increased cardiac deaths/implantable cardioverter-defibrillator shocks, and in those with increased CRS (log-rank: 34.81; P 0.001), mainly for increased HF hospitalizations. Patients with both abnormal BRS and CRS showed the worst outcome. Reduced BRS (HR: 2.76 [95% CI: 1.36-5.63]; P = 0.005) and increased CRS (HR: 2.91 [95% CI: 1.34-6.31]; P = 0.007) were independently associated with the primary outcome and increased risk stratification when added to standard HF prognosticators (P 0.05).In subjects with HF on modern treatment, abnormal BRS and CRS are frequently observed. BRS and CRS elicit autonomic imbalance, exercise limitation, unstable ventilation, and predict adverse outcomes.

BACKGROUND: TB caused by rifampicin-resistant (RR) and multidrug-resistant (MDR) Mycobacterium tuberculosis strains is a major concern to TB control globally. However, in the European Union, MDR-TB notifications among all bacteriologically confirmed TB cases with available drug susceptibility testing (DST) results decreased over the last years.METHODS: We conducted a retrospective analysis on DST results reported from 2011 to 2020 by 46 laboratories in 19 out of 20 regions in Italy in order to evaluate resistance trends to first- and second-line drugs in MDR/RR-TB strains isolated from Italian-born persons (IBPs) and foreign-born persons (FBPs).RESULTS: Of 23,972 M. tuberculosis strains examined (15,519 from FBPs and 8,453 from IBPs), MDR-TB decreased from 3.2% in 2011 to 2.2% in 2020. High MDR/RR-TB rates occurred mostly in FBPs from former Soviet Union countries. In 2017, a MDR/RR-TB increase was detected in FBPs from sub-Saharan Africa. MDR-TB strains showed consistent increase in resistance to pyrazinamide (PZA), slight increase in resistance to fluoroquinolones and a decrease in resistance to other drugs.CONCLUSION: While MDR/RR-TB cases slightly decreased, a worrisome increase of resistance to PZA and fluoroquinolones among MDR/RR-TB patients was seen. This implies that a fast and efficient diagnosis aligned with therapy is crucial for TB control.

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Càncer hematològic; Malalties infeccioses Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cáncer hematológico; Enfermedades infecciosas Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Haematological cancer; Infectious diseases COVID-19 is posing a significant threat to health in vulnerable patients, such as immunocompromised patients. For hematopoietic cell transplantation (HCT) recipients and patients with hematologic malignancies it is known that COVID-19 leads to severe morbidity and high mortality as compared to the general population [1–3]. For patients treated with Chimeric Antigen Receptor T-cell (CAR-T-cell) therapy for B-cell malignancies however, descriptions of the clinical course and outcome are still limited to small case series and case reports [4–8]. CAR-T-cell therapy recipients are believed to be at high risk of poor outcomes from COVID-19 due to their severely immunocompromised state, caused by prior lymphodepleting immunochemotherapy and CAR-T-cell therapy related side effects such as B-cell depletion, hypogammaglobulinemia, and cytopenias. In order to rapidly inform the medical field on the impact of COVID-19 on CAR-T-cell therapy recipients, the EBMT Infectious Diseases Working Party and the EHA Lymphoma Group joined forces and present the clinical course of COVID-19 in the largest European cohort to date.

Subclinical paroxysmal atrial fibrillation (AF) is one of the main occult causative mechanisms of embolic stroke of undetermined source (ESUS). Aim of this study was to identify AF predictors, and to develop a score to predict the probability of AF detection in ESUS.We retrospectively analyzed ESUS patients undergoing 2-week external electrocardiographic monitoring. Patients with and without AF detection were compared. On the basis of multivariate analysis, predictors of AF were identified and used to develop a predictive score, which was then compared with other existing literature scores.Eighty-two patients, 48 females, mean age±SD 72±10 years, were included. In 36 patients (43.9%) AF was detected. The frequency of age 75 years or above and arterial hypertension, and the median CHA 2 DS 2 -VASc score were significantly higher in patients with AF compared with those without. National Institutes of Health Stroke Scale (NIHSS) score ≥8 was the only independent variable associated with AF detection. We derived the Empoli ESUS-AF (E 2 AF) score (NIHSS ≥8 5 points, arterial hypertension 3 points, age 75 years or above 2 points, age 65 to 74 years 1 point, history of coronary/peripheral artery disease 1 point, left atrial enlargement 1 point, posterior lesion 1 point, cortical or cortical-subcortical lesion 1 point), whose predictive power in detecting AF was good (area under the curve: 0.746, 95% confidence interval: 0.638-0.836) and higher than that of CHA 2 DS 2 -VASc and other scores.In our study NIHSS score ≥8 was the only independent predictor of post-ESUS-AF detection. The E 2 AF score appears to have a good predictive power for detecting AF. External validations are required.

The aim of this study is to verify if (1) there is a link between hypovitaminosis D and benign paroxysmal positional vertigo, (2) the number of benign paroxysmal positional vertigo relapses decreases after vitamin D supplementation; and (3) benign paroxysmal positional vertigo response to physical therapy improves after hypovitaminosis D correction.We enrolled 26 patients with benign paroxysmal positional vertigo and 24 subjects, who never suffered from vertigo, as a control group. All benign paroxysmal positional vertigo patients underwent physical therapy, once a week, until benign paroxysmal positional vertigo resolution. All participants were subjected to a dosage of serum 25(OH) vitamin D. In patients with hypovitaminosis D, we prescribed cholecalciferol. After 3 months of therapy, all patients were asked to undergo a second dosage of serum 25(OH) vitamin D. For each patient, we counted the number of maneuvers required to resolve each episode of benign paroxysmal positional vertigo before and after vitamin D supplementation.Our results suggest that (1) there is a relationship between vitamin D deficiency and the onset of BPPV and (2) hypovitaminosis correction is able to reduce both the number of patients relapsing and the number of relapses per patient.We have not found a significant effect of vitamin D supplementation as regards the responsivity of benign paroxysmal positional vertigo to physical therapy.

BACKGROUND Reduced access to dental care may increase cardiovascular risk; however, socioeconomic factors are believed to confound the associations. We hypothesized that the relation persists despite economic wellness and high education, with reduced access to dental care affecting cardiovascular risk at least in part through its effect on blood pressure (BP), possibly mediated by systemic inflammation. METHODS We first assessed the sociodemographic and clinical characteristics related to last dental visit timing (≤ or >6 months; self-reported) using national representative cross-sectional data. Then, the association of last dental visit timing with clinic BP was selectively investigated in highly educated, high income participants, further matched for residual demographic and clinical confounders using propensity score matching (PSM). The mediating effect of systemic inflammation was formally tested. Machine learning was implemented to investigate the added value of dental visits in predicting high BP over the variables included in the Framingham Hypertension Risk Score among individuals without an established diagnosis of hypertension. RESULTS Of 27,725 participants included in the population analysis, 46% attended a dental visit ≤6 months. In the PSM cohort (n = 2,350), last dental visit attendance >6 months was consistently associated with 2 mmHg higher systolic BP (p = 0.001) and with 23 to 35% higher odds of high/uncontrolled BP compared with attendance ≤6 months. Inflammation mildly mediated the association. Access to dental care improved the prediction of high BP by 2%. CONCLUSIONS Dental care utilization impacts on BP profiles independent of socioeconomic confounders, possibly through systemic inflammation. Regular dental visits may contribute to preventive medicine. This article is protected by copyright. All rights reserved.

Background: It has been speculated that stains are neuroprotective and are associated with a reduced risk of Parkinson’s disease (PD), but only a few studies have investigated the influence of statins on the progression of PD. Objective: To evaluate whether long-term statin use may affect motor progression in a large cohort of de novo patients with PD. Methods: We conducted a 4-year retrospective observational cohort study to assess patients with PD. The patients were consecutively recruited from a single tertiary center between January 2015 and January 2017. Information on motor function was obtained using the MDS-Unified Parkinson Disease Rating Scale (UPDRS)-III and all subjects were extensively characterized, including information about lifestyle habits, cardiovascular risk factors and cholesterol blood levels. Results: Of the 181 participants included in the study, 104 patients were evaluated for eligibility (42 patients were exposed to statin therapies and 62 were not treated with statins). They presented similar scores in UPDRS III at baseline but the statin users had a lower motor impairment at 4 years compared to non-user PD patients. Additionally, statin treatment resulted in slower progression of the rigidity score of UPDRS over 4 years. No other significant differences were observed between PD patients with and without statins. Conclusion: Early PD patients with long-term statin usage showed lower motor deterioration after 4 years of disease duration compared with patients not taking statins at diagnosis, suggesting a possible influence of statins on disease progression in PD. Further investigation is warranted to understand the potential beneficial effects of statin treatment on clinical symptoms in PD.

Conditioned pain modulation (CPM) can discriminate between healthy and chronic pain patients. However, its relationship with neurophysiological pain mechanisms is poorly understood. Brain oscillations measured by electroencephalography (EEG) might help gain insight into this complex relationship. Objective To investigate the relationship between CPM response and self-reported pain intensity in non-specific chronic low back pain (NSCLBP) and explore respective EEG signatures associated to these mechanisms. Design Cross-sectional analysis. Participants Thirty NSCLBP patients participated. Methods Self-reported low back pain, questionnaires, mood scales, CPM (static and dynamic quantitative sensory tests), and resting surface EEG data were collected and analyzed. Linear regression models were used for statistical analysis. Results CPM was not significantly correlated with self-reported pain intensity scores. Relative power of EEG in the beta and high beta bands as recorded from the frontal, central, and parietal cortical areas were significantly associated with CPM. EEG relative power at delta and theta bands as recorded from the central area were significantly correlated with self-reported pain intensity scores while controlling for self-reported depression. Conclusions Faster EEG frequencies recorded from pain perception areas may provide a signature of a potential cortical compensation caused by chronic pain states. Slower EEG frequencies may have a critical role in abnormal pain processing.

Background Stroke burden characterization studies in low‐ and middle‐income countries are scarce. We estimated the burden of stroke and its risk factors in Latin America and the Caribbean (LAC). Methods and Results We extracted GBD (Global Burden of Disease) study 2019 data on overall stroke and 3 subtypes (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) for 20 LAC countries. We estimated absolute and age‐standardized rates of disability‐adjusted life years, years of life lost, years lived with disability, and deaths. The population‐attributable fractions of 17 risk factors were estimated. All analyses were performed at regional and national levels by stroke subtype, sex, and age subgroups. In 2019, the LAC region had the fourth largest stroke burden worldwide (6.8 million disability‐adjusted life years), predominantly attributable to premature deaths (89.5% of disability‐adjusted life years). Intracerebral hemorrhage was the primary cause of the overall stroke burden (42% of disability‐adjusted life years), but ischemic stroke was the leading cause of disability (69% of total years lived with disability). Haiti and Honduras had the highest age‐standardized rates. Older adults and men had the largest burdens, although women had the highest rate of disability. Socioeconomic development level did not influence the burden. The major risk factor clusters were metabolic (high systolic blood pressure [population‐attributable fraction=53%] and high body mass index [population‐attributable fraction=37%]), which were more influential in hemorrhagic events, women, and older adults. Household air pollution was an important risk factor in low‐income countries in LAC. Conclusions The stroke burden and stroke‐related mortality in LAC are higher than the worldwide averages. However, stroke is a highly preventable disease in this region. Up to 90% of the burden could be reduced by targeting 2 modifiable factors: blood pressure and body mass index. Further research and implementation of primary and secondary prevention interventions are needed, as well as integrated national stroke care programs for acute, subacute, and rehabilitation management in LAC.

Dear Editor, cutaneous chronic graft versus host disease (cGVHD) is a pathological process consisting of donor-derived T-cells aimed at the antigens of the recipient. It exhibits a large range of clinical presentations resembling morphea and deep sclerosis/fasciitis, all characterized by both inflammation and progressive dermal and hypodermic fibrosis (1). Although classic scleroderma-like lesions in cGVHD are nummular or irregular plaques and linear bundles associated with hypo- or hyperpigmentation (2), we report an atypical case with ulcerative presentation. No other case-reports of morphea-like or scleroderma-like cGVHD with an ulcerated appearance after liver transplantation (LT) and magnetic resonance imaging (MRI) correlation have been found in the literature. CASE REPORT Ten months after LT due to an end-stage cirrhosis associated with multifocal hepatocarcinoma (HCC), a 61-year-old man on immunosuppressive therapy with Tacrolimus (1 mg) and Everolimus (10 mg) presented to our clinic for a skin lesion in the right scapular region. We observed a flat ulcerated plaque with areas of sclerosis, minimal necrosis, and well-defined slightly erythematous margins (Figure 1, a). On palpation, the plaque had a hard consistency and was slightly painful. The skin lesion had been preceded by subjective discomfort with stinging sensation for seven months before its onset. Gradually lesion developed starting from a small, flat, oval purplish plaque associated with a progressive increase in pain. Patient denied dysphagia, retrosternal heartburn, Raynaud's phenomenon, arthralgia, and dyspnea. A previous MRI (Figure 2, a,b) showed subcutaneous and muscle edema. Blood tests showed abnormal liver function indexes due to extrahepatic cholestasis, while C-reactive protein, erythrocyte sedimentation rate, and leukocytes were within normal ranges. Self-reactive antibodies were negative. Histological examination (Figure 1, b) identified rare dyskeratotic keratinocytes and basal lymphocyte infiltrate, a dermal dense fibrosis with the disappearance of the skin appendages, and large fibrous septa in the adipose panniculus. It led to the diagnosis of scleroderma/morphea, based on the patient's clinical history. The diagnosis of graft versus host disease scleroderma-like post liver transplant was established. The lesion was treated by topical application of 0.05% clobetasol once a day. We did not use systemic immunosuppressive therapy in order to prevent HCC recurrence. The patient is currently in clinical follow-up to identify worsening or neoplastic degeneration. CASE DISCUSSION Cutaneous cGVHD often presents clinically as an ulcerative evolution in the context of fibrosis and diffuse skin atrophy (2), but very rarely initially appears as a well-delimited ulcerated plaque. Only few cases of ulcer have been found in literature, all in patients undergoing hematopoietic stem cell transplantation (HSCT), which is associated with the highest risk of developing GVHD, 20-50% (3,4), while LT has quite low incidence, at 0.5-2% (5). To our knowledge, this is the first case report of a scleroderma-like cGVHD lesion with ulcer appearance in LT. Our patient underwent two MRIs during post-transplant follow-up, which allowed us to evaluate the deep disease evolution. The T2-weighted MRI (Figure 2, c,d) performed approximately 1 year after transplantation, demonstrated fibrous septa in the subcutaneous fat and fascial thickening, with associated muscle hypotrophy and edema. The previous MRI, performed seven months after transplantation, already showed subcutaneous tissues and fascial edema, highlighting active inflammation. This evidence suggests that MRI could identify the lesion location before clinical manifestations, providing an opportunity to intervene promptly. To the best of our knowledge, this is the first reported case of cGVHD with atypical scleroderma-like presentation in a liver transplant patient whose clinical and MRI correlations have been traced. Our suggestions are supported by the results of other previous studies (6,7) evaluating MRI performance for assessing disease extent and activity, as well as therapeutic response in HSCT.

Background: Pulmonary hypertension (PH) is a frequent and detrimental condition. Right heart catheterization (RHC) is the gold standard to identify PH subtype (precapillary from postcapillary PH) and is key for treatment allocation. In this study, the novel echocardiographic biventricular coupling index (BCI), based on the ratio between right ventricular stroke work index and left ventricular E/E′ ratio, was tested for the discrimination of PH subtype using RHC as the comparator. Methods: BCI was derived in 334 consecutive patients who underwent transthoracic echocardiography and RHC for all indications. BCI was then tested in a validation cohort of 1,349 patients. Results: The accuracy of BCI to identify precapillary PH was high in the derivation cohort (area under the curve, 0.82; 95% CI, 0.78-0.88; P < .001; optimal cut point, 1.9). BCI identified patients with precapillary PH with high accuracy also in the validation cohort (area under the curve, 0.87 [95% CI, 0.85-0.89; P < .001]; subgroup with PH: area under the curve, 0.91 [95% CI, 0.89-0.93; P < .001]; cut point, 1.9; sensitivity, 82%; specificity, 89%; positive predictive value, 77%; negative predictive value, 92%). BCI outperformed both the D'Alto score (Z = 3.56; difference between areas = 0.05; 95% CI, 0.02-0.07; P < .001) and the echocardiographic pulmonary–to–left atrial ratio index (Z = 2.88; difference between areas = 0.02; 95% CI, 0.01-0.04; P = .004). Conclusions: BCI is a novel, noninvasive index based on routinely available echocardiographic parameters that identifies with high accuracy patients with precapillary PH. BCI may be of value in the screening workup of patients with PH.

Motivation Sepsis is a leading cause of death and disability in children globally, accounting for ∼3 million childhood deaths per year. In pediatric sepsis patients, the multiple organ dysfunction syndrome (MODS) is considered a significant risk factor for adverse clinical outcomes characterized by high mortality and morbidity in the pediatric intensive care unit. The recent rapidly growing availability of electronic health records (EHRs) has allowed researchers to vastly develop data-driven approaches like machine learning in healthcare and achieved great successes. However, effective machine learning models which could make the accurate early prediction of the recovery in pediatric sepsis patients from MODS to a mild state and thus assist the clinicians in the decision-making process is still lacking. Results This study develops a machine learning-based approach to predict the recovery from MODS to zero or single organ dysfunction by 1 week in advance in the Swiss Pediatric Sepsis Study cohort of children with blood-culture confirmed bacteremia. Our model achieves internal validation performance on the SPSS cohort with an area under the receiver operating characteristic (AUROC) of 79.1% and area under the precision-recall curve (AUPRC) of 73.6%, and it was also externally validated on another pediatric sepsis patients cohort collected in the USA, yielding an AUROC of 76.4% and AUPRC of 72.4%. These results indicate that our model has the potential to be included into the EHRs system and contribute to patient assessment and triage in pediatric sepsis patient care. Availability and implementation Code available at https://github.com/BorgwardtLab/MODS-recovery. The data underlying this article is not publicly available for the privacy of individuals that participated in the study. Supplementary information Supplementary data are available at Bioinformatics online.

Vaccination against coronavirus disease 2019 (COVID-19) is the safest and most effective strategy for controlling the pandemic. However, some cases of acute cardiac events following vaccine administration have been reported, including myocarditis and myocardial infarction (MI). While post-vaccine myocarditis has been widely discussed, information about post-vaccine MI is scarce and heterogenous, often lacking in histopathological and pathophysiological details. We hereby present five cases (four men, mean age 64 years, range 50-76) of sudden death secondary to MI and tightly temporally related to COVID-19 vaccination. In each case, comprehensive macro- and microscopic pathological analyses were performed, including

The widespread use of noninvasive/invasive coronary imaging increased the probability of recognition of coronary aneurysms. Left main coronary aneurysms (LMCA), though rare, are potentially life-threatening but in the absence of controlled studies, guidelines do not provide any specific recommendation for their management. We, therefore, aimed to investigate the epidemiology, clinical presentation, therapeutic strategies, and prognostic implication of LMCA.A systematic review of the literature was performed to retrieve all the reported cases of LMCA as of December 2021, which were summarized and classified according to their etiology, clinical presentation, and therapeutic management.Out of 1997 works retrieved, 180 studies were analyzed, describing 209 LMCA cases (aged 51 ± 19 years, 68% males). Atherosclerosis was the most common etiology (40%), followed by inflammatory (12%), congenital (9%), or degenerative (6%) conditions. Stable angina (43%) and acute coronary syndromes (32%) were more often the first clinical manifestations, while 29 (14%) LMCA were incidental findings. Most cases were treated surgically (53%), while percutaneous intervention was rarely adopted (7%). Data about antithrombotic therapies were scarce and heterogeneous. Finally, when longitudinal data were reported (n = 81), LMCA resulted associated with a severe prognosis, with a 15% mortality over an 8-month median follow-up.LMCA are most frequently, but not exclusively, caused by advanced atherosclerosis. Irrespective of their etiology and clinical presentation, LMCA may be associated with high short-term mortality. In absence of controlled studies, a careful evaluation of each case is warranted to optimize therapeutic strategies.

Aims This study aimed to evaluate a novel echocardiographic algorithm for quantitative estimation of pulmonary artery wedge pressure (PAWP) and pulmonary vascular resistance (PVR) in patients with heart failure and pulmonary hypertension (PH) scheduled to right heart catheterization (RHC). Methods and results In this monocentric study, 795 consecutive patients (427 men; age 68.4 ± 12.1 years) undergoing echocardiography and RHC were evaluated. Multiple regression analysis was performed to identify echocardiographic predictors of PAWP and PVR measured by RHC in the derivation group (the first 200 patients). The diagnostic accuracy of the model was then tested in the validation group (the remaining 595 patients). PH was confirmed by RHC in 507 (63.8%) patients, with 192 (24.2%) cases of precapillary PH, 248 (31.2%) of postcapillary PH, and 67 (8.4%) of combined PH. At regression analysis, tricuspid regurgitation maximal velocity, mitral E/e′ ratio, left ventricular ejection fraction, right ventricular fractional area change, inferior vena cava diameter, and left atrial volume index were included in the model (R = 0.8, P

OBJECTIVES To determine circulating levels of ascorbic acid (VitC) and thiamine (VitB1) in neonates and children with blood culture-proven sepsis. DESIGN Nested single-center study of neonates and children prospectively included in the Swiss Pediatric Sepsis Study. SETTING One tertiary care academic hospital. PATIENTS Sixty-one neonates and children 0-16 years old. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS VitC and VitB1 were quantified in serum of patients (median age, 10.5 mo; interquartile range [IQR], 0.5-62.1 mo) with blood culture-proven sepsis. Median time between sepsis onset and sampling for measurement of vitamins was 3 days (IQR, 2-4 d). Median serum levels of VitC and VitB1 were 32.4 μmol/L (18.9-53.3 μmol/L) and 22.5 nmol/L (12.6-82 nmol/L); 36% of the patients (22/61) had low VitC and 10% (6/61) had VitC deficiency; and 72% (44/61) had low VitB1 and 13% (8/61) had VitB1 deficiency. Children with low VitC were older (p = 0.007) and had higher C-reactive protein (p = 0.004) compared with children with VitC within the normal range. Children with low VitB1 levels were older (p = 0.0009) and were less frequently receiving enteral or parenteral vitamin supplementation (p = 0.0000003) compared with children with normal VitB1 levels. CONCLUSIONS In this cohort of newborns and children with sepsis, low and deficient VitC and VitB1 levels were frequently observed. Age, systemic inflammation, and vitamin supplementation were associated with vitamin levels during sepsis.

SIGNIFICANCE. Children are being fitted at younger ages with soft contact lenses for myopia control. This three-year investigation of adverse events related to contact lens wear in 7–11 year old participants helps optometrists understand what to expect when fitting children with soft contact lenses. PURPOSE. The purpose of this paper is to report the frequency and type of ocular and non-ocular adverse events related to soft contact lens wear in children. METHODS. Seven to 11 year old children wore soft contact lenses for three years. Adverse events were defined by a slit lamp examination finding of grade 3 or worse; parental report of a clinically meaningful change (determined by the examiner) in eyes, vision, or health; or a clinically meaningful response (determined by examiner) to a symptom checklist. Adverse events were categorized and reported by examiners and finalized by the executive committee. The presence or absence of an infiltrate and a list of diagnoses was determined at the conclusion of the study. RESULTS. The 294 participants wore their contact lenses 73.0 ± 26.5 hours per week, and 220 (74.8%) encountered at least one adverse event. Of the 432 adverse events, 75.2% were ocular and 24.8% were non-ocular. Contact lens wear was probably or definitely related to 60.6% of the ocular and 2.8% of the non-ocular adverse events. None of the ocular adverse events were serious, severe, or caused permanent contact lens discontinuation. The corneal infiltrate incidence was 185 cases/10,000 patient-years of wear (95% CI: 110—294). The incidence of moderate ocular adverse events that were definitely or probably related to contact lens wear was 405 cases/10,000 patient-years of wear (95% CI: 286—557). CONCLUSIONS. The adverse events experienced by 7–11 year old myopic children rarely required meaningful treatment and never led to permanent discontinuation of contact lens wear or loss of best-corrected vision.

Background It has been documented that income is a strong determinant of dental care use in Canada, mostly due to the lack of public coverage for dental care. We assess the contributions of food insecurity and home ownership to income-related equity in dental care use and access. We add to the literature by adding these two variables among other socio-economic determinants of equity in dental care use and access to dental care. Evidence on equity in access to and use of dental care in Canada can inform policymaking. Methods We estimate income-related horizontal inequity indexes for the probability of 1) receiving at least one dental visit in the last 12 months; and 2) lack of dental visits during the 3 years before the interview. We conduct the analyses using data from the 2013–2014 Canadian Community Health Survey (CCHS) at the national and regional level. Results There is pro-rich inequity in the probability of visiting a dentist or an orthodontist and in access to dental care in Ontario. Inequities vary across jurisdictions. Housing tenure and food insecurity contribute importantly to both use of and access to dental care, adding information not captured by standard socio-economic determinants. Conclusions Redistributing income may not be enough to reduce inequities. Careful monitoring of equity in dental care is needed together with interventions targeting fragile groups not only in terms of income but also in improving house and food security.

Background The lack of a consensus definition of neonatal sepsis and a core outcome set (COS) proves a substantial impediment to research that influences policy and practice relevant to key stakeholders, patients and parents. Methods A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the included studies, the described outcomes were extracted in accordance with the provisions of the Core Outcome Measures in Effectiveness Trials (COMET) handbook and registered. Results Among 884 abstracts identified, 90 randomised controlled trials (RCTs) were included in this review. Only 30 manuscripts explicitly stated the primary and/or secondary outcomes. A total of 88 distinct outcomes were recorded across all 90 studies included. These were then assigned to seven different domains in line with the taxonomy for classification proposed by the COMET initiative. The most frequently reported outcome was survival with 74% (n = 67) of the studies reporting an outcome within this domain. Conclusions This systematic review constitutes one of the initial phases in the protocol for developing a COS in neonatal sepsis. The paucity of standardised outcome reporting in neonatal sepsis hinders comparison and synthesis of data. The final phase will involve a Delphi Survey to generate a COS in neonatal sepsis by consensus recommendation. Impact This systematic review identified a wide variation of outcomes reported among published RCTs on the management of neonatal sepsis. The paucity of standardised outcome reporting hinders comparison and synthesis of data and future meta-analyses with conclusive recommendations on the management of neonatal sepsis are unlikely. The final phase will involve a Delphi Survey to determine a COS by consensus recommendation with input from all relevant stakeholders.

Sleep and breathing 25(2), 705-717 (2021). doi:10.1007/s11325-020-02159-1, Published by Springer, Berlin

Purpose Post-hemorrhagic hydrocephalus (PHH) is a rare but serious complication among premature babies in the neonatal intensive care unit. The causes of PHH are still not entirely understood, and its prevention and treatment are controversial. We tried to analyze the risk factors for such complication in our cohort. Methods We reviewed our neonatology data bank and included all preterms below 28 weeks who were born in the period between 1999 and 2014 and suffered from an intraventricular hemorrhage (IVH). We reviewed gestational age, gender, birth weight, type of birth, IVH degree, comorbidities, therapy, complications, time to event, protein content of cerebrospinal fluid, and clinical follow-up. Results We identified 180 patients, divided into two subgroups, “B1” with 37 cases (IVH + PHH) and “B2” with 143 cases (IVH − PHH). In group B1, the presence of IVH grades I, II, III, or IV was in 11%, 19%, and 70% respectively. Nineteen patients were treated with a ventricular access device (VAD) or external ventricular drain (EVD). A total of 20 shunts were implanted, with 11 revisions (55%). One patient suffered from thrombocytopenia. In subgroup B2, 51% showed IVH grade I, whereas severe IVH grades were only present in 22%. 25.9% suffered from thrombocytopenia. Thrombocytopenia was significantly higher in patients who did not develop PHH (p value: 0.002). Conclusion According to our results, thrombocytopenia could play a decisive role in avoiding development of PHH as a sequel of IVH. We recommend a randomized controlled trial to assess the possible efficacy of antiplatelet drugs in avoiding PHH in this vulnerable group.

Aims Increased chemosensitivity to carbon dioxide (CO2 ) is an important trigger of central apnoeas (CA) in heart failure (HF), with negative impact on outcome. We hypothesized that buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity and CA in HF. Methods and results The BREATH study was a randomized, double-blind, placebo-controlled, crossover study (EudraCT-code 2015-005383-42). Outpatients with systolic HF (left ventricular ejection fraction 0.5 L/min/mmHg. The primary safety endpoint was freedom from serious adverse events. Sixteen patients (age 71.3 ± 5.8 years, all males, left ventricular ejection fraction 29.8 ± 7.8%) were enrolled. In the intention-to-treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction >0.5 L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%) (difference between groups 43%, 95% confidence interval 14-73%, P = 0.016). Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity (P = 0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all P 0.05). No patient reported buspirone-related serious adverse events. Conclusions Buspirone reduces CO2 chemosensitivity and improves CA and oxygen saturation across the 24 h in patients with HF.

The characterization of brain cortical activity in heart-failure patients affected by Cheyne-Stokes Respiration might provide relevant information about the mechanism underlying this pathology. Central autonomic network is gaining increasing attention for its role in the regulation of breathing and cardiac functions. In this scenario, evaluating changes in cortical connectivity associated with Cheyne-Stokes Respiration may be of interest in the study of specific brain-activity related to such disease. Nonetheless, the inter subject variability, the temporal dynamics of Central-Apnea/Hyperpnea cycles and the limitations of clinical setups lead to different methodological challenges. To this aim, we present a framework for the assessment of cortico-cortical interactions from Electroencephalographic signals acquired using low-density caps and block-design paradigms, arising from endogenous triggers. The framework combines ICA-decomposition, unsupervised clustering, MVAR modelling and a permutation-bootstrap strategy for evaluating significant connectivity differences between conditions. A common network, lateralized towards the left hemisphere, was depicted across 8 patients exhibiting Cheyne-Stokes Respiration patterns during acquisitions. Significant differences in connectivity at the group level were observed based on patients' ventilatory condition. Interactions were significantly higher during hyperpnea periods with respect to central apneas and occurred mainly in the delta band. Opposite-sign differences were observed for higher frequencies (i.e. beta, low-gamma).

In non-ischaemic dilated cardiomyopathy (NIDCM), it is uncertain which late gadolinium enhancement (LGE) pattern, extent and location predict ventricular arrhythmias.We analysed 183 NIDCM patients (73% men, median age 66 years) receiving an implantable cardioverter defibrillator (ICD) for primary prevention, undergoing cardiac magnetic resonance within 1 month before implantation. The primary endpoint was appropriate ICD shock, the secondary endpoint was a composite of appropriate ICD shock and cardiac death.LGE was found in 116 patients (63%), accounting for 9% of LV mass (5-13%). Over a 30-month follow-up (10-65), 20 patients (11%) experienced the primary and 30 patients (16%) the secondary endpoint. LGE presence, inferior wall LGE, diffuse (≥2 wall) LGE, the number of segments with LGE, the number of segments with 50-75% transmural LGE, and percent LGE mass were univariate predictors of both endpoints. Also septal LGE predicted the primary, and lateral LGE predicted the secondary endpoint. LGE limited to right ventricular insertion points did not predict any endpoint. Percent LGE mass had an area under the curve of 0.734 for the primary endpoint, with 13% as the best cut-off (55% sensitivity, 86% specificity, 32% PPV, 94% NPV), conferring a 7-fold higher risk compared to patients with no LGE or LGE13%. Survival free from both endpoints was significantly worse for patients with LGE ≥13%.In patients with NIDCM receiving a defibrillator for primary prevention, LGE presence and extent predicted appropriate ICD shock and cardiac mortality; also specific LGE patterns and locations predicted a worse prognosis.

Metabolic reprogramming as well as the flexible utilisation of fuel sources by tumour cells has been considered not only intrinsic to malignant cells but also sustained by resident and/or recruited stromal cells. The complexity of tumour-stroma cross-talk is experienced by neoplastic cells through profound changes in the own metabolic machinery. In such context, mitochondria are dynamic organelles that receive, orchestrate and exchange a multiplicity of stromal cues within the tumour cells to finely regulate key metabolic and signalling pathways, allowing malignant cells to adapt and thrive in an ever-changing environment. In this review, we focus on how tumour mitochondria are coached by stromal metabolic supply and how this re-education sustains tumour malignant traits.

Background Central apneas (CA) are a frequent comorbidity in patients with heart failure (HF) and are associated with worse prognosis. The clinical and prognostic relevance of CA in each sex is unknown. Methods and Results Consecutive outpatients with HF with either reduced or mildly reduced left ventricular ejection fraction (n=550, age 65±12 years, left ventricular ejection fraction 32%±9%, 21% women) underwent a 24‐hour ambulatory polygraphy to evaluate CA burden and were followed up for the composite end point of cardiac death, appropriate implantable cardioverter‐defibrillator shock, or first HF hospitalization. Compared with men, women were younger, had higher left ventricular ejection fraction, had lower prevalence of ischemic etiology and of atrial fibrillation, and showed lower apnea‐hypopnea index (expressed as median [interquartile range]) at daytime (3 [0–9] versus 10 [3–20] events/hour) and nighttime (10 [3–21] versus 23 [11–36] events/hour) (all P P P =0.037), nighttime apnea‐hypopnea index ≥15 events/hour (HR, 2.84; 95% CI, 1.28–6.32; P =0.010), and nighttime CA index ≥10 events/hour (HR, 5.01; 95% CI, 1.88–13.4; P =0.001) were independent predictors of the primary end point in women but not in men (all P >0.05), also after matching women and men for possible confounders. Conclusions In chronic HF, CA are associated with a greater risk of adverse events in women than in men.

Otosclerosis is a frequent ear disorder causing a stapedo-ovalar ankylosis and conductive hearing loss. Stapedoplasty, performed under both general (GA) and local anaesthesia (LA), is the most advisable surgical solution. Auditory recovery relies on the patient's conditions and on the intervention itself. The aim of our work was to compare hearing outcomes with stapedoplasty performed under GA or LA and to investigate patients' compliance to both methods.Fifty-five otosclerotic patients underwent stapedoplasty both under GA (32/55) and LA (23/55). Pre- and post-operative air and bone tone audiometry threshold values as well as the air-bone gap and its closure score, were analysed. All patients filled in a satisfaction questionnaire regarding their concern and level of appreciation of the type of anaesthesia.Our data show that the auditory results with stapedoplasty are good and do not differ between LA and GA. Even considering the advantages and limits of the two methods, one cannot favour one or the other type of anaesthesia. Finally, the patient's satisfaction cannot be considered a criterion of choice, since this was found to be high in both cases.Risultati uditivi e gradimento nei pazienti operati di stapedoplastica in anestesia locale e generale.L’otosclerosi è una frequente patologia otologica che provoca anchilosi stapedo-ovalare e ipoacusia trasmissiva. La stapedoplastica, eseguita in anestesia generale (AG) o locale (AL), è la soluzione chirurgica ideale. Il recupero uditivo dipende da variabili legate al paziente e all’intervento. Scopo del nostro lavoro è stato confrontare i risultati uditivi dopo stapedoplastica eseguita in AG e AL e indagare il grado di soddisfazione dei pazienti nei riguardi delle due metodiche.Abbiamo studiato 55 pazienti con otosclerosi sottoposti a stapedoplastica in AG (32/55) e AL (23/55). Abbiamo valutato la soglia audiometrica tonale pre- e post-operatoria, il valore del gap trasmissivo via aerea-ossea e la sua chiusura. I pazienti hanno compilato un questionario di soddisfazione riguardo alla preoccupazione e al livello di apprezzamento del tipo di anestesia.I nostri dati mostrano che i risultati uditivi dopo stapedoplastica sono buoni e non differiscono in base al tipo di anestesia. Anche considerando i vantaggi e i limiti delle due metodiche non si può propendere per la scelta dell’uno o dell’altro tipo di anestesia. Infine, la soddisfazione del paziente non può essere considerata un criterio di scelta, poiché questa è risultata elevata in entrambi i casi.

Three-dimensional (3D) culture models have gained relevant interest in tissue engineering and drug discovery owing to their suitability to reproduce in vitro some key aspects of human tissues and to provide predictive information for in vivo tests. In this context, the use of hydrogels as artificial extracellular matrices is of paramount relevance, since they allow closer recapitulation of (patho)physiological features of human tissues. However, most of the analyses aimed at characterizing these models are based on time-consuming and endpoint assays, which can provide only static and limited data on cellular behavior. On the other hand, biosensing systems could be adopted to measure on-line cellular activity, as currently performed in bi-dimensional, i.e., monolayer, cell culture systems; however, their translation and integration within 3D hydrogel-based systems is not straight forward, due to the geometry and materials properties of these advanced cell culturing approaches. Therefore, researchers have adopted different strategies, through the development of biochemical, electrochemical and optical sensors, but challenges still remain in employing these devices. In this review, after examining recent advances in adapting existing biosensors from traditional cell monolayers to polymeric 3D cells cultures, we will focus on novel designs and outcomes of a range of biosensors specifically developed to provide real-time analysis of hydrogel-based cultures.

On 31st January 2020, the Italian cabinet declared a 6-month national emergency after the detection of the first two COVID-19 positive cases in Rome, two Chinese tourists travelling from Wuhan. Between then and the total lockdown introduced on 22nd March 2020 Italy was hit by an unprecedented crisis. In addition to being the first European country to be heavily swept by the COVID-19 pandemic, Italy was the first to introduce stringent lockdown measures. The SARS-CoV-2 outbreak and related COVID-19 pandemic have been the worst public health challenge endured in recent history by Italy. Two months since the beginning of the first wave, the estimated excess deaths in Lombardy, the hardest hit region in the country, reached a peak of more than 23,000 deaths. The extraordinary pressures exerted on the Italian Servizio Sanitario Nazionale (SSN) inevitably leads to questions about its preparedness and the appropriateness and effectiveness of responses implemented at both national and regional levels. The aim of the paper is to critically review the Italian response to the COVID-19 crisis spanning from the first early acute phases of the emergency (March–May 2020) to the relative stability of the epidemiological situation just before the second outbreak in October 2020.

Effective control of trunk muscles is fundamental to perform most daily activities. Stroke affects this ability also when sitting, and the Modified Functional Reach Test is a simple clinical method to evaluate sitting balance. We characterize the upper body kinematics and muscular activity during this test. Fifteen chronic stroke survivors performed twice, in separate sessions, three repetitions of the test in forward and lateral directions with their ipsilesional arm. We focused our analysis on muscles of the trunk and of the contralesional, not moving, arm. The bilateral activations of latissimi dorsi, trapezii transversalis and oblique externus abdominis were left/right asymmetric, for both test directions, except for the obliquus externus abdominis in the frontal reaching. Stroke survivors had difficulty deactivating the contralesional muscles at the end of each trial, especially the trapezii trasversalis in the lateral direction. The contralesional, non-moving arm had muscular activations modulated according to the movement phases of the moving arm. Repeating the task led to better performance in terms of reaching distance, supported by an increased activation of the trunk muscles. The reaching distance correlated negatively with the time-up-and-go test score.

AIMS: To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF).METHODS AND RESULTS: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death.CONCLUSIONS: In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

Respiratory research 23(1), 187 (2022). doi:10.1186/s12931-022-02100-y, Published by BioMed Central, London

Objective: To report trends in Juvenile Nasopharyngeal Angiofibroma (JNA) hospitalizations and identify key factors affecting treatment outcomes and cost of care in JNA patients. Methods: The Healthcare Cost and Utilization Project (HCUP) Kids’ Inpatient Database was queried for all cases of JNA between the years of 1997 and 2016. Key factors extracted were patient demographics, geographic region, hospital size, teaching status, elective admissions, and number of diagnoses and procedures performed during the hospitalization. These elements were correlated to length of stay (LOS) and cost-per-day (CPD) using a multiple linear regression (MLR). Regional variation in JNA diagnosis and changes in LOS and CPD trends over time were also analyzed. Results: A total of 614 JNA patients were hospitalized in this time period, with a majority of patients identifying as male (98%) and Caucasian/White (55%). The average LOS has decreased by 0.14 day per year since 1997 ( P = .0034) whereas the CPD has steadily increased by $2 380 per year ( P Conclusion: These results indicate hospital characteristics, such as teaching status and geographic region, may predict differences in JNA outcomes and cost. Healthcare providers should be cognizant of these variations to ensure optimal patient outcomes and expenditures.

Evidence of sympathetic and renin-angiotensin-aldosterone system activation provided a rationale for neurohormonal antagonism in heart failure with reduced ejection fraction (HFrEF), while no data are available in patients with milder degree of systolic dysfunction. We aimed to investigate neurohormonal function in HF with preserved and mid-range EF (HFpEF/HFmrEF).Three cohorts (n = 189/each) of stable HFpEF, HFmrEF and HFrEF patients were selected (median age 70, 67 and 67 years; male 56%, 73% and 74%, respectively). Patients received a baseline clinical assessment including plasma renin activity (PRA), aldosterone, catecholamines, and N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) assays, and were followed-up for all-cause death.Neuroendocrine profile was similar between HFpEF and HFmrEF, while all neurohormones except epinephrine were higher in HFrEF than in HFmrEF (NT-proBNP 2332 ng/L, IQR 995-5666 vs 575 ng/L, 205-1714; PRA 1.7 ng/mL/h, 0.4-5.6 vs 0.6 ng/mL/h, 0.2-2.6; aldosterone 153 ng/L, 85-246 vs 113 ng/L, 72-177; norepinephrine 517 ng/L, 343-844 vs 430 ng/L, 259-624; all p 0.001, epinephrine 31 ng/L, 10-63 vs 25 ng/L, 10-44; p = 0.319). These findings were unrelated to treatment heterogeneity. Ten percent of HFpEF patients had elevated PRA, aldosterone and norepinephrine vs. 8% in HFmrEF and 21% in HFrEF. During a 5-year follow-up, survival decreased with the number of neurohormones elevated (HFpEF: log-rank 7.8, p = 0.048; HFmrEF: log-rank 11.8, p = 0.008; HFrEF: log-rank 8.1, p = 0.044).Neurohormonal activation is present only in a subset of patients with HFpEF and HFmrEF, and may hold clinical significance. Neurohormonal antagonism may be useful in selected HFpEF/HFmrEF population.

Surgical resection, chemotherapy and radiotherapy were, for many years, the only available cancer treatments. Recently, the use of immune checkpoint inhibitors and adoptive cell therapies has emerged as promising alternative. These cancer immunotherapies are aimed to support or harness the patient’s immune system to recognize and destroy cancer cells. Preclinical and clinical studies, based on the use of T cells and more recently NK cells genetically modified with chimeric antigen receptors retargeting the adoptive cell therapy towards tumor cells, have already shown remarkable results. In this review, we outline the latest highlights and progress in immunotherapies for the treatment of Diffuse Large B-cell Lymphoma (DLBCL) patients, focusing on CD19-targeted immunotherapies. We also discuss current clinical trials and opportunities of using immunotherapies to treat DLBCL patients.

Aims Clinical trials and observational cohorts show that beneficial effects of sacubitril/valsartan are less strong in an appreciable proportion of patients with heart failure with reduced ejection fraction (HFrEF). Lower blood pressure and impaired renal function predict suboptimal sacubitril/valsartan titration and a less favourable response. Circulating renin encompasses neurohormonal activation, intravascular volume, and renal function. We hypothesized that renin may predict response to sacubitril/valsartan, assessed by changes in N‐terminal fraction of pro‐brain natriuretic peptide (NT‐proBNP). Methods and results We performed a prospective, open‐label, real‐life cohort study. The study population consisted of 80 consecutive HFrEF patients (age 66 ± 10 years, 83% men) planned to initiate sacubitril/valsartan. Clinical and biohumoral assessment, including a full neurohormonal panel, was performed at baseline and at 1, 3, and 6 month follow‐up. Response to sacubitril/valsartan was defined as ≥30% reduction in NT‐proBNP levels from baseline to 6 months. Patients in the lower renin tertile had higher blood pressure and plasma sodium concentration (all P

The tumour microenvironment (TME) is now recognised as a hallmark of cancer, since tumour:stroma crosstalk supports the key steps of tumour growth and progression. The dynamic co-evolution of the tumour and stromal compartments may alter the surrounding microenvironment, including the composition in metabolites and signalling mediators. A growing number of evidence reports the involvement of the endocannabinoid system (ECS) in cancer. ECS is composed by a complex network of ligands, receptors, and enzymes, which act in synergy and contribute to several physiological but also pathological processes. Several in vitro and in vivo evidence show that ECS deregulation in cancer cells affects proliferation, migration, invasion, apoptosis, and metastatic potential. Although it is still an evolving research, recent experimental evidence also suggests that ECS can modulate the functional behaviour of several components of the TME, above all the immune cells, endothelial cells and stromal components. However, the role of ECS in the tumour:stroma interplay remains unclear and research in this area is particularly intriguing. This review aims to shed light on the latest relevant findings of the tumour response to ECS modulation, encouraging a more in-depth analysis in this field. Novel discoveries could be promising for novel anti-tumour approaches, targeting the microenvironmental components and the supportive tumour:stroma crosstalk, thereby hindering tumour development.

Monitoring of heart rate characteristics (HRC) index may improve outcomes of late-onset neonatal sepsis (LOS) through early detection. We aimed at describing the association between LOS and elevated HRC index.This single-center retrospective case-control study included neonates who presented with blood culture-proven hospital-acquired LOS. Controls were matched to cases (ratio 1:2) based on gestational age, postnatal age, and birthweight. We compared the highest HRC indexes in the 48 h preceding blood culture sampling in LOS cases to the highest HRC indexes at the same postnatal days in controls.In 59 LOS cases and 123 controls, an HRC index 2 was associated with LOS (OR 7.1, 95% CI 2.6-19.0). Sensitivity and specificity of an HRC index 2 to predict LOS were 53% (32/59) and 79% (98/123). Sensitivity increased from 25% in infants born 32 weeks to 76% in infants born 28 weeks. Specificity decreased from 97% in infants 32 weeks to 63% in those born 28 weeks.An increase of HRC index 2 has a significant association with the diagnosis of LOS, supporting the use of HRC monitoring to assist early detection of LOS. Clinicians using HRC monitoring should be aware of its diagnostic accuracy and limitations in different gestational age groups.There is a paucity of data regarding the predictive value of heart rate characteristics (HRC) monitoring for early diagnosis of late-onset neonatal sepsis (LOS) in daily clinical practice. Monitoring of heart rate characteristics provides valuable information to assist the early diagnosis of LOS across all gestational age groups. However, the strong influence of gestational age on positive and negative predictive values adds complexity to the interpretation of HRC indexes.

Brain disease, in its many forms, has recently demonstrated a great socio-economic impact and represents one of the hardest challenges of present research. Although each pathology of this highly heterogenous group is characterized by individual features, there is an increasing number of common toxicological mechanisms that have been evidenced. This review aims to summarize the state-of-art knowledge concerning the role of environmental bacteria in brain diseases focusing on different mechanisms of action that could be interacting in an additive or synergistic way.For this wide-range subject, we focused on two emerging types of bacterial-derived brain exposure and damage and specifically treated representative examples: i) environmental bacterial-derived compounds in the form of the cyanobacterial product BMAA (β-N-methylamino-L-alanine) toxin and its isomers DAB (2,4-diaminobutyric acid) and AEG (N-(2-aminoethyl)glycine) and ii) toxicity related to bacterial infections in the form of the emerging Lyme neuroborreliosis (LNB), determined by Borrelia burgdorferi (Bb).Defined as pleiotropic contaminants, BMAA and Bb act through multiple toxicological pathways including inflammation, oxidative stress and excitotoxicity. Multiple investigations in in vitro and in vivo models have underlined the involved mechanisms of action but further investigations are needed to clarify the role of possible cocktail effects and underline possible new targets of intervention.Environmental bacteria represent emerging risk factors because of environmental changes, anthropogenic activities and human lifestyle evolutions. Future directions and research ambitions are here discussed in order to evaluate human risk and possible ways of intervention and prevention.

We studied the impact of HLA mismatching on the outcome of 318 consecutive patients who received an unmanipulated haploidentical bone marrow transplant, followed by post-transplant cyclophosphamide (PTCy). The number of HLA-mismatched antigens was tested for its impact on overall survival (OS) and nonrelapse mortality (NRM), whereas HLA mismatches in the graft-versus-host (GVH) direction were tested for prediction of graft-versus-host disease (GVHD and relapse. Finally, we studied whether graft rejection correlated with the number of HLA mismatched antigens in host-versus-graft (HVG) direction. Two hundred thirty-one donor–recipient pairs (72%) had 4/8 mismatches at the -A, -B, -C, -DRB1 HLA loci. HLA mismatches did not predict the 2-year OS (hazard ratio, .83; P = .58) and NRM (subhazard ratio, 1.08; P = .93). The cumulative incidence of acute GVHD (P = .13), 1-year chronic GVHD (P = .84), and relapse rate (P = .26) did not correlate with univectorial GVH mismatches. Similarly, no correlation was observed between the amount of HLA mismatch in the HVG direction and graft rejection. In multivariate analysis advanced disease at transplant was the strongest predictor of survival, NRM, relapse, and graft rejection. In conclusion, the degree of HLA mismatching should not be used as a criterion to select family haploidentical donors when using bone marrow as stem cell source and PTCy for GVHD prophylaxis.

Our aim was to develop and validate a predictive risk score for bronchopulmonary dysplasia (BPD), according to two clinically used definitions: 1. Need for supplementary oxygen during ≥ 28 cumulative days, BPD28, 2. Need for supplementary oxygen at 36 weeks postmenstrual age (PMA), BPD36. Logistic regression was performed in a national cohort (infants born in Switzerland with a birth weight < 1501 g and/or between 23 0/7 and 31 6/7 weeks PMA in 2009 and 2010), to identify predictors of BPD. We built the score as the sum of predicting factors, weighted according to their ORs, and analysed its discriminative properties by calculating the area under the ROC (receiver operating characteristic) curves (AUCs). This score was then applied to the Swiss national cohort from the years 2014–2015 to perform external validation. The incidence of BPD28 was 21.6% in the derivation cohort (n= 1488) and 25.2% in the validation cohort (n= 2006). The corresponding numbers for BPD36 were 11.3% and 11.1%, respectively. We identified gestational age, birth weight, antenatal corticosteroids, surfactant administration, proven infection, patent ductus arteriosus and duration of mechanical ventilation as independent predictors of BPD28. The AUCs of the BPD risk scores in the derivation cohort were 0.90 and 0.89 for the BPD28 and BPD36 definitions, respectively. The corresponding AUCs in the validation cohort were 0.92 and 0.88, respectively.Conclusion: This score allows for predicting the risk of a very low birth weight infant to develop BPD early in life and may be a useful tool in clinical practice and neonatal research.What is Known:• Many studies have proposed scoring systems to predict bronchopulmonary dysplasia (BPD).• Such a risk prediction may be important to identify high-risk patients for counselling parents, research purposes and to identify candidates for specific treatment.What is New:• A predictive risk score for BPD was developed and validated in a large national multicentre cohort and its performance assessed by two indices of accuracy.• The developed scoring system allows to predict the risk of BPD development early but also at any day of life with high validity.