Rare ATG7 genetic variants predispose patients to severe fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants. METHODS: We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level. RESULTS: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [OR] 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p <0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in the Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p <0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers. CONCLUSIONS: We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. LAY SUMMARY: We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation.

Pharmacokinetic profile of beclometasone dipropionate/formoterol fumarate administered through a novel dry-powder inhaler in Chinese healthy volunteers.

INTRODUCTION: An extrafine formulation of the inhaled corticosteroid beclometasone dipropionate (BDP) plus the long-acting ß2-agonist formoterol fumarate (FF) has been available for years via a pressurised metered-dose inhaler for the management of asthma and chronic obstructive pulmonary disease. More recently, the same extrafine BDP/FF formulation has become available in a multidose dry-powder inhaler (DPI) called the NEXThaler. The pharmacokinetics (PK) of BDP/FF via this DPI have previously been evaluated in a Caucasian population. The current study aimed to evaluate the PK profile of BDP/FF via DPI in healthy Chinese volunteers. The results were then compared to previous Caucasian data. METHODS: This open-label parallel group study randomised subjects to single-dose BDP/FF 200/12, 400/24, or 800/48 µg via DPI. Blood samples were taken up to 24 h post-dose for PK evaluation of BDP, beclometasone 17-monopropionate (B17MP, active metabolite of BDP) and formoterol. The primary objective of the study was to evaluate the PK of BDP/FF (BDP, B17MP and formoterol). The study is registered on the World Health Organization International Clinical Trials Registry Platform (ChiCTR1900021899). RESULTS: Of 36 subjects randomised, all completed the study. Following inhalation of all three doses, plasma concentration of formoterol and BDP increased rapidly, with peak mean values at the first post-dose timepoint (5 min), then rapidly decreasing; B17MP reached peak concentration slightly later. Plasma exposure to formoterol, BDP and B17MP increased broadly in a dose-proportional manner to BDP/FF dose, with tmax values similar across the dose range. All BDP/FF doses were generally well tolerated. CONCLUSIONS: Therapeutic and supra-therapeutic doses of BDP/FF administered via DPI resulted in approximately dose-proportional plasma exposure in healthy Chinese subjects, with PK profiles that were comparable to previous data from Caucasian subjects.

Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. METHODS: We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). RESULTS: In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10-5) and without cirrhosis (p <0.05). CONCLUSIONS: Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings. LAY SUMMARY: By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.

Comparison of the effect of beclometasone/formoterol in asthma patients after methacholine-induced bronchoconstriction: A noninferiority study using metered dose vs. dry powder inhaler.

AIMS: To demonstrate the noninferiority of extrafine beclomethasone/formoterol fumarate (BDP/FF) dry powder inhaler (DPI) vs. extrafine BDP/FF pressurized metered dose inhaler (pMDI; Foster® 100/6 µg NEXThaler and pMDI, respectively) in the onset of reliever effect after methacholine induced bronchospasm in asthmatic patients, evaluated in terms of forced expiratory volume in 1 s (FEV1 ) at 5 min postdose. The DPI provides an alternative device option for patients who cannot use a pMDI properly during an acute asthma attack. METHODS: Sixty-five patients received one inhalation of BDP/FF DPI, BDP/FF pMDI or placebo after methacholine challenge, according to a double-blind, double-dummy, cross-over design. Lung function and Borg dyspnoea score were assessed up to 30 min postdose. RESULTS: FEV1 adjusted mean difference between BDP/FF DPI and BDP/FF pMDI at 5 min postdose was 2 ml (95% confidence interval: -0.060; 0.065). A similar result was observed at the other time points. Median time to 85% recovery in FEV1 was 8 min for BDP/FF DPI, 7.5 min for BDP/FF pMDI and 28 min for placebo (P = 0.554 DPI vs. pMDI). The Borg score improved after treatment with both BDP/FF DPI and pMDI and the effect was greater than after placebo. Median time to reach 50% recovery was 4.2 min for BDP/FF DPI, 4.0 min for BDP/FF pMDI and 10.0 min for placebo (P = 0.609 DPI vs. pMDI). CONCLUSIONS: Extrafine Foster® NEXThaler, a flow-independent DPI, is comparable to extrafine Foster® pMDI when administered as reliever therapy after methacholine challenge, thus supporting the maintenance and reliever therapy approach also with Foster® NEXThaler.

Nutritional Online Information for Cancer Patients: a Randomized Trial of an Internet Communication Plus Social Media Intervention.

We hypothesized that cancer patients using an Internet website would show an improvement in the knowledge about healthy eating habits, and this might be enhanced by social media interaction. A 6-month randomized intervention was set up. Eligible subjects were allocated in intervention (IG) and control groups (CG). IG had access to the website, and CG was provided with printed versions. All enrolled participants filled in Nutrition Questionnaire (NQ), Quality of Life Questionnaire (QoL) and Psychological Distress Inventory (PDI), at baseline and after 6 months. The difference between post- vs pre-questionnaires was calculated. Seventy-four subjects (CG 39; IG 35) completed the study. There was an increase in the score after the intervention in both groups for the NQ, even if not statistically significant. Dividing the IG into three categories, no (NI), low (LI) and high interactions (HI), we found a decreased score (improvement) in the CG (-0.2) and in the HI (-1.7), and an increased score (worsening) in the NI (+3.3) (p = NS) analysing the PDI. We found an increased score in the QoL both in CG and IG (adjusted LSMeans +3.5 and +2.8 points, respectively; p = NS). This study represents an example for support cancer patients. Despite the lack of significant effects, critical points and problems encountered may be of interest to researchers and organization working in the cancer setting. Intervention strategies to support patients during the care process are needed in order to attain the full potential of patient-centred care on cancer outcomes.

The Paradox of Pelvic Exenteration: The Interaction of Clinical and Psychological Variables.

OBJECTIVES: To text the feasibility of a psychological intervention package administered to 49 pelvic exenteration candidates, aimed at evaluating the preoperative prevalence of psychological distress and assessing the presence of any correlation between preoperative psychological distress and clinical variables such as pain and hospitalization length. METHODS: Patients were referred to the psychology unit from the very beginning of their clinical pathway and were administered the Psychological Distress Inventory (PDI) and the Mini-Mental Adjustment to Cancer (Mini-MAC) questionnaire at prehospital admission. Patients presenting with a significant level of distress received nonstandardized psychological support. Statistical analyses were performed to detect the presence of any correlation between psychological variables at prehospital admission and clinical outcomes. RESULTS: The 40% of patients had significant levels of distress at prehospital admission (PDI ≥ 30). As regards Mini-MAC, the mean value of fighting spirit attitude and fatalism was higher in our sample than in the normative sample of the Mini-MAC validation study in the Italian cancer population. Their anxious preoccupation attitude was lower. There were no correlations between clinical and psychological variables: level of postsurgery pain was higher (3.7) in the subgroup of patients with presurgery PDI < 30 compared with those with PDI ≥ 30 (3.5). However, this difference was not statistically significant (P = 1.00). Considering hospitalization length, the above described trend was similar. CONCLUSIONS: Although highly distressed, pelvic exenteration candidates show an adaptive range of coping mechanisms. This calls for a greater effort in studying the complexity of their psychoemotional status to provide them with the best multidisciplinary care. Extensive study of the real effectiveness of psychological intervention is warranted: randomized clinical trials could help in detecting the presence of any correlation between clinical and psychological variables in a multidisciplinary approach.

Reporting combined outcomes with Trifecta and survival, continence, and potency (SCP) classification in 337 patients with prostate cancer treated with image-guided hypofractionated radiotherapy.

OBJECTIVE: To report the image-guided hypofractionated radiotherapy (hypo-IGRT) outcome for patients with localised prostate cancer according to the new outcome models Trifecta (cancer control, urinary continence, and sexual potency) and SCP (failure-free survival, continence and potency). PATIENTS AND METHODS: Between August 2006 and January 2011, 337 patients with cT1-T2N0M0 prostate cancer (median age 73 years) were eligible for a prospective longitudinal study on hypo-IGRT (70.2 Gy/26 fractions) in our Department. Patients completed four questionnaires before treatment, and during follow-up: the International Index of Erectile Function-5 (IIEF-5), the International Prostate Symptom Score (IPSS), and the European Organization for Research and Treatment of Cancer prostate-cancer-specific Quality of Life Questionnaires (QLQ) QLQ-PR25 and QLQ-C30. Baseline and follow-up patient data were analysed according to the Trifecta and SCP outcome models. Cancer control, continence and potency were defined respectively as no evidence of disease, score 1 or 2 for item 36 of the QLQ-PR25 questionnaire, and total score of >16 on the IIEF-5 questionnaire. Patients receiving androgen-deprivation therapy (ADT) at any time were excluded. RESULTS: Trifecta criteria at baseline were met in 72 patients (42% of all ADT-free patients with completed questionnaires). Both at 12 and 24 months after hypo-IGRT, 57% of the Trifecta patients at baseline were still meeting the Trifecta criteria (both oncological and functional success according to the SCP model). The main reason for failing the Trifecta criteria during follow-up was erectile dysfunction: in 18 patients after 6 months follow-up, in 12 patients after 12 months follow-up, and in eight patients after 24 months. Actuarial 2-year Trifecta failure-free survival rate was 44% (95% confidence interval 27-60%). In multivariate analysis no predictors of Trifecta failure were identified. Missing questionnaires was the main limitation of the study. CONCLUSION: The Trifecta and SCP classifications can be used as tools to report RT outcome.

Brain metastases from colorectal cancer: main clinical factors conditioning outcome.

BACKGROUND: The aim of our study is to evaluate the outcome of patients affected by brain metastases from colorectal cancer and to correlate the outcome with prognostic factors. METHODS: Patients were retrospectively evaluated. Survival distributions were estimated by using the Kaplan-Meier method. The log-rank test was used to assess the impact on survival of individual factors. RESULTS: Among 41 patients (25M and 16F; median age 58), 58.5 % had rectal cancer and 39 % synchronous metastatic disease; 95 % had extracranial metastases, most common site was lung (87.8 %). Seven patients had synchronous brain metastases. Median overall survival after diagnosis of brain metastases was 5 months [95 % confidence interval 3-12 months]. Median survival from brain metastases diagnosis was 4.2 months in patients treated with radiotherapy (29.3 %), 11.9 months in those with radio- and chemotherapy (21.9 %) and 21.4 months in those with surgery with/without radiotherapy or chemotherapy (29.3 %) (P < 0.0001). On multivariate analysis, no independent prognostic factors were found for disease-free interval from diagnosis to brain metastases and overall survival; amount of chemotherapy before brain metastases have no statistically significant relation to brain-metastases-free-interval even if patients who received more than one line of chemotherapy have a longer median brain-metastases-free-interval than those who received less than one. KRAS was found mutated in 17/28 patients without statistically significant correlation to outcome due to the small sample size. CONCLUSIONS: Prognosis of brain-metastases-patients is poor. An interesting tool is to evaluate the correlation of KRAS status and brain metastases with aim to tailor treatment and follow-up.

Image guided hypofractionated radiotherapy and quality of life for localized prostate cancer: prospective longitudinal study in 337 patients.

PURPOSE: We prospectively analyzed quality of life in a cohort of patients with prostate cancer undergoing a course of hypofractionated image guided radiotherapy. MATERIALS AND METHODS: Between August 2006 and January 2011, 337 patients with a median age of 73 years who had cT1-T2N0M0 prostate cancer were eligible for this prospective, longitudinal study of hypofractionated image guided radiotherapy (70.2 Gy/26 fractions) using 1 of 3 image guided radiotherapy modalities (transabdominal ultrasound, x-ray or cone beam computerized tomography) available in our radiation oncology department. Patients completed 4 questionnaires before treatment, and 6, 12 and 24 months later, including the International Index of Erectile Function-5, International Prostate Symptom Score, and EORTC (European Organization for Research and Treatment of Cancer) prostate cancer specific QLQ-PR25 and QLQ-C30. RESULTS: Patient followup was updated to at least the last questionnaire time point. Median followup was 19 months. Significant deterioration in erectile function on the International Index of Erectile Function-5 was documented with time only in patients without androgen deprivation (p = 0.0002). No change with time was observed in urinary symptom related quality of life on the QLQ-PR25 or International Prostate Symptom Score. Slight deterioration in QLQ-PR25 bowel symptom related quality of life was observed (p = 0.02). Overall QLQ-C30 Global Health Status improved with time (p = 0.03). On univariate analysis it significantly correlated with the maximum RTOG (Radiation Therapy Oncology Group)/EORTC urinary and bowel late toxicity scores after radiotherapy. CONCLUSIONS: The regimen of hypofractionated image guided radiotherapy with multiple imaging modalities adopted in our radiation oncology department for localized prostate cancer might be a successful strategy for dose escalation with a limited impact on different aspects of quality of life with time.

Reasons and Determinants of BoNT-A Treatment Discontinuation in Patients Living with Spasticity: A 10-Year Retrospective Analysis.

BACKGROUND: The present study aimed to evaluate the reasons and determinants of BoNT-A discontinuation in patients with stroke, multiple sclerosis, spinal cord injury, and traumatic brain injury. METHODS: It is a retrospective study of 56 discontinuer patients treated with botulinum toxin between January 2011 and December 2021. Discontinuation rates and their predictors were estimated using Kaplan-Meier, Log rank test, and Cox's regression method of analyses. RESULTS: The mean age was 56.54 years, 53.57% were affected by post-stroke spasticity, 17.86% by spinal cord injury, 12.5% and 16.07% by traumatic brain injury and multiple sclerosis, respectively. The median discontinuation time was 5 months. The main reason for discontinuation were logistic problems (37%) and orthopedic surgeries or intrathecal baclofen (27%). Discontinuers were more likely to have severe spasticity (R = 1.785), have no pain (HR = 1.320), no access to rehabilitation services (HR = 1.402), and have cognitive impairment (HR = 1.403). CONCLUSIONS: The main reasons for discontinuation are related to logistic issues (due to distance or the absence of an adequate caregiver) and surgical interventions for spasticity, including intrathecal baclofen. It is crucial to identify possible predictors of discontinuation to improve the effectiveness of a multidisciplinary management. The study confirms the crucial role of rehabilitation and caregivers in achieving better long-term outcomes.

Positive surgical margins after robotic assisted radical prostatectomy: a multi-institutional study.

PURPOSE: Positive surgical margins are an independent predictive factor for biochemical recurrence after radical prostatectomy. We analyzed the incidence of and associative factors for positive surgical margins in a multi-institutional series of 8,418 robotic assisted radical prostatectomies. MATERIALS AND METHODS: We analyzed the records of 8,418 patients who underwent robotic assisted radical prostatectomy at 7 institutions. Of the patients 323 had missing data on margin status. Positive surgical margins were categorized into 4 groups, including apex, bladder neck, posterolateral and multifocal. The records of 6,169 patients were available for multivariate analysis. The variables entered into the logistic regression models were age, body mass index, preoperative prostate specific antigen, biopsy Gleason score, prostate weight and pathological stage. A second model was built to identify predictive factors for positive surgical margins in the subset of patients with organ confined disease (pT2). RESULTS: The overall positive surgical margin rate was 15.7% (1,272 of 8,095 patients). The positive surgical margin rate for pT2 and pT3 disease was 9.45% and 37.2%, respectively. On multivariate analysis pathological stage (pT2 vs pT3 OR 4.588, p<0.001) and preoperative prostate specific antigen (4 or less vs greater than 10 ng/ml OR 2.918, p<0.001) were the most important independent predictive factors for positive surgical margins after robotic assisted radical prostatectomy. Increasing prostate weight was associated with a lower risk of positive surgical margins after robotic assisted radical prostatectomy (OR 0.984, p<0.001) and a higher body mass index was associated with a higher risk of positive surgical margins (OR 1.032, p<0.001). For organ confined disease preoperative prostate specific antigen was the most important factor that independently correlated with positive surgical margins (4 or less vs greater than 10 ng/ml OR 3.8, p<0.001). CONCLUSIONS: The prostatic apex followed by a posterolateral site was the most common location of positive surgical margins after robotic assisted radical prostatectomy. Factors that correlated with cancer aggressiveness, such as pathological stage and preoperative prostate specific antigen, were the most important factors independently associated with an increased risk of positive surgical margins after robotic assisted radical prostatectomy.

Concurrent cisplatin, continuous infusion fluorouracil and radiotherapy followed by tailored consolidation treatment in non metastatic anal squamous cell carcinoma.

BACKGROUND: To evaluate efficacy and feasibility of chemo-radiotherapy in patients with non-metastatic anal squamous-cell-cancer. METHODS: TNM staged anal squamous-cell cancer patients were treated with pelvic radiotherapy concomitant to continuous infusion fluorouracil plus cisplatin for at least 2 cycles. In T3-T4 or any T - N+ tumours or in "slow-responder" cases, 1-2 chemotherapy courses were subsequently administered. Tumour assessment was performed at baseline and 6-8 weeks after radiotherapy to evaluate response. RESULTS: 29 patients were enrolled: 4 males, 25 females; median age 57 years; baseline T1/T2/T3/T4 2/12/7/8; N involvement 17. Median dose pelvic radiotherapy was 59.4 Gy (range: 54-74). In 5 patients 2 chemotherapy courses, in 12 patients three and in 12 patients four courses were performed. At first evaluation, 27 CR (93.1%; 95% CI: 78% - 98%) and 2 SD were observed. Main grade (G) 3 toxic events were neutropenia (8%), diarrhoea (8%) and dermatitis (62%). Most frequent late events G3-G4 occurred in 14 patients: proctitis (5), dermatitis (4), bladder dysfunctions (2), sexual dysfunctions (9), lower extremity venous thromboses (2), dysuria (1), stenosis (1) and tenesmus (1). Five patients reported G1 leucopoenia. The rate of colostomy was 14%. After a median follow up of 42 months (range: 4-81), 20 patients are still alive without relapse and 3 died due to PD. The estimated 7-year DFS was 83.4% (C.I.: 68.3%-98.5%) and the estimated 7-year OS was 85.7% (C.I.: 70% - 100%). The 1-year and the estimated 7-year colostomy-free survivals were 85.9% (C.I.: 73.1% - 98.7%). CONCLUSIONS: Concurrent cisplatin plus fluorouracil and radiotherapy is associated with favourable local control rates and acute toxicity. Future investigations will be directed towards research into molecular biomarkers related to disease progression and resistance to chemo-radiotherapy and to the evaluation of new cytotoxic agents or targeted drugs, such as anti-epidermal growth factor receptor, concomitant to RT and to determining the role of intensity-modulated radiotherapy.

'LESS' radical prostatectomy: a pilot feasibility study with a personal original technique.

OBJECTIVE: We evaluated the feasibility and the potential advantages of a modification of the single-port laparoscopic radical prostatectomy using a periumbilical multichannel port plus a second port placed in the left fossa with the aim of having an adequate working angle during the most critical steps of the procedure. PATIENTS AND METHODS: Between March and September 2009 we operated on five patients with early-stage prostate cancer (T1c) and a normal body mass index (<25). The procedure was carried out with a specially-designed multichannel trocar which contains two 5 mm and one 10 mm ports plus a 5 mm port placed in the left iliac fossa in order to have an adequate working angle. The first two patients received a nerve sparing radical prostatectomy. RESULTS: All cases were completed successfully in a mean operative time of 225 minutes (range 210-250) with blood losses of less than 100 ml. All patients were discharged from the hospital in 3rd postoperative day and the catheter was always removed seven days from surgery. No intraoperative complications occurred. The pathological tumour stage revealed pT2bNo prostate cancer in all five cases without positive surgical margins. After a mean follow-up of 4 months (range 1-7) all patients have an undetectable prostate-specific antigen level and no postoperative early major complications. The first two patients were fully continent respectively after 3 and 8 weeks after surgery, the third patient uses one safety pad after three month from surgery. The last two patients have a moderate incontinence and are currently under rehabilitation. Regarding potency the first patient had intercourses without any therapies after two months from surgery while the second one (6 months follow up) has partial penile tumescence using oral vardenafil. CONCLUSION: Two ports laparoscopic radical prostatectomy is feasible in very selected cases. However, our pilot study should be still considered a technical report and the limits of the technique must still be defined in a larger population and by other investigators.

A systematic review and meta-analysis of the prognostic role of age in oral tongue cancer.

While evidence suggests an increasing incidence of tongue cancer in young adults, published findings regarding the prognostic role of age at diagnosis are inconsistent. We performed a meta-analysis of the literature to highlight key points that might help in understanding the association between age of oral tongue cancer patients at diagnosis and their prognosis. According to age at diagnosis, a systematic literature review of all published cohort studies assessing the recurrence risks and mortality associated with tongue cancer was conducted. We compared the risk estimates between patients aged >45 years and those aged <45 years at diagnosis. Random-effects models were used to calculate summary relative risk estimates (SRRs) according to different clinical outcomes and sources of between-study heterogeneity (I2 ) and bias. We included 31 independent cohort studies published between 1989 and 2019; these studies included a total of 28,288 patients. When risk estimations were not adjusted for confounders, no significant association was found between age at diagnosis and overall survival (OS). Conversely, after adjustment for confounders, older age at diagnosis was associated with a significantly increased risk of mortality. The difference between SRRs for adjusted and unadjusted estimates was significant (p < 0.01). Younger patients had a significantly higher risk of local recurrence. Younger patients with oral tongue cancer have better OS but a greater risk of recurrence than older patients. These findings should be validated in a large prospective cohort study which considers all confounders and prognostic factors.

Transcranial Direct Current Stimulation Combined with Botulinum Neurotoxin Type A Injections for Treatment of Upper Limb Intention Tremor in Multiple Sclerosis: A Case Report.

Upper limb intention tremor is a common cause of disability in multiple sclerosis (MS). Transcranial direct current stimulation (tDCS) is an emerging form of brain stimulation used to improve sensorimotor impairments in many neurological disorders. Here, we describe a combined therapeutic approach with botulinum neurotoxin type A (BoNT-A) and tDCS for the treatment of upper limb tremor in a patient with MS. We administered a cathodal tDCS 15 days after the injections of BoNT-A. Both post-injection and post-stimulation evaluation revealed a considerable improvement of the tremor. This approach positively affected the patient's activities of daily living. Our case report shows a safe and beneficial effect of tDCS in the treatment of action tremor in MS especially as a possible adjunctive synergic treatment with BoNT-A injections.

Ischemic Stroke in a 29-Year-Old Patient with COVID-19: A Case Report.

Increasing evidence reports a greater incidence of stroke among patients with Coronavirus disease 2019 (COVID-19) than the non-COVID-19 population and suggests that SARS-CoV-2 infection represents a risk factor for thromboembolic and acute ischemic stroke. Elderly people have higher risk factors associated with acute ischemic stroke or embolization vascular events, and advanced age is strongly associated with severe COVID-19 and death. We reported, instead, a case of an ischemic stroke in a young woman during her hospitalization for COVID-19-related pneumonia. A 29-year-old woman presented to the emergency department of our institution with progressive respiratory distress associated with a 2-day history of fever, nausea, and vomiting. The patient was transferred to the intensive care unit (ICU) where she underwent a tracheostomy for mechanical ventilation due to her severe clinical condition and her very low arterial partial pressure of oxygen. The nasopharyngeal swab test confirmed SARS-CoV-2 infection. Laboratory tests showed neutrophilic leucocytosis, a prolonged prothrombin time, and elevated D-dimer and fibrinogen levels. After 18 days, during her stay in the ICU after suspension of the medications used for sedation, left hemiplegia was reported. Central facial palsy on the left side, dysarthria, and facial drop were present, with complete paralysis of the ipsilateral upper and lower limbs. Computed tomography (CT) of the head and magnetic resonance imaging of the brain confirmed the presence of lesions in the right hemisphere affecting the territories of the anterior and middle cerebral arteries, consistent with ischemic stroke. Pulmonary and splenic infarcts were also found after CT of the chest. The age of the patient and the absence of serious concomitant cardiovascular diseases place the emphasis on the capacity of SARS-CoV-2 infection to be an independent cerebrovascular risk factor. Increased levels of D-dimer and positivity to ß2-glycoprotein antibodies could confirm the theory of endothelial activation and hypercoagulability, but other mechanisms - still under discussion - should not be excluded.

Discontinuation of botulinum neurotoxin type-A treatment during COVID-19 pandemic: an Italian survey in post stroke and traumatic brain injury patients living with spasticity.

BACKGROUND: The COVID-19 pandemic has affected health-care systems worldwide, including the outpatient spasticity care with botulinum neurotoxin toxin type A (BoNT-A). AIM: The aim of this study was to investigate the impact of discontinuation of BoNT-A treatment on patients living with spasticity during the COVID-19 quarantine. DESIGN: A multicentric cross-sectional study. SETTING: Outpatients setting. POPULATION: Patients with spasticity after stroke and traumatic brain injury treated with BoNT-A. METHODS: A phone-based survey was conducted from March to May, 2020. Based on the International Classification of Functioning, Disability and Health (ICF), an ad hoc questionnaire CORTOX (CORonavirus TOXin survey) was developed to investigate patients' experiences following the discontinuation of their usual treatment for spasticity due to the lockdown and its implication on their health perception. It assessed patients' condition and explored different ICF domains related to spasticity: unpleasant sensations, mobility, self-care, facilitators and psychosocial factors. The sum of those represented the CORTOX score (Max 142). The questionnaire also collected data about the impact of COVID-19 on patients' wellbeing (mood, sleep, relationships, community life, motivation). RESULTS: A total of 151 participants completed the survey. Most participants (72.2%) experienced a worsening in perceived spasticity, 53% got worse in independence and 70.9% had a negative impact on quality of life. The mean CORTOX score was 52.85±27.25, reflecting a perceived worsening in all ICF domains investigated. Moderate to strong correlations were found between different sub-scores of the questionnaire and severity of spasticity (P<0.001). COVID-19 psychosocial related factors were associated with loss of independence (P<0.05) but only mood was associated with worsening of spasticity (P<0.001). The lack of rehabilitation therapy was significantly associated with the worsening of independence but not with the worsening of spasticity. Finally, respondents reported that BoNT-A was useful to their condition and should not be discontinued. CONCLUSIONS: The discontinuation of BoNT-A treatment was associated with worsening of activities and participation and perceived spasticity. COVID-19 related problems and rehabilitation showed an association with loss of independence. CLINICAL REHABILITATION IMPACT: This study will provide useful information in the field of spasticity management using a patient's centred approach, with consistent quantitative and qualitative information.

SARS-CoV-2 seroprevalence trends in healthy blood donors during the COVID-19 outbreak in Milan.

BACKGROUND: The Milan metropolitan area in Northern Italy was among the most severely hit by the SARS-CoV-2 outbreak. The aim of this study was to examine the seroprevalence trends of SARS-CoV-2 in healthy asymptomatic adults, and the risk factors and laboratory correlates of positive tests. MATERIALS AND METHODS: We conducted a cross-sectional study in a random sample of blood donors, who were asymptomatic at the time of evaluation, at the beginning of the first phase (February 24th to April 8th 2020; n=789). Presence of IgM/IgG antibodies against the SARS-CoV-2-Nucleocapsid protein was assessed by a lateral flow immunoassay. RESULTS: The test had a 100/98.3 sensitivity/specificity (n=32/120 positive/negative controls, respectively), and the IgG test was validated in a subset by an independent ELISA against the Spike protein (n=34, p<0.001). At the start of the outbreak, the overall adjusted seroprevalence of SARS-CoV-2 was 2.7% (95% CI: 0.3-6%; p<0.0001 vs 120 historical controls). During the study period, characterised by a gradual implementation of social distancing measures, there was a progressive increase in the adjusted seroprevalence to 5.2% (95% CI: 2.4-9.0; 4.5%, 95% CI: 0.9-9.2% according to a Bayesian estimate) due to a rise in IgG reactivity to 5% (95% CI: 2.8-8.2; p=0.004 for trend), but there was no increase in IgM+ (p=not significant). At multivariate logistic regression analysis, IgG reactivity was more frequent in younger individuals (p=0.043), while IgM reactivity was more frequent in individuals aged >45 years (p=0.002). DISCUSSION: SARS-CoV-2 infection was already circulating in Milan at the start of the outbreak. The pattern of IgM/IgG reactivity was influenced by age: IgM was more frequently detected in participants aged >45 years. By the end of April, 2.4-9.0% of healthy adults had evidence of seroconversion.