Light-induced charge generation in polymeric nanoparticles restores vision in advanced-stage retinitis pigmentosa rats.

Retinal dystrophies such as Retinitis pigmentosa are among the most prevalent causes of inherited legal blindness, for which treatments are in demand. Retinal prostheses have been developed to stimulate the inner retinal network that, initially spared by degeneration, deteriorates in the late stages of the disease. We recently reported that conjugated polymer nanoparticles persistently rescue visual activities after a single subretinal injection in the Royal College of Surgeons rat model of Retinitis pigmentosa. Here we demonstrate that conjugated polymer nanoparticles can reinstate physiological signals at the cortical level and visually driven activities when microinjected in 10-months-old Royal College of Surgeons rats bearing fully light-insensitive retinas. The extent of visual restoration positively correlates with the nanoparticle density and hybrid contacts with second-order retinal neurons. The results establish the functional role of organic photovoltaic nanoparticles in restoring visual activities in fully degenerate retinas with intense inner retina rewiring, a stage of the disease in which patients are subjected to prosthetic interventions.

Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Gut-oriented interventions in patients with multiple sclerosis: fact or fiction?

OBJECTIVE: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, disimmune disease of the central nervous system whose etiology and pathogenesis remain poorly understood, due to its complex and multifactorial nature. Evidence of a bidirectional connection linking the gut microbiome with the intestinal barrier and the immune system (the gut-brain axis) may have implications for the pathogenesis of inflammatory demyelinating diseases such as MS. This narrative review summarizes the evidence for the gut-brain axis involvement in the pathogenesis of MS and examines the role of gut-oriented interventions in MS. PATIENTS AND METHODS: We reviewed all available studies in PubMed concerning gut-directed interventions and MS. This research was conducted using different combinations of pertinent keywords (multiple sclerosis, immune-mediated inflammatory diseases, autoimmune diseases, first demyelinating event, neurocognition, neurological disorders, neurology practice, risk factors, taxonomic biomarkers, nutrition, diet, dietary additives, complementary treatment, gut bacteria, gut microbiome, microbiome, gut-brain axis, epidemiology, alpha-linolenic acid, fermentative metabolites, fat, saturated fat, monounsaturated fat, polyunsaturated fat, omega-3 fatty acids, calorie restricted diet, fasting, fecal microbiome, fecal microbiota transplantation, animal testing). RESULTS: There is an emerging evidence that alterations in the gut microbiome and increased intestinal permeability may be causative factors in the complex interplay between nutrition, metabolic status and the immune-inflammatory response in patients with MS. This suggests the possibility that modification of lifestyle and the microbiome, for example by specific diets or fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers, may positively influence the pathogenesis of MS. CONCLUSIONS: Although the role of nutritional factors in the pathogenesis of MS remains to be established, there is evidence that appropriate gut-directed interventions such as diet, nutritional supplementation or fecal transplantation may modulate the inflammatory response and improve the course of MS as a complementary treatment in the disease.

Systematic review of medication related osteonecrosis of the jaw (MRONJ) in patients undergoing only antiangiogenic drug therapy: surgery or conservative therapy?

Osteonecrosis of the jaw is a severe adverse condition affecting patients exposed to specific types of medications. Previous studies have highlighted that osteonecrosis of the jaw is triggered by invasive dental procedures and can be very challenging to manage, especially in patients with cancer. The primary aim of this review was to analyse all available evidence on the management (surgical and/or conservative) of medication related osteonecrosis of the jaws (MRONJ) in patients with a history of antiangiogenic drugs therapy and who had not been previously exposed to any antiresorptive drug treatments. A multi-database search (PubMed, MEDLINE, EMBASE and CINAHL) was performed to identify related multi-language papers published from January 2003 until November 2020. Data were extracted from relevant papers and analysed according to the outcomes selected in this review. The search generated 28 studies eligible for the analysis. The total number of patients included in the analysis was 36. Sixteen patients were treated with anti-vascular endothelial growth factor drugs (anti-VEGF) while the remaining patients were administered a combination of antiangiogenic drugs. The most common MRONJ site was the mandible in 29 patients. MRONJ recurrence after treatment was only reported in six patients, the majority of which were treated conservatively. The data reviewed confirmed that an invasive procedure was the most common trigger of MRONJ with relatively high frequency of postoperative recurrence following treatment. However, due to the low quality of available research in the literature, it is difficult to draw a definitive conclusion on the validity of the presented treatment to manage patients affected by MRONJ associated with angiogenic therapy.

Is there any biomaterial substitute for peri-implant soft tissue phenotype modification? A network meta-analysis of the appraisal literature.

Evidence shows that an increased width and thickness of the keratinized mucosa favours peri-implant health. The aim of this network meta-analysis was to compare the clinical effects of alternative biomaterials for peri-implant soft tissue phenotype modification (PSPM) in patients with dental implants when compared to autologous tissue grafts. An electronic search without language or date limitations was performed in four databases and the grey literature for articles published until November 2020. The eligibility criteria included randomized clinical trials (RCTs) evaluating the clinical outcomes of biomaterials for PSPM. A pairwise and network meta-analysis was conducted for each parameter to assess and compare the outcomes between the different treatment arms for the primary and secondary outcomes. A total of 11 RCTs were included in this review. The free gingival graft (FGG) showed the best clinical effect for increasing keratinized mucosa width (KMW). When compared in a network, the FGG demonstrated the best treatment ranking of probability results, followed by connective tissue graft (CTG), acellular dermal matrix (ADM), and xenogeneic collagen matrix (XCM). For the parameters 'mucosa thickness' and 'participant satisfaction with aesthetics', the results were CTG > ADM > XCM and XCM > ADM > CTG, respectively. Autogenous tissue grafts (FGG/CTG) demonstrate the best results in increasing KMW and mucosa thickness when compared to the other biomaterials.

Evaluation of segmental mandibular resection without microvascular reconstruction in patients affected by medication-related osteonecrosis of the jaw: a systematic review.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe condition that affects the jaw in patients exposed to specific drugs. More often it has been described in association with bisphosphonates (BP), but nowadays it has been observed with the use of other medications, such as denosumab (a RANK ligand inhibitor and monoclonal antibody agent) and antiangiogenic drugs. Managing the condition has unfortunately proven difficult and still remains a major challenge for clinicians and surgeons. The aim of this systematic review was to identify and analyse the evidence on mandibular segmental resection in patients with advanced MRONJ. A multi-database (PubMed, MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials) systematic search was performed. Any type of study on human patients treated with antiresorptive and antiangiogenic drugs was considered. The primary aim was to understand the success of mandibular segmental resection in the short, medium, and long term, and to understand its effects before, during, and after the operation. The search yielded 11 studies that were eligible for analysis with a total of 67 patients. Of the 11 studies, seven reported no complications, and overall, postoperative complications were seen in 16 cases. Recurrence of osteonecrosis was reported in one study. The most common postoperative complication was removal of hardware (n = 11). The mean (SD) follow-up time for eight studies was 35.57 (17.73) months. According to the limited data available in the literature, mandibular segmental resection is a viable treatment that has been used successfully in patients with various stages of MRONJ. The data show a relatively high percentage of recurrence. Additional data based on a larger cohort of patients or case-control studies are necessary to justify routine use of this type of intervention in patients affected by the condition.

The role of illicit drugs in developing medication-related osteonecrosis (MRONJ): a systematic review.

Medication-related osteonecrosis of the jaw (MRONJ) is a challenging condition to treat. It has primarily been associated with anti-resorptive and anti-angiogenic drugs, which are increasingly being used to prevent adverse skeletally-related complications in patients with cancer and bone pathologies. Although these medications have been proven to cause osteonecrosis of the jaws (ONJ) there are also a number of other drugs that could potentially cause this condition. The aim of this systematic review is to ascertain whether there is an associated risk of osteonecrosis of the jaw (ONJ) in recreational drug users (RDU). Three authors independently searched PubMed, MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials for published reports of osteonecrosis of the jaw (ONJ) in recreational drug users (RDU) or illicit drug users (IDU) who had no history of treatment with anti-angiogenic or anti-resorptive agents. Only 30 studies were eligible for analysis, and all were independently assessed for risk of bias. There was a total of 101 patients with ONJ attributed solely to illicit drug consumption. The most common site of ONJ was the maxilla (n=54). The most common illicit drug related to ONJ was desmorphine, known as 'Krokodil', this was followed by cocaine, methamphetamine, anabolic steroids, and hydrocodone/acetaminophen. In 52 of the cases, the ONJ resolved following treatment, however, eight showed a recurrence. Although all the studies were judged to be at a high risk of bias, the limited data suggest that some patients are at risk of developing ONJ as a result of illicit drug usage. Studies of higher quality are needed to establish the relative risk of ONJ in this patient group.

Dedicated 3D-T2-STIR-ZOOMit Imaging Improves Demyelinating Lesion Detection in the Anterior Visual Pathways of Patients with Multiple Sclerosis.

BACKGROUND AND PURPOSE: Demyelinating lesions in the anterior visual pathways represent an underestimated marker of disease dissemination in patients with MS. We prospectively investigated whether a dedicated high-resolution MR imaging technique, the 3D-T2-STIR-ZOOMit, improves demyelinating lesion detection compared with the current clinical standard sequence, the 2D-T2-STIR. MATERIALS AND METHODS: 3T MR imaging of the anterior visual pathways (optic nerves, chiasm, and tracts) was performed using 3D-T2-STIR-ZOOMit and 2D-T2-STIR, in patients with MS and healthy controls. Two experienced neuroradiologists assessed, independently, demyelinating lesions using both sequences separately. 3D-T2-STIR-ZOOMit scan-rescan reproducibility was tested in 12 patients. The Cohen κ was used for interrater agreement, and the intraclass correlation coefficient for reproducibility. Between-sequence detection differences and the effects of location and previous acute optic neuritis were assessed using a binomial mixed-effects model. RESULTS: Forty-eight patients with MS with (n = 19) or without (n = 29) past optic neuritis and 19 healthy controls were evaluated. Readers' agreement was strong (3D-T2-STIR-ZOOMit: 0.85; 2D-T2-STIR: 0.90). The 3D-T2-STIR-ZOOMit scan-rescan intraclass correlation coefficient was 0.97 (95% CI, 0.96-0.98; P < .001), indicating excellent reproducibility. Overall, 3D-T2-STIR-ZOOMit detected more than twice the demyelinating lesions (n = 89) than 2D-T2-STIR (n = 43) (OR = 2.7; 95% CI, 1.7-4.1; P < .001). In the intracranial anterior visual pathway segments, 33 of the 36 demyelinating lesions (91.7%) detected by 3D-T2-STIR-ZOOMit were not disclosed by 2D-T2-STIR. 3D-T2-STIR-ZOOMit increased detection of demyelinating lesion probability by 1.8-fold in patients with past optic neuritis (OR = 1.8; 95% CI, 1.2-3.1; P = .01) and 5.9-fold in patients without past optic neuritis (OR = 5.9; 95% CI, 2.5-13.8; P < .001). No false-positive demyelinating lesions were detected in healthy controls. CONCLUSIONS: Dedicated 3D-T2-STIR-ZOOMit images improved substantially the detection of MS disease dissemination in the anterior visual pathways, particularly in the intracranial segments and in patients without past optic neuritis.

Real-life efficacy and safety of Ustekinumab as second- or third-line therapy in Crohn's disease: results from a large Italian cohort study.

OBJECTIVE: Ustekinumab (UST) is an anti-IL12/23 antibody for the treatment of Crohn's Disease (CD). The aim of this study was to compare the efficacy and safety of UST in a large population-based cohort of CD patients who failed previous treatment with other biologics. PATIENTS AND METHODS: 194 CD patients (108 males and 86 females, mean age 48 years (range 38-58 years) were retrospectively reviewed. 147 patients were already treated with anti-TNFα (75.8%), and 47 (24.2%) patients were already treated with anti-TNFα and vedolizumab. Concomitant treatment with steroids was present in 177 (91.2%) patients. RESULTS: At week 12, clinical remission was achieved in 146 (75.2%) patients. After a mean follow-up of 6 months, clinical remission was maintained in 135 (69.6%) patients; at that time, mucosal healing was assessed in 62 (31.9%) patients, and it was achieved in 33 (53.2) patients. Three (1.5%) patients were submitted to surgery. Steroid-free remission was achieved in 115 (59.3%) patients. Both serum C-Reactive Protein and Fecal Calprotectin (FC) levels were significantly reduced with respect to baseline levels during follow-up. A logistic regression, UST therapy as third-line therapy (after both anti-TNFα and vedolizumab), FC >200 µg/g, and HBI ≥8 were significantly associated with lack of remission. Adverse events occurred in 5 (2.6%) patients, and four of them required suspension of treatment. CONCLUSIONS: UST seemed to be really effective and safe in CD patients unresponsive to other biologic treatments, especially when used as second-line treatment.

Identifying the impact of the confinement of Covid-19 on emotional-mood and behavioural dimensions in children and adolescents with attention deficit hyperactivity disorder (ADHD).

The current study examined the impact of the lockdown due to the Covid-19 disease on mood state and behaviours of children and adolescents with ADHD. Nine hundred ninety-two parents of children and adolescents with ADHD filled out an anonymous online survey through the ADHD family association website. The survey investigated the degree of severity of six emotional and mood states (sadness, boredom, little enjoyment/interest, irritability, temper tantrums, anxiety) and five disrupted behaviours (verbal and physical aggression, argument, opposition, restlessness) based on their frequency/week (absent; low: 1-2 days/week; moderate: 3-4 days/week; severe: 5-7 days/week) before and during the lockdown. Important fluctuations were found in all dimensions during the lockdown independently by the severity degree. Subjects with previous low severity degree of these behaviors significantly worsened in almost all dimensions during the lockdown. On the contrary, ADHD patients with moderate and severe degree showed important improvement during the lockdown. Little enjoyment/interests and boredom resulted the dimensions more strongly affected by the condition of restriction, overall in children. Children vs. adolescents showed substantially similar trend but the former resulted significantly more vulnerable to emotive changes. The results provided both the individuation of domains affected, and the indirect benefits produced by restriction condition.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Infusion-related reactions during Natalizumab treatment: Do we still need a post-infusion observation period?

BACKGROUND: Natalizumab (NTZ) is a humanized monoclonal antibody used in the treatment of relapsing remitting multiple sclerosis. Although NTZ is usually well-tolerated, infusion-related reactions (IRRs) may occur, and the patients have to be monitored during the infusion and for one hour afterwards. OBJECTIVE: To identify frequency and severity of IRRs during NTZ infusions and one-hour post-infusion observation period in a clinical practice setting. METHODS: Multicenter, observational study involving three Swiss (Lugano, St. Gallen and Luzern) and two Italian (Milano and Napoli) tertiary MS centers. Predisposing factors to IRRs were investigated using multivariate Cox regression models. RESULTS: A total of 11'133 infusions received by 302 MS patients were analyzed (68.9% females, median age 33.6 years, median EDSS 2.5). IRRs occurred in 24 (8%) patients during NTZ infusions and in 7 (2%) during one-hour post-infusion. Only 8 patients needed pharmacological treatment, of whom 7 during NTZ infusion. Age, sex and history of allergies were not associated with risks for IRR. The frequency of post infusion IRRs after the fifth cycle was low compared to that during the first four infusions (0.83% vs 0.06%). CONCLUSION: In our cohort, NTZ associated IRR mainly occurred during the infusion period compared to the one-hour observational period. Also, the first IRR exclusively occurred within the first 4 NTZ administrations. However, further multi-center studies with a larger sample size are needed to capture rare and serious events that could emerge during the observational period and to make clinical recommendations.

Osteonecrosis and osteomyelitis of the jaw associated with tumour necrosis factor-alpha (TNF-α) inhibitors: a systematic review.

Tumour necrosis factor-α (TNF-α) inhibitors are increasingly being used as immunomodulators to manage inflammatory conditions such as rheumatoid arthritis and Crohn's disease. Reported serious side effects include an increased incidence of lymphoma and greater susceptibility to infections such as tuberculosis. The aim of this systematic review was to find out whether there is an associated risk of medication-related osteonecrosis of the jaw (MRONJ). Three authors independently searched PubMed, MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials for published reports of oral osteonecrosis (ONJ) or osteomyelitis (OM) in patients who took anti TNF-α drugs and had no history of antiangiogenic agents or antiresorptive treatment. All types of studies on humans treated with TNF-α inhibitors were considered. Only six were eligible for analysis, and all were independently assessed for risk of bias. They included six patients with ONJ or OM that was attributed solely to TNF-α inhibitors. The most common site of ONJ was the posterior mandible (n=5). The mean (SD) duration of anti-TNF-α treatment before the development of bony lesions was 62.5 (47.4) months. Invasive surgery was reported as a precipitating factor in five cases, and the ONJ/OM resolved with conservative management in five. Although all the studies were judged to be at high risk of bias, the limited data suggest that some patients will potentially develop ONJ/OM as a result of treatment with TNF-α inhibitors. Studies of higher quality are now needed to establish the relative risk of MRONJ in patients who take them.

Differential phenotype of immune cells in blood and milk following pegylated granulocyte colony-stimulating factor therapy during a chronic Staphylococcus aureus infection in lactating Holsteins.

Neutrophils are principal host innate immune cell responders to mastitis infections. Thus, therapies have been developed that target neutrophil expansion. This includes the neutrophil-stimulating cytokine granulocyte colony-stimulating factor (gCSF). Pegylated gCSF (PEG-gCSF; Imrestor, Elanco Animal Health, Greenfield, IN) has been shown to reduce the natural incidence of mastitis in periparturient cows in commercial settings and reduce severity of disease against experimental mastitis challenge. Pegylated gCSF stimulates neutrophil expansion but also induces changes in monocyte and lymphocyte circulating numbers, surface protein expression changes, or both. We hypothesized that PEG-gCSF modulates surface expression of monocytes and neutrophils and facilitates their migration to the mammary gland. We challenged 8 mid-lactation Holsteins with approximately 150 cfu of Staphylococcus aureus (Newbould 305) in a single quarter via intramammary infusion. All animals developed chronic infections as assessed by bacteria counts and somatic cell counts (SCC). Ten to 16 wk postchallenge, 4 of the animals were treated with 2 subcutaneous injections of PEG-gCSF 7 d apart. Complete blood counts, SCC, bacterial counts, milk yield, feed intake, neutrophils extracellular trap analysis, and flow cytometric analyses of milk and blood samples were performed at indicated time points for 14 d after the first PEG-gCSF injection. The PEG-gCSF-treated cows had significantly increased numbers of blood neutrophils and lymphocytes compared with control cows. Flow cytometric analyses revealed increased surface expression of myeloperoxidase (MPO) on neutrophils and macrophages in milk but not in blood of treated cows. Neutrophils isolated from blood of PEG-gCSF-treated cows had decreased surface expression of CD62L (L-selectin) in blood, consistent with cell activation. Surprisingly, CD62L cell surface expression was increased on neutrophils and macrophages sourced from milk from treated animals compared with cells isolated from controls. The PEG-gCSF-treated cows did not clear the S. aureus infection, nor did they significantly differ in SCC from controls. These findings provide evidence that PEG-gCSF therapy modifies cell surface expression of neutrophils and monocytes. However, although surface MPO+ cells accumulate in the mammary gland, the lack of bacterial control from these milk-derived cells suggests an incomplete role for PEG-gCSF treatment against chronic S. aureus infection and possibly chronic mammary infections in general.

Comorbidity of Attention Deficit Hyperactivity Disorder and Generalized Anxiety Disorder in children and adolescents.

The aim of the study is to explore the impact of Generalized Anxiety Disorder (GAD) comorbidity in children with Attention Deficit Hyperactivity Disorder (ADHD). Six hundred children with ADHD (mean age = 9.12 years), recruited from 2013 to 2017, participated in the study. A total of 96 (16%) children with ADHD displayed a comorbidity with GAD. ADHD + GAD were compared to 504 ADHD children without GAD in terms of cognitive and psychiatric profile, ADHD subtype and family psychiatric history. The ADHD + GAD, predominantly represented from ADHD combined (72.6%), displayed higher psychiatry comorbidity, in particular with depressive disorders, and were associated with higher rates of maternal depression, of ADHD in fathers, and bipolar disorders in second degree relatives. Moreover, younger preschool-primary school age children with ADHD + GAD showed significant higher frequency of depressive disorders versus younger preschool-primary children with ADHD without GAD. ADHD + GAD comorbidity represents a more complex clinical condition compared to ADHD without GAD, characterized by the higher frequency of multiple comorbidities and by a psychiatric family with higher rates of mood and disruptive disorders.

Superhydrophobic lab-on-chip measures secretome protonation state and provides a personalized risk assessment of sporadic tumour.

Secretome of primary cultures is an accessible source of biological markers compared to more complex and less decipherable mixtures such as serum or plasma. The protonation state (PS) of secretome reflects the metabolism of cells and can be used for cancer early detection. Here, we demonstrate a superhydrophobic organic electrochemical device that measures PS in a drop of secretome derived from liquid biopsies. Using data from the sensor and principal component analysis (PCA), we developed algorithms able to efficiently discriminate tumour patients from non-tumour patients. We then validated the results using mass spectrometry and biochemical analysis of samples. For the 36 patients across three independent cohorts, the method identified tumour patients with high sensitivity and identification as high as 100% (no false positives) with declared subjects at-risk, for sporadic cancer onset, by intermediate values of PS. This assay could impact on cancer risk management, individual's diagnosis and/or help clarify risk in healthy populations.

Evaluating Sex and Age Differences in ADI-R and ADOS Scores in a Large European Multi-site Sample of Individuals with Autism Spectrum Disorder.

Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology.

Use of robotic colonoscopy in patients with previous incomplete colonoscopy.

OBJECTIVE: Conventional colonoscopy (CC) is the gold standard to diagnostic and therapeutic approach to colon. However, in few cases, cecal intubation could fail due to colon anatomy, patient compliance and physician expertise. Endotics robotic colonoscopy is a novel, safe, mini-invasive modality to explore the entire colon. Our aim was to assess, in a retrospective study, Endotics ability of cecal intubation in all cases in which CC failed. PATIENTS AND METHODS: Between January 2008 and December 2012, 276 Endotics robotic colonscopy examinations were performed at the Gastroenterology and Metabolic Diseases Unit of Pisa University Hospital, Pisa, Italy, in a series of consecutive patients who had undergone CC and failed cecal intubation. RESULTS: We assessed the cecal intubation rate in 102 patients addressed to Endotics after previous incomplete CC. Overall, endotics system was successful in 93.1% of the incomplete conventional colonoscopy cases (95% performance). CONCLUSIONS: Whenever the intended exploration of the entire colon with CC failed, the endotics robotic endoscopy represented a useful tool as it helped examine the entire colon in almost all cases.

Brain Perivascular Spaces as Biomarkers of Vascular Risk: Results from the Northern Manhattan Study.

BACKGROUND AND PURPOSE: Dilated perivascular spaces in the brain are associated with greater arterial pulsatility. We hypothesized that perivascular spaces identify individuals at higher risk for systemic and cerebral vascular events. MATERIALS AND METHODS: Stroke-free participants in the population-based Northern Manhattan Study had brain MR imaging performed and were followed for myocardial infarction, any stroke, and death. Imaging analyses distinguished perivascular spaces from lesions presumably ischemic. Perivascular spaces were further subdivided into lesions with diameters of ≤3 mm (small perivascular spaces) and >3 mm (large perivascular spaces). We calculated relative rates of events with Poisson models and hazard ratios with Cox proportional models. RESULTS: The Northern Manhattan Study participants who had MR imaging data available for review (n = 1228; 59% women, 65% Hispanic; mean age, 71 ± 9 years) were followed for an average of 9 ± 2 years. Participants in the highest tertile of the small perivascular space score had a higher relative rate of all deaths (relative rate, 1.38; 95% CI, 1.01-1.91), vascular death (relative rate, 1.87; 95% CI, 1.12-3.14), myocardial infarction (relative rate, 2.08; 95% CI, 1.01-4.31), any stroke (relative rate, 1.79; 95% CI, 1.03-3.11), and any vascular event (relative rate, 1.74; 95% CI, 1.18-2.56). After we adjusted for confounders, there was a higher risk of vascular death (hazard ratio, 1.06; 95% CI, 1.01-1.11), myocardial infarction (hazard ratio, 2.22; 95% CI, 1.12-4.42), and any vascular event (hazard ratio, 1.04; 95% CI, 1.01-1.08) with higher small perivascular space scores. CONCLUSIONS: In this multiethnic, population-based study, participants with a high burden of small perivascular spaces had increased risk of vascular events. By gaining pathophysiologic insight into the mechanism of perivascular space dilation, we may be able to propose novel therapies to better prevent vascular disorders in the population.