Laryngeal features in Lipoid proteinosis: a systematic review and meta-analysis of individual participant data.

PURPOSE: Lipoid proteinosis (LP) or Urbach-Wiethe disease (OMIM 247100) is a rare syndrome characterised by early vocal folds infiltration and subsequent multi-organ involvement. LP is often unrecognised and its associated hoarseness is overlooked. The main objective of the study was to investigate hoarseness in LP and implement a diagnosis among otolaryngologists. METHODS: PubMed/MEDLINE and OMIM databases were systematically searched. Authors concentrated the search on published articles starting from the discovery of the pathogenesis of LP by Hamada et al. in 2002. Only cases in which a diagnosis was reported both clinically and through biopsy and/or genetic molecular testing were included. Characteristics of the LP cases were extracted from each included study. Results were obtained through Generalized Estimating Equations. RESULTS: The search strategy yielded 217 articles, of which 74 (34.1%) met the selection criteria. A total of 154 cases were included. Hoarseness was described in all LP cases and clearly stated as the onset symptom in 68.8%. The onset was on average at 19 months of age (CI: 3.00-20.00), while the mean age at diagnosis was 15 years (CI: 10.00-30.00). Therefore, the diagnostic delay amounted to 13.42 years (CI: 8.00-23.83). Hoarseness alone was responsible for an LP diagnosis in only 14.3% of cases. In 43.5% of cases, genetic analysis of the ECM1 gene was performed and exon 6 was the most frequently altered portion. CONCLUSION: Analysing the largest number of published cases, the study underlined that hoarseness is the key symptom for diagnosing LP since early childhood, though frequently overlooked.

Residents' satisfaction and suggestions to improve nephrology residency in Italy, and comparison with the organization in other European countries.

BACKGROUND: In Italy, nephrology residency is available in twenty-one nephrology schools, each with its own strengths and weaknesses. The present study is aimed at exploring the residents' satisfaction with their training programs. METHODS: Between April 20th and May 19th, 2021, a questionnaire on residency satisfaction consisting of 49 items was sent to 586 residents and 175 recently certified specialists (qualified to practice as nephrologists in 2019 and 2020), with a response rate of 81% and 51%, respectively. The teaching organization was contextualized with a survey involving 13 European nephrology schools. RESULTS: Most residency fellowship programs received a good rating with regard to "satisfaction", in particular for the following items: number of hospitalizations followed-up, chronic hemodialysis training, follow-up of transplanted patients, diagnosis and treatment of glomerulonephritis. The teachings that were identified as being of lower quality or insufficient intensity included vascular access management, ultrasound diagnostics and renal nutrition. The need for improvement in formal teaching programs was underlined. Young nephrologists were rather satisfied with their salary and with the quality of the work they were doing, but only few were interested in an academic career since it was generally held that it is "too difficult" to obtain a university position. Many young nephrologists who filled in the questionnaire felt that lack of experience in peritoneal dialysis and vascular access management was a barrier to finding an ideal job. Compared to other European training programs, the Italian program differs with regard to longer exposure to nephrology (as compared to internal medicine), and greater flexibility for internships in different settings, including abroad. CONCLUSIONS: This first nationwide survey on the satisfaction of residents in nephrology indicates that, despite rather good overall satisfaction, there is room for improvement to make nephrology a more appealing choice and to fulfill the needs of a growing number of renal disease patients.

Multi-parametric MRI in the diagnosis and scoring of gastrointestinal acute graft-versus-host disease.

OBJECTIVES: Acute gastrointestinal graft-versus-host disease (GI-aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Diagnosis relies on clinical, endoscopic, and pathological investigations. Our purpose is to assess the value of magnetic resonance imaging (MRI) in the diagnosis, staging, and prediction of GI-aGVHD-related mortality. METHODS: Twenty-one hematological patients who underwent MRI for clinical suspicion of acute GI-GVHD were retrospectively selected. Three independent radiologists, blinded to the clinical findings, reanalyzed MRI images. The GI tract was evaluated from stomach to rectum by analyzing fifteen MRI signs suggestive of intestinal and peritoneal inflammation. All selected patients underwent colonoscopy with biopsies. Disease severity was determined on the basis of clinical criteria, identifying 4 stages of increasing severity. Disease-related mortality was also assessed. RESULTS: The diagnosis of GI-aGVHD was histologically confirmed with biopsy in 13 patients (61.9%). Using 6 major signs (diagnostic score), MRI showed 84.6% sensitivity and 100% specificity in identifying GI-aGVHD (AUC = 0.962; 95% confidence interval 0.891-1). The proximal, middle, and distal ileum were the segments most frequently affected by the disease (84.6%). Using all 15 signs of inflammation (severity score), MRI showed 100% sensitivity and 90% specificity for 1-month related mortality. No correlation with the clinical score was found. CONCLUSION: MRI has proved to be an effective tool for diagnosing and scoring GI-aGVHD, with a high prognostic value. If larger studies will confirm these results, MRI could partly replace endoscopy, thus becoming the primary diagnostic tool for GI-aGVHD, being more complete, less invasive, and more easily repeatable. KEY POINTS: • We have developed a new promising MRI diagnostic score for GI-aGVHD with a sensitivity of 84.6% and specificity of 100%; results are to be confirmed by larger multicentric studies. • This MRI diagnostic score is based on the six MRI signs most frequently associated with GI-aGVHD: small-bowel inflammatory involvement, bowel wall stratification on T2-w images, wall stratification on post-contrast T1-w images, ascites, and edema of retroperitoneal fat and declivous soft tissues. • A broader MRI severity score based on 15 MRI signs showed no correlation with clinical staging but high prognostic value (100% sensitivity, 90% specificity for 1-month related mortality); these results also need to be confirmed by larger studies.

A decade of WHO 2010: total sperm number temporal trend and role of lifestyle factors.

After a huge decline in sperm concentration between 1938 and 1991 was reported, many researchers investigated the possibility of a worsening of human sperm quality. Despite massive efforts, published evidence is still controversial. Similarly, the role of lifestyle factors on semen parameters is debated. We conducted a monocentric Italian study to evaluate the total sperm number trend over the last 10 years (from 2010 to 2019). Additionally, we evaluated the association between lifestyle factors and total sperm number in order to identify possible damaging factors. We performed a retrospective study analyzing subjects aged 18-55 years who had their semen analyzed between 2010 and 2019. A total of 3329 subjects were included: 1655 subjects referred to our department (Department of Experimental Medicine, Sapienza University of Rome, Roma, Italy) for idiopathic infertility and 1674 subjects referred for preconceptional or andrological screening with no confirmed andrological diseases. Semen samples were examined according to World Health Organization (WHO) 2010 criteria by two seminologists with the same training and the same equipment. For statistical evaluations, only total sperm number (×10 6 per ejaculate) was taken into consideration. We detected no significant changes in mean total sperm number during the last decade, in either the entire population or the two subgroups (infertile group and control group). In a multivariate analysis total sperm number was significantly associated with the history of infertility, body mass index (BMI) and cigarette smoking. Our results suggest that infertile men are "vulnerable" subjects, particularly susceptible to several negative factors, many of which still remain unknown. Our study highlights the need for studies addressing men's lifestyle in order to find and reduce deleterious agents.

The ADA (Age-D-Dimer-Albumin) Score to Predict Thrombosis in SARS-CoV-2.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-related pneumonia is associated with venous and arterial thrombosis. Aim of the study was to find out a new score for predicting thrombosis in patients with SARS-CoV-2. METHODS: We included a cohort of 674 patients affected by SARS-CoV-2, not requiring intensive care units, and followed-up during the hospitalization until discharge. Routine analyses performed at in-hospital admission included also serum albumin and D-dimer while arterial and venous thromboses were the endpoints of the study. RESULTS: During the follow-up, 110 thrombotic events were registered; patients with thrombotic events were older and had lower albumin and higher D-dimer, compared with thrombotic event-free ones. On multivariable logistic regression with step-by-step procedure age, serum albumin, and D-dimer were independently associated with thrombotic events. The linear combination of age, D-dimer, and albumin allowed to build-up the ADA (age-D-dimer-albumin) score, whose area under the curve (AUC) was 0.752 (95% confidence interval [CI], 0.708-0.795). ADA score was internally validated by bootstrap sampling procedure giving an AUC of 0.752 (95% CI: 0.708-0.794). CONCLUSION: Combination of age, D-dimer, and albumin in the ADA score allows identifying SARS-CoV-2 patients at higher risk of thrombotic events.

Impact of Prior Antibiotic Use in Primary Care on Escherichia coli Resistance to Third Generation Cephalosporins: A Case-Control Study.

Research is lacking on the reversibility of antimicrobial resistance (AMR). Thus, we aimed to determine the influence of previous antibiotic use on the development and decay over time of third generation cephalosporin (3GC)-resistance of E. coli. Using the database of hospital laboratories of the Autonomous Province of Bolzano/Bozen (Italy), anonymously linked to the database of outpatient pharmaceutical prescriptions and the hospital discharge record database, this matched case-control study was conducted including as cases all those who have had a positive culture from any site for 3GC resistant E. coli (3GCREC) during a 2016 hospital stay. Data were analyzed by conditional logistic regression. 244 cases were matched to 1553 controls by the date of the first isolate. Male sex (OR 1.49, 95% CI 1.10-2.01), older age (OR 1.11, 95% CI 1.02-1.21), the number of different antibiotics taken in the previous five years (OR 1.20, 95% CI 1.08-1.33), at least one antibiotic prescription in the previous year (OR 1.92, 95% CI 1.36-2.71), and the diagnosis of diabetes (OR 1.57, 95% CI 1.08-2.30) were independent risk factors for 3GCREC colonization/infection. Patients who last received an antibiotic prescription two years or three to five years before hospitalization showed non-significant differences with controls (OR 0.97, 95% CI 0.68-1.38 and OR 0.85, 95% CI 0.59-1.24), compared to an OR of 1.92 (95% CI 1.36-2.71) in those receiving antibiotics in the year preceding hospitalization. The effect of previous antibiotic use on 3GC-resistance of E. coli is highest after greater cumulative exposure to any antibiotic as well as to 3GCs and in the first 12 months after antibiotics are taken and then decreases progressively.

Baseline CD44v6-positive circulating tumor cells to predict first-line treatment failure in patients with metastatic colorectal cancer.

CD44v6, the CD44 isoform mostly involved in cancer cell migration and invasion, has been identified as a functional biomarker and therapeutic target in colon cancer stem cells. We here provide evidence that baseline CD44v6-positive CTC predict treatment failure in patients with metastatic colorectal cancer undergoing first-line chemotherapy. We suggest that CD44v6-positive CTC can be used to early detect intrinsic drug resistance in this cancer type.

Does the length of uniportal video-assisted thoracoscopic lobectomy affect postoperative pain? Results of a randomized controlled trial.

BACKGROUND: Uniportal video-assisted thoracoscopic surgery (VATS) lobectomy has become a common approach for the treatment of early stage lung cancer. Here, we aimed to establish whether the length of uniportal incision could affect postoperative pain and surgical outcomes in consecutive patients undergoing uniportal VATS lobectomy for early stage lung cancer. METHODS: This was a unicenter Randomized Control Trial (NCT03218098). Consecutive patients undergoing uniportal VATS lobectomy for Stage I lung cancer were randomly assigned to a Small Incision group or Long Incision group in 1:1 ratio based on whether patients received a 4 cm or 8 cm incision. The endpoints were to compare the intergroup difference regarding (i) postoperative pain measured by brief pain inventory (BPI) questionnaire (first endpoint); (ii) operative time; (iii) length of chest drainage; (iv) length of hospital stay; (v) postoperative complications; and (vi) pulmonary functional status (secondary endpoints). RESULTS: A total of 48 patients were eligible for the study. Four patients were excluded; the study population included 44 patients: 23 within the Small Incision group, and 21 within the Long Incision group. The 11 BPI scores between the two groups showed no significant difference. Small Incision group presented higher operative time than Long Incision group (138.69 vs. 112.14 minutes; P = 0.0001) while no significant differences were found regarding length of hospital stay (P = 0.95); respiratory complications (P = 0.92); FEV1% (P = 0.63), and 6-Minute Walking Test (P = 0.77). CONCLUSIONS: A larger incision for uniportal VATS lobectomy significantly reduced the operative time due to better exposure of the anatomical structures without increasing postoperative pain or affecting the surgical outcome. KEY POINTS: A larger incision for uniportal VATS lobectomy significantly reduced the operative time due to better exposure of the anatomical structures without increasing postoperative pain or affecting the surgical outcome. To perform a larger incision could be a valuable strategy, particularly in nonexpert hands or when the patient's anatomy or tumor size make exposure of anatomic structures through smaller incisions difficult.

MRI reveals different Crohn's disease phenotypes in children and adults.

OBJECTIVES: To identify differences between two cohorts of adult and pediatric patients affected by Crohn's disease (CD), with regard to lesion location in the small intestine and colon-rectum, lesion activity, and prevalence of perianal disease (PD), using MRI as the main diagnostic tool. METHODS: We retrospectively reviewed 350 consecutive MRI examinations performed between 2013 and 2016 in outpatients or inpatients with histologically proven CD, monitored by the Gastroenterology and Pediatric Units of our Hospital. The magnetic resonance enterography (MRE) protocol for adult and pediatric CD patients routinely includes evaluation of nine different intestinal segments (from jejunum to rectum) and of the anal canal. Intestinal activity was also calculated using a validated score. Perianal disease (PD) was staged. Fisher's exact test was used and the odds ratio (OR) was calculated. RESULTS: Two hundred and nineteen out of 350 MRI studies (118 adults and 101 children) were included. The prevalence of PD was 34.6% in children and 16.1% in adults (OR = 2.8; p = 0.0017). Pediatric patients showed more frequent rectal involvement (29.7% vs 13.5%, OR = 2.7; p = 0.0045) and higher risk of PD in the presence of rectal disease (p = 0.043; OR = 4.5). In pediatric patients with severe colorectal disease, the prevalence of PD was twofold (86.7% vs 40%; p = 0.072). Using the clinical Montreal classification for lesion location, no significant differences emerged between the two patient populations. CONCLUSIONS: MRI showed a significantly higher prevalence of rectal involvement and perianal disease in the pediatric population. These results may have a relevant clinical impact and deserve further investigation. KEY POINTS: • To our knowledge, this is the largest morphological comparative study available in the literature using MRI as the main diagnostic tool to compare adult patients and children with Crohn's disease. • Our study showed significant differences between adults and children: a higher prevalence of rectal and perianal fistulous disease (PD) in pediatric patients and an increased prevalence of PD in the presence of severe colon-rectum involvement. • The association of rectal and perianal disease implies a poorer clinical prognosis and a higher risk of disabling complications in pediatric patients.

Differential Redox State Contributes to Sex Disparities in the Response to Influenza Virus Infection in Male and Female Mice.

Influenza virus replicates intracellularly exploiting several pathways involved in the regulation of host responses. The outcome and the severity of the infection are thus strongly conditioned by multiple host factors, including age, sex, metabolic, and redox conditions of the target cells. Hormones are also important determinants of host immune responses to influenza and are recently proposed in the prophylaxis and treatment. This study shows that female mice are less susceptible than males to mouse-adapted influenza virus (A/PR8/H1N1). Compared with males, PR8-infected females display higher survival rate (+36%), milder clinical disease, and less weight loss. They also have milder histopathological signs, especially free alveolar area is higher than that in males, even if pro-inflammatory cytokine production shows slight differences between sexes; hormone levels, moreover, do not vary significantly with infection in our model. Importantly, viral loads (both in terms of viral M1 RNA copies and tissue culture infectious dose 50%) are lower in PR8-infected females. An analysis of the mechanisms contributing to sex disparities observed during infection reveals that the female animals have higher total antioxidant power in serum and their lungs are characterized by increase in (i) the content and biosynthesis of glutathione, (ii) the expression and activity of antioxidant enzymes (peroxiredoxin 1, catalase, and glutathione peroxidase), and (iii) the expression of the anti-apoptotic protein Bcl-2. By contrast, infected males are characterized by high expression of NADPH oxidase 4 oxidase and phosphorylation of p38 MAPK, both enzymes promoting viral replication. All these factors are critical for cell homeostasis and susceptibility to infection. Reappraisal of the importance of the host cell redox state and sex-related effects may be useful in the attempt to develop more tailored therapeutic interventions in the fight against influenza.

Correction to: Major adverse cardiovascular events in non-valvular atrial fibrillation with chronic obstructive pulmonary disease: the ARAPACIS study.

In the original publication, one of the ARAPACIS collaborators Dr. "Leonardo Di Gennaro" name has been erroneously mentioned as "Leonardo De Gennaro".

Neurophysiological correlates of bradykinesia in Parkinson's disease.

Many neurophysiological abnormalities have been described in the primary motor cortex of patients with Parkinson's disease. However, it is unclear whether there is any relationship between them and bradykinesia, one of the cardinal motor features of the condition. In the present study we aimed to investigate whether objective measures of bradykinesia in Parkinson's disease have any relationship with neurophysiological measures in primary motor cortex as assessed by means of transcranial magnetic stimulation techniques. Twenty-two patients with Parkinson's disease and 18 healthy subjects were enrolled. Objective measurements of repetitive finger tapping (amplitude, speed and decrement) were obtained using a motion analysis system. The excitability of primary motor cortex was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and facilitation. Plasticity-like mechanisms in primary motor cortex were indexed according to the amplitude changes in motor-evoked potentials after the paired associative stimulation protocol. Patients were assessed in two sessions, i.e. OFF and ON medication. A canonical correlation analysis was used to test for relationships between the kinematic and neurophysiological variables. Patients with Parkinson's disease tapped more slowly and with smaller amplitude than normal, and displayed decrement as tapping progressed. They also had steeper input/output curves, reduced short-interval intracortical inhibition and a reduced response to the paired associative stimulation protocol. Within the patient group, bradykinesia features correlated with the slope of the input/output curve and the after-effects of the paired associative stimulation protocol. Although dopaminergic therapy improved movement kinematics as well as neurophysiological measures, there was no relationship between them. In conclusion, neurophysiological changes in primary motor cortex relate to bradykinesia in patients with Parkinson's disease, although other mechanisms sensitive to dopamine levels must also play a role.

Major adverse cardiovascular events in non-valvular atrial fibrillation with chronic obstructive pulmonary disease: the ARAPACIS study.

Chronic obstructive pulmonary disease (COPD) increases the risk of mortality in non-valvular atrial fibrillation (NVAF) patients. Data on the relationship of COPD to major cardiovascular events (MACE) in AF have not been defined. The aim of the study is to assess the predictive value of COPD on incident MACE in NVAF patients over a 3-year follow-up. In the Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study (ARAPACIS) cohort, we evaluate the impact of COPD on the following clinical endpoints: MACE (including vascular death, fatal/non-fatal MI and stroke/TIA), cardiovascular (CV) death and all-cause mortality. Among 2027 NVAF patients, patients with COPD (9%) are more commonly male, elderly and at higher thromboembolic risk. During a median 36.0 months follow-up, 186 patients experienced MACE: vascular death (n = 72), MI (n = 57), stroke/TIA (n = 57). All major outcomes (including stroke/TIA, MI, vascular death, and all-cause death) are centrally adjudicated. Kaplan-Meier curves show that NVAF patients with COPD are at higher risk for MACE (p < 0.001), CV death (p < 0.001) and all-cause death (p < 0.001). On Cox proportional hazard analysis, COPD is an independent predictor of MACE (Hazard ratio [HR] 1.77, 95% Confidence Intervals [CI] 1.20-2.61; p = 0.004), CV death (HR 2.73, 95% CI 1.76-4.23; p < 0.0001) and all-cause death (HR 2.16, 95% CI 1.48-3.16; p < 0.0001). COPD is an independent predictor of MACE, CV death and all-cause death during a long-term follow-up of NVAF patients.

Epstein-Barr virus lytic infection promotes activation of Toll-like receptor 8 innate immune response in systemic sclerosis monocytes.

BACKGROUND: Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma; SSc), with increased expression of interferon (IFN)-regulatory genes and inflammatory cytokines, suggesting dysregulation of the innate immune response in autoimmunity. In this study, we investigated whether the lytic form of Epstein-Barr virus (EBV) infection (infectious EBV) is present in scleroderma monocytes and contributes to their activation in SSc. METHODS: Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) depleted of the CD19+ cell fraction, using CD14/CD16 negative-depletion. Circulating monocytes from SSc and healthy donors (HDs) were infected with EBV. Gene expression of innate immune mediators were evaluated in EBV-infected monocytes from SSc and HDs. Involvement of Toll-like receptor (TLR)8 in viral-mediated TLR8 response was investigated by comparing the TLR8 expression induced by infectious EBV to the expression stimulated by CL075/TLR8/agonist-ligand in the presence of TLR8 inhibitor in THP-1 cells. RESULTS: Infectious EBV strongly induced TLR8 expression in infected SSc and HD monocytes in vitro. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were upregulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally induced TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral mRNA and proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes. CONCLUSION: This study provides the first evidence of infectious EBV in monocytes from patients with SSc and links EBV to the activation of TLR8 and IFN innate immune response in freshly isolated SSc monocytes. This study provides the first evidence of EBV replication activating the TLR8 molecular pathway in primary monocytes. Immunogenicity of infectious EBV suggests a novel mechanism mediating monocyte inflammation in SSc, by which EBV triggers the innate immune response in infected cells.

Carotid plaque detection improves the predictive value of CHA2DS2-VASc score in patients with non-valvular atrial fibrillation: The ARAPACIS Study.

BACKGROUND AND AIMS: Vascular disease (VD), as assessed by history of myocardial infarction or peripheral artery disease or aortic plaque, increases stroke risk in atrial fibrillation (AF), and is a component of risk assessment using the CHA2DS2-VASc score. We investigated if systemic atherosclerosis as detected by ultrasound carotid plaque (CP) could improve the predictive value of the CHA2DS2-VASc score. METHODS: We analysed data from the ARAPACIS study, an observational study including 2027 Italian patients with non-valvular AF, in whom CP was detected using Doppler Ultrasonography. RESULTS: VD was reported in 351 (17.3%) patients while CP was detected in 16.6% patients. Adding CP to the VD definition leaded to higher VD prevalence (30.9%). During a median [IQR] follow-up time of 36months, 56 (2.8%) stroke/TIA events were recorded. Survival analysis showed that conventional VD alone did not increase the risk of stroke (Log-Rank: 0.009, p=0.924), while addition of CP to conventional VD was significantly associated to an increased risk of stroke (LR: 5.730, p=0.017). Cox regression analysis showed that VD+CP was independently associated with stroke (HR: 1.78, 95% CI: 1.05-3.01, p=0.0318). Reclassification analysis showed that VD+CP allowed a significant risk reclassification when compared to VD alone in predicting stroke at 36months (NRI: 0.192, 95% CI: 0.028-0.323, p=0.032). CONCLUSIONS: In non-valvular AF patients the addition of ultrasound detection of carotid plaque to conventional VD significantly increases the predictive value of CHA2DS2-VASc score for stroke.

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer.

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8(+) and CD4(+) T cells. A differential compartmentalization was detected between Helios(high) and Helios(low) Treg subsets (thymus-derived versus peripherally induced): while Helios(low) Tregs were enriched in both sites, only Helios(high) Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression.

Ankle-Brachial Index and cardiovascular events in atrial fibrillation. The ARAPACIS Study.

Atrial fibrillation (AF) patients are at high risk for thrombotic and vascular events related to their cardiac arrhythmia and underlying systemic atherosclerosis. Ankle-Brachial Index (ABI) is a non-invasive tool in evaluating systemic atherosclerosis, useful in predicting cardiovascular events in general population; no data are available in AF patients. ARAPACIS is a prospective multicentre observational study performed by the Italian Society of Internal Medicine, analysing association between low ABI (≤ 0.90) and vascular events in NVAF out- or in-patients, enrolled in 136 Italian centres. A total of 2,027 non-valvular AF (NVAF) patients aged > 18 years from both sexes followed for a median time of 34.7 (interquartile range: 22.0-36.0) months, yielding a total of 4,614 patient-years of observation. Mean age was 73 ± 10 years old with 55 % male patients. A total of 176 patients (8.7 %) experienced a vascular event, with a cumulative incidence of 3.81 %/patient-year. ABI≤ 0.90 was more prevalent in patients with a vascular event compared with patients free of vascular events (32.2 vs 20.2 %, p< 0.05). On Cox proportional hazard analysis, ABI≤ 0.90 was an independent predictor of vascular events (hazard ratio (HR): 1.394, 95 % confidence interval (CI): 1.042-1.866; p=0.02), vascular death (HR: 2.047, 95 % CI: 1.255-3.338; p=0.004) and MI (HR: 2.709, 95 % CI: 1.485-5.083; p=0.001). This latter association was also confirmed after excluding patients with previous MI (HR: 2.901, 95 % CI: 1.408-5.990, p=0.004). No association was observed between low ABI and stroke/transient ischaemic attack (p=0.91). In conclusion, low ABI is useful to predict MI and vascular death in NVAF patients and may independently facilitate cardiovascular risk assessment in NVAF patients.

Correlation among periodontal health status, maternal age and pre-term low birth weight.

PURPOSE: To assess correlations between periodontal status, maternal age and adverse pregnancy outcomes, such as pre-term and low birth weight in a sample of pregnant women. METHODS: Study population was represented by outpatient pregnant women, gestational age > 26 weeks. Medical history questionnaires were administered to all participants who underwent clinical evaluation; clinical obstetric outcome records were collected after delivery. A questionnaire was administered regarding personal information, socio-economic status, oral hygiene habits, and oral health conditions. A clinical oral examination was performed to collect Simplified Oral Hygiene Index (OHI-S) and Community Periodontal Index (CPI). Pregnancy outcome records included: delivery week, kind and causes of delivery, any relevant complications, and birth weight. Descriptive statistics were used to depict the data from the questionnaire while the relationship between delivery week, birth weight, maternal age and periodontal status was evaluated through multivariate tests of significance. RESULTS: 88 pregnant women were enrolled in the study. The results showed a statistically significant correlation (P< 0.001) among participants older than 40 years of age, between periodontal disease and adverse pregnancy outcomes. No statistical correlation was found among pre-term and low birth weight, smoking, ethnicity and educational level of mothers. The results highlight the importance of including a routine oral and periodontal health examination in pregnant women older than 40 years of age. CLINICAL SIGNIFICANCE: The correlation between periodontal status and adverse pregnancy outcomes in older mothers indicates the need for routine oral health examination and periodontal status assessment and care in pregnant women older than 40 years of age.