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Background: The etiology of pediatric-onset multiple sclerosis is unknown although putative genetic and environmental factors appear to be involved. Among children multiple sclerosis onset occurs closer to the susceptibility window thank in adults and the exposure to etiological environmental factors is more informative. An Italian multicentre case-control study (the PEDiatric Italian Genetic and enviRonment ExposurE, PEDIGREE study ) was designed to investigate environmental exposures in pediatric-onset multiple sclerosis and their interaction with genetics., Objectives: To collect evidence on exposures to environmental risk factors in pediatric-onset multiple sclerosis, a questionnaire was developed for the Italian population (PEDIGREE Questionnaire) and is presented., Methods: PEDIGREE Questionnaire develops from an existing tool used in case-control studies on pediatric-onset multiple sclerosis in US Americans, and was translated, adapted and tested for the contents perceived relevance, acceptability, feasibility and reliability in a population of Italian pediatric subjects and their parents recruited from clinics and general population., Results: PEDIGREE Questionnaire contents were overall deemed relevant by the study population, acceptable for 100% participants and feasible for at least 98%. PEDIGREE Questionnaire degree of reliability ranged 56% to 72%., Conclusion: PEDIGREE Questionnaire proves to be an efficient tool to assess environmental exposures in the Italian pediatric population. We encourage the dissemination of population-specific questionnaires and shared methodology to optimize efforts in MS etiological research., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2021.)

Background: Short-term outcomes of optic neuritis (ON) have been well characterized. Limited data exists on longer-term visual outcomes in patients who present with ON. The large MSBase registry allows for characterization of long-term visual outcomes after ON., Methods: Via the MSBase Registry, data on patients from 41 centers was collected during routine clinical and research visits. Physical and visual disability were measured using the expanded disability status scale (EDSS) and the visual function score (VFS). Inclusion criteria for this analysis included age ≥ 18 years, clinically isolated syndrome (CIS), ON-onset, baseline visit within 6 months of onset, and at least one follow-up visit. Survival analysis was used to evaluate the association of disease-modifying treatment with time to conversion to clinically definite MS or sustained EDSS/VFS progression., Results: Data from 60,933 patients were obtained from the MSBase registry in July 2019. Of these, 1317 patients met inclusion criteria; 935 were treated at some point in disease course, while 382 were never treated. At baseline, mean age was 32.3 ± 8.8 years, 74% were female, median EDSS was 2 (IQR 1-2), and median VFS was 1 (IQR 0-2). Median follow-up time was 5.2 years (IQR 2.4-9.3). Treatment was associated with reduced risk and delayed conversion to clinically definite MS (HR = 0.70, p < 0.001), sustained EDSS progression (HR = 0.46, p < 0.0001) and sustained VFS (HR = 0.41, p < 0.001) progression., Conclusions: In the MSBase cohort, treatment after ON was associated with better visual and neurological outcomes compared to no treatment. These results support early treatment for patients presenting with ON as the first manifestation of MS., (Copyright © 2021. Published by Elsevier B.V.)

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups., Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation., Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants., Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5)., Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

Background and Objectives: Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work we aim to predict disability progression by optimally extracting information from longitudinal patient data in the real-world setting, with a special focus on the sporadic sampling problem., Methods: We use machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization. A subset of 6682 patients from the MSBase registry is used., Results: We can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.85, which represents a 32% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features., Conclusions: Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction and represents a step forward towards AI-assisted precision medicine in MS., Competing Interests: Declaration of Competing Interest The authors declare the following conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: To test the hypothesis that combined resistance and endurance training would improve muscle strength, fatigue, depression, and quality of life in persons with MS. Methods: Twenty-seven women with MS were randomly assigned to either control (CON, n = 13) or the experimental (EXP, n = 14) group. The participants in the EXP group trained twice a week for 12 weeks, followed by 12 weeks of detraining. Both CON and EXP groups were tested before and after 12 weeks of the intervention period, as well as 12 weeks after training cessation (follow-up), where measures of muscle strength, fatigue, depression, and quality of life were evaluated. Results: There were significant changes in maximal voluntary isometric contraction (MVIC), 1RM leg extension, and 1RM chest press following the intervention period in the EXP group ( P < 0.05), but not in the CON group ( P > 0.05). These changes persisted after 12 weeks of detraining. Similar findings were found for fatigue, depression, and physical and mental composites of quality of life. Conclusion: These results suggest that combined exercise training, at a minimum, prevents the disease-related deterioration of muscular performance and quality of life and well-being in persons with MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Correale, Buzzachera, Liberali, Codrons, Mallucci, Vandoni, Montomoli and Bergamaschi.)

Objective: To identify baseline factors associated with disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) under teriflunomide treatment., Methods: This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment., Results: At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75 years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity (especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0-4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007)., Conclusions: Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Background: A recent Norwegian moratorium challenged the status quo of transanal total mesorectal excision for rectal cancer by reporting increased early multifocal local recurrences., Objective: The aim of this systematic review and meta-analysis was to evaluate the local recurrence rates following transanal total mesorectal excision as well as to assess statistical, clinical, and methodological bias in reports published to date., Data Sources: The PubMed and MEDLINE (via Ovid) databases were systematically searched., Study Selection: Descriptive or comparative studies reporting rates of local recurrence at a median follow-up of 6 months (or more) after transanal total mesorectal excision were included., Interventions: Patients underwent transanal total mesorectal excision., Main Outcome Measures: Local recurrence was any recurrence located in the pelvic surgery site. The untransformed proportion method of 1-arm meta-analysis was utilized. Untransformed percent proportion with 95% confidence interval was reported. Ad hoc meta-regression with the Omnibus test was utilized to assess risk factors for local recurrence. Among-study heterogeneity was evaluated: statistically by I2 and τ2, clinically by summary tables, and methodologically by a 33-item questionnaire., Results: Twenty-nine studies totaling 2906 patients were included. The pooled rate of local recurrence was 3.4% (2.7%-4.0%) at an average of 20.1 months with low statistical heterogeneity (I2 = 0%). Meta-regression yielded no correlation between complete total mesorectal excision quality (p = 0.855), circumferential resection margin (p = 0.268), distal margin (p = 0.886), and local recurrence rates. Clinical heterogeneity was substantial. Methodological heterogeneity was linked to the excitement of novelty, loss aversion, reactivity to criticism, indication for transanal total mesorectal excision, nonprobability sampling, circular reasoning, misclassification, inadequate follow-up, reporting bias, conflict of interest, and self-licensing., Limitations: The studies included had an observational design and limited sample and follow-up., Conclusion: This systematic review found a pooled rate of local recurrence of 3.4% at 20 months. However, given the substantial clinical and methodological heterogeneity across the studies, the evidence for or against transanal total mesorectal excision is inconclusive at this time., Competing Interests: Twenty-nine studies totaling 2906 patients were included. The pooled rate of local recurrence was 3.4% (2.7%–4.0%) at an average of 20.1 months with low statistical heterogeneity (I2 = 0%). Meta-regression yielded no correlation between complete total mesorectal excision quality (p = 0.855), circumferential resection margin (p = 0.268), distal margin (p = 0.886), and local recurrence rates. Clinical heterogeneity was substantial. Methodological heterogeneity was linked to the excitement of novelty, loss aversion, reactivity to criticism, indication for transanal total mesorectal excision, nonprobability sampling, circular reasoning, misclassification, inadequate follow-up, reporting bias, conflict of interest, and self-licensing., (Copyright © The ASCRS 2021.)

In the pain management evolution, opioid-free analgesia and multimodal analgesia strategies have emerged as feasible in many surgical settings including colorectal surgery. This was a retrospective cohort study including patients having undergone elective bowel resection between February 2012 and June 2018 aiming to evaluate whether there was reduction in opioid use after implementation of opioid-free analgesia in one medical centre. Trend analysis was conducted using Joinpoint regression employing nine-month intervals. The primary outcome for each interval was the proportion of patients receiving postoperative opioid-free analgesia, defined as forgoing all opioid analgesics after the day of surgery. This study showed a significant increasing trend in opioid-free analgesia in elective bowel resection from 0 to 42.5% over 4.5 years.

Background: The aim of this study was to assess failure rates following nonoperative management of acute diverticulitis complicated by abscess and trends thereof., Method: Pubmed, MEDLINE, EMBASE, CINAHL, Cochrane Library, and Web of Science were systematically searched. Nonoperative management was defined as a combination of nil per os, IV fluids, IV antibiotics, CT scan-guided percutaneous drainage, and total parenteral nutrition. The primary endpoint was failure of nonoperative management defined as persistent or worsening abscess and/or sepsis, development of new complications, such as peritonitis, ileus, or colocutaneous fistula, and urgent surgery within 30-90 days of index admission. Data were stratified by three arbitrary time intervals: 1986-2000, 2000-2010, and after 2010. The primary outcome was calculated for those groups and compared., Results: Thirty-eight of forty-four eligible studies published between 1986 and 2019 were included in the quantitative synthesis of data (n = 2598). The pooled rate of failed nonoperative management was 16.4% (12.6%, 20.2%) at 90 days. In studies published in 2000-2010 (n = 405), the pooled failure rate was 18.6% (10.5%, 26.7%). After 2000 (n = 2140), the pooled failure rate was 15.3% (10.7%, 20%). The difference was not statistically significant (p = 0.725). After controlling for heterogeneity in the definition of failure of nonoperative management, subgroup analysis yielded the pooled rate of failure of 21.8% (16.1%, 27.4%)., Conclusion: This meta-analysis found that failure rates following nonoperative management of acute diverticulitis complicated by abscess did not significantly decrease over the past three decades. The general quality of published data and the level and certainty of evidence produced were low.

Objective: To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort., Methods: Using data from the MSBase Registry, we included pregnancies conceived after 31 Dec 2010 from women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse, and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses., Results: We included 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41-0.91], p=0.016). 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum., Conclusion: Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation, with early re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications., (© 2021 American Academy of Neurology.)

Background: The aim of this meta-analysis was to evaluate whether adoption of DaVinci Xi ® had any impact upon intra- and postoperative metrics in colorectal surgery., Methods: The Pubmed, CINAHL, Cochrane Library and MEDLINE (Ovid) databases were systematically searched. Operating time as well as docking and surgeon console times were the primary endpoints. Conversion and postoperative complication rates were the secondary endpoints., Results: Six studies totaling 610 patients (320 Si and 290 Xi) were included. Total operating time [MD (95% CI) = 30.553 (15.071, 46.035); p < 0.001], docking time [MD (95% CI) = 4.178 (2.120, 6.235); p < 0.001] and surgeon console time [MD (95% CI) = 17.246 (-0.479, 34.971); p = 0.056] were longer in DaVinci Si ® as compared to DaVinci Xi ® . No significant difference was found in conversion (p = 0.816) and postoperative complication rates (p = 0.405)., Conclusion: This meta-analysis found that the adoption of DaVinci Xi ® was associated with significantly decreased total operating time as well as docking and surgeon console times. Conversion and complication rates were similar., (© 2021 John Wiley & Sons Ltd.)

Background and Aims: No consensus exists on how aggressively to treat relapsing-remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC)., Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups., Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5-11.7) years. Mean annual delta-EDSS values were all significantly ( p  < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01-0.19, p  = 0.03) at 1 year to 0.30 (0.07-0.53, p  = 0.009) at 5 years and to 0.67 (0.31-1.03, p  = 0.0003) at 10 years., Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time., Competing Interests: Conflict of interest statement: All the authors report no competing interest related to this specific project. The authors report no conflicts of interest with respect to the contents of the current study, but note that the patients in the study were treated with a number of disease modifying drugs and that authors Pietro Iaffaldano, Giuseppe Lucisano, Francesca Caputo, Damiano Paolicelli, Francesco Patti, Mauro Zaffaroni, Vincenzo Brescia Morra, Carlo Pozzilli, Giovanna De Luca, Matilde Inglese, Giuseppe Salemi, Giorgia Teresa Maniscalco, Eleonora Cocco, Patrizia Sola, Giacomo Lus, Antonella Conte, Maria Pia Amato, Franco Granella, Claudio Gasperini, Paolo Bellantonio, Rocco Totaro, Marco Rovaris, Marco Salvetti, Valentina Liliana Adriana Torri Clerici, Roberto Bergamaschi, Davide Maimone, Elio Scarpini, Marco Capobianco, Giancarlo Comi, Massimo Filippi and Maria Trojano report having received advisory board membership, speaker’s honoraria, travel support, research grants, consulting fees, or clinical trial support from the manufacturers of those drugs, including Actelion, Allergan, Almirall, Bayer Schering, Biogen, Celgene, Excemed, Genzyme, Forward Pharma, Ipsen, Medday, Merck, Merz, Mylan, Novartis, Sanofi, Roche, Teva, and their local affiliates., (© The Author(s), 2021.)

Transanal minimally invasive surgery (TAMIS) can be performed robotically assisted (R-TAMIS) for easier rectal defect suture closure particularly on the anterior rectal wall. The surgical technique described in this technical note emphasizes three safety points: 1) decreased likelihood for rectal injury when the ports are inserted into the GelPOINT® Path Transanal Access Platform (Applied Medical, Rancho Santa Margarita, California) on the back table rather than being inserted into the rectum; 2) decreased external collision between ports when using ports of different length; and 3) increased stabilization of pneumorectum when insufflating with an AirSeal™ port (Intelligent Flow System, ConMed, Utica, New York). Although R-TAMIS can be safely performed with the da Vinci® Si® or Xi® (Intuitive Surgical Inc., Sunnyvale, California) patient cart, the following differences are noteworthy: a) the Si® vertically-mounted arms design forces the patient in an uncomfortable position with asymmetrical hip flexion as opposed to the Xi® boom-mounted horizontal arm design; b) the 28cm circumference of each Si® patient cart arms operating between the patient's legs offer decreased maneuvering freedom as opposed to the 19cm circumference of the Xi® counterparts; and c) the abduction pattern of movement of the Si® arms potentially increases the risk of external collision with the patient's legs as opposed to the Xi® "jack-knife" pattern of movement.

Technology has had a dramatic impact on how diseases are diagnosed and treated. Although cut, sew, and tie remain the staples of surgical craft, new technical skills are required. While there is no replacement for live operative experience, training outside the operating room offers structured educational opportunities and stress modulation. A stepwise program for acquiring new technical skills required in robotic surgery involves three modules: ergonomic, psychomotor, and procedural. This is a prospective, educational research protocol aiming at evaluating the responsiveness of general surgery residents in Robotic-Assisted Surgery Training (RAST). Responsiveness is defined as change in performance over time. Performance is measured by the following content-valid metrics for each module. Module 1 proficiency in ergonomics includes: cart deploy, boom control, cart driving, camera port docking, targeting anatomy, flex joint, clearance joint and port nozzle adjusting, and routine and emergent undocking. Module 2 proficiency in psychomotor skills includes tissue handling, accuracy error, knot quality, and operating time. Module 3 proficiency in procedural skills prevents deviations from standardized sequential procedural steps in order to test length of specimen resection, angle for transection, vessel stump length post ligation, distance of anastomosis from critical landmarks, and proximal and distal resection margins. Resident responsiveness over time will be assessed comparing the results of baseline testing with final testing. Educational interventions will include viewing one instructional video prior to module commencement, response to module-specific multiple-choice questions, and individual weekly training sessions with a robotic instructor in the operating room. Residents will progress through modules upon successful final testing and will evaluate the educational environment with the Dundee Ready Educational Environment Measure (DREEM) inventory. The RAST program protocol outlined herein is an educational challenge with the primary endpoint to provide evidence that formal instruction has an impact on proficiency and safety in executing robotic skills.

Minimally invasive surgery has rapidly evolved from the once novel laparoscopic approach to advanced robotic surgery. In the past few decades alone, robotic systems have gone from systems which were significantly limited to full-fledged platforms featuring 3D vision, articulated instruments, integrated ultrasound and fluorescence capabilities, and even the latest wireless connectivity, as is now standard. In this review, we aimed to summarize features of currently commercialized and utilized robotic surgical systems as well as currently unfolding platforms. The pros and cons of different robotic surgical systems were discussed. In addition, we discussed the future perspectives of robotic platforms used in general surgery. In this regard, we emphasized that the market, once dominated by Intuitive Surgical Inc., has become occupied by several worthy competitors with new technological giants such as Google. Eventually, the question facing hospital systems will not be of whether or not to invest in robotic surgery, but instead of how they will strike balance between price, features, and availability when choosing robots from the growing market to best equip their surgeons.

Aim: There is not sufficient evidence about whether stool DNA methylation tests allow prioritizing patients to colonoscopy. Due to the COVID-19 pandemic, there will be a wait-list for rescheduling colonoscopies once the mitigation is lifted. The aim of this meta-analysis was to evaluate the accuracy of stool DNA methylation tests in detecting colorectal cancer., Methods: The PubMed, Cochrane Library and MEDLINE via Ovid were searched. Studies reporting the accuracy (Sackett phase 2 or 3) of stool DNA methylation tests to detect sporadic colorectal cancer were included. The DerSimonian-Laird method with random-effects model was utilized for meta-analysis., Results: Forty-six studies totaling 16 149 patients were included in the meta-analysis. The pooled sensitivity and specificity of all single genes and combinations was 62.7% (57.7%, 67.4%) and 91% (89.5%, 92.2%), respectively. Combinations of genes provided higher sensitivity compared to single genes (80.8% [75.1%, 85.4%] vs. 57.8% [52.3%, 63.1%]) with no significant decrease in specificity (87.8% [84.1%, 90.7%] vs. 92.1% [90.4%, 93.5%]). The most accurate single gene was found to be SDC2 with a sensitivity of 83.1% (72.6%, 90.2%) and a specificity of 91.2% (88.6%, 93.2%)., Conclusions: Stool DNA methylation tests have high specificity (92%) with relatively lower sensitivity (81%). Combining genes increases sensitivity compared to single gene tests. The single most accurate gene is SDC2, which should be considered for further research., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)

Background: Coronavirus disease 2019 (COVID-19) raises particular concerns for people with multiple sclerosis (PwMS) on disease-modifying treatments (DMTs), and for physicians caring for them. The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on PwMS receiving DMTs that inhibit immune cell trafficking, such as natalizumab (NTZ) and fingolimod (FTY), remains to be determined, as do the possible effects of these drugs on both the infection and the related disease., Aims: To describe self-reported COVID-19 symptoms and disease severity in PwMS on NTZ or FTY who received serology confirmation of SARS-CoV-2 infection., Methods: From 27th April to 3rd May 2020, telephone interviews were conducted with 140 PwMS under treatment with NTZ or FTY in order to collect structured data on multiple sclerosis (MS) and COVID-19. The patients, all followed at our center, were classified as symptomatic, paucisymptomatic or asymptomatic on the basis of their self-reported clinical characteristics. COVID-19 severity was rated on a 7-point ordinal scale. In addition, in the period 4th May to 3rd June 2020 SARS-CoV-2 serology testing, using the Roche SARS-CoV-2 IgG assay (Elecsys Ⓡ ), was performed in 104/140 (74.2%) of the interviewed PwMS (50 treated with NTZ and 54 with FTY)., Results: 14/104 (13.4%) PwMS on NTZ or FTY had anti-SARS-CoV-2 antibodies: 8 met the criteria for asymptomatic, 3 for paucisymptomatic and 3 for symptomatic COVID-19 (COVID-19 severity score lower than 3). None of them required hospitalization or showed severe COVID-19 complications., Conclusions: Despite the relatively high SARS CoV-2 seroprevalence found in this sample of PwMS, all the positive cases showed either no or only mild COVID-19 symptoms. These reassuring findings indicate a lack of COVID-19 complications in PwMS on DMTs and support the hypothesis that it is safe to maintain ongoing treatment with these drugs in the current setting., (Copyright © 2021. Published by Elsevier B.V.)

Background: Endothelial progenitor cells (EPCs) have been shown to increase during physiological pregnancy and are believed to play a fundamental role in the process of placentation. Reduced levels of EPCs during pregnancy have been associated with preeclampsia and miscarriage. Women with multiple sclerosis (MS) are not at increased risk of preeclampsia nor of general adverse obstetric outcome, in contrast with some other autoimmune diseases., Objective: The aim of this study was to evaluate circulating EPCs levels in pregnant patients with MS., Methods: CD34+ and CD133+ were longitudinally detected by flow cytometry in the maternal plasma of 29 healthy controls and 9 MS patients and in the cord blood of their newborns., Results: EPCs were affected by pregnancy with the same trend in both groups (CD34+ p = 0.0342; CD133+ p = 0.0347). EPCs during pregnancy were increased in MS (mean ± SD: CD34+ cells 0.038 ± 0.010; CD133+ 0.024 ± 0.009) with respect to healthy controls (mean ± SD: CD34+ cells 0.022 ± 0.006; CD133+ 0.016 ± 0.004), CD34+ p = 0.0004; CD133+ p = 0.0109. EPCs levels of the cord blood of MS patients' newborns mild correlated with maternal EPC levels at delivery (CD34+: spearman's Rho 0.658, p = 0.054; CD133+: spearman's Rho 0.758, p = 0.018)., Conclusions: This work identified increased circulating EPC levels during pregnancy, following the same trend both in MS patients and healthy controls. Despite the similar trend, the levels of circulating EPCs were significantly higher in MS patients with respect to the control population. A correlation was also found in MS patients between cord blood EPCs and circulating EPCs at delivery.

The radiation-induced injury to normal tissue is a well-described phenomenon that incites tissue hypoxia, vascular damage, and parenchymal cell death. In addition to the morbidity caused by the radiation-induced injury itself, surgical management adds to the overall morbidity in these patients. We herein present a case demonstrating challenges of surgical management of urological complications in a radiated pelvis including delayed bladder perforation, recurrence of vesicovaginal fistula, and ureteral stricture. Nonoperative management strategies should be exhausted prior to surgical intervention.

Multiple sclerosis (MS) refers to chronic inflammation of the central nervous system including the brain and spinal cord. Assessing for the presence of dysphagia in subjects with MS represents a challenge for neurologists in clinical practice. The aim of the present study was to verify the relationship between DYMUS scores, a patient-reported scale, and objective symptoms using the Dysphagia Outcome Severity Score (DOSS), based on fiber-optic endoscopy. Data were collected in a multicenter study. Two hundred and fifteen MS patients were enrolled, irrespective of self-reported dysphagia. DOSS revealed dysphagia in 122 subjects (56.7%). Compared with non-dysphagic subjects, the presence of dysphagia was related to more severe disability, longer disease duration, and a progressive form of the disease. A DYMUS score of 0 strongly correlated with a DOSS of 6 (sensitivity 100%) while DYMUS score of > 2 correlated with a DOSS < 7 (specificity 82%) of the self-reported scale. The DYMUS questionnaire can be a useful clinical tool for red-flagging patients who should undergo objective testing and referral to a otorhinolaryngologist.

Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear., Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms., Methods: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores., Results: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p  < 0.001) and EDSS (β = 0.16, p  < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89, p  = 0.01) and EDSS (β = -0.06, p  < 0.001). Neither presentation was associated with changes in relapse risk., Conclusion: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.

Background: The aim of this study was to evaluate the impact of surgeons' learning curve in robotic surgery for rectal cancer on circumferential resection margin (CRM) involvement and reoperation rates., Methods: Learning curve data were prospectively collected from four centers. Patients undergoing robotic proctectomy for resectable rectal cancer were included. CRM was involved when ≥1 mm. TME quality was classified as complete, nearly complete, or incomplete. T-test and χ 2 tests were used to compare continuous and categorical variables, respectively. Risk-adjusted cumulative sum (RA-CUSUM) analysis was utilized to evaluate the effect of the learning curve on primary endpoints. Univariate analysis of potential risk factors for CRM involvement and reoperation was performed. Factors with the P value ≤0.2 were included in the multivariate logistic regression model for further RA-CUSUM analysis., Results: A total of 221 patients (80, 36, 62, and 43 patients operated on by surgeons 1, 2, 3, and 4, respectively) who underwent robotic surgery for rectal cancer during the surgeons' learning curves were included. CRM involvement rate was 0%, 11%, 3%, and 5% in surgeons 1, 2, 3, and 4, respectively. Reoperation rate was 3.7%, 8.3%, 4.8%, and 11.6%, respectively. RA-CUSUM analysis of CRM involvement (R 2 =0.9886) and reoperation (R 2 =0.9891) found a statistically significant decreasing trend in aggregate CUSUM values throughout the learning curve., Conclusions: This study found a continued significant decrease in CRM involvement and reoperation rates throughout the learning curve in robotic rectal cancer surgery.

Background: No uniform criteria for a sensitive identification of the transition from relapsing-remitting multiple sclerosis (MS) to secondary-progressive multiple sclerosis (SPMS) are available., Objective: To compare risk factors of SPMS using two definitions: one based on the neurologist judgment (ND) and an objective data-driven algorithm (DDA)., Methods: Relapsing-onset MS patients ( n  = 19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible Expanded Disability Status Scale (EDSS) 6.0, after SP transition, were estimated using multivariable Cox regression models., Results: SPMS identified by the DDA ( n  = 2343, 12.1%) were older, more disabled and with a faster progression to severe disability ( p  < 0.0001), than those identified by the ND ( n  = 3868, 20.0%). In both groups, the most consistent risk factors ( p  < 0.05) for SPMS were a multifocal onset, an age at onset >40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the disease-modifying therapy (DMT) exposure. DMT exposure during SP did not impact the risk of reaching irreversible EDSS 6.0., Conclusion: A DDA definition of SPMS identifies more aggressive progressive patients. DMT exposure reduces the risk of SPMS conversion, but it does not prevent the disability accumulation after the SP transition.

Objective: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients., Methods: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity., Results: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10 -9 ) and worsening of disability (0.81, 0.67-0.99, p = 0.043)., Conclusion: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term., Classification of Evidence: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability., (© 2020 American Academy of Neurology.)

Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below -3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non-oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage-bone stem cell population., (© 2020 Wiley Periodicals LLC.)

Objective: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments., Methods: Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors., Results: The overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity p = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity p < 0.0001)., Conclusions: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice., (© 2020 American Academy of Neurology.)

Some environmental factors are associated with an increased risk of multiple sclerosis (MS). Air pollution could be a main one. This study was conducted to investigate the association of particulate matter 2.5 (PM 2.5 ) concentrations with MS prevalence in the province of Pavia, Italy. The overall MS prevalence in the province of Pavia is 169.4 per 100,000 inhabitants. Spatial ground-level PM 2.5 gridded data were analysed, by municipality, for the period 2010-2016. Municipalities were grouped by tertiles according to PM 2.5 concentration. Ecological regression and Bayesian statistics were used to analyse the association between PM 2.5 concentrations, degree of urbanization, deprivation index and MS risk. MS risk was higher among persons living in areas with an average winter PM 2.5 concentration above the European annual limit value (25 μg/m 3 ). The Bayesian map revealed sizeable MS high-risk clusters. The study found a relationship between low MS risk and lower PM 2.5 levels, strengthening the suggestion that air pollution may be one of the environmental risk factors for MS.

Several different operative techniques have been applied in minimally invasive right colectomy. Data reported in literature confirm the advantages of laparoscopic approach, however, there is no sure evidence of which one is the best. The pure laparoscopic technique with intracorporeal anastomosis seems to show some advantages compared to the other laparoscopic and open procedures, although for the price of technical difficulty and a longer operating time.

The circular stapler has played a critical role in fashioning colorectal anastomoses following low anterior resection for rectal cancer. One of the greatest benefits of the circular stapler has been the feasibility of constructing ultra-low anastomoses, thereby decreasing permanent colostomy rates. A notable US innovation to the original design was the addition of disposable cartridges of various sizes, which greatly decreased assembly time and made the instrument more versatile. Another important modification was the ability to detach the anvil from the stapler shaft. This markedly simplified the construction of anastomoses by negating the need for a double purse-string and avoiding an open rectal stump. An additional modification to facilitate transanal stapler extraction was the tilted-top anvil, which flipped parallel to the shaft once the stapler was fired. The circular stapler continues to evolve while maintaining the basic elements of Hültl's brilliant concept from over a century ago.

Introduction: Current evidence suggests that transanal hemorrhoidal dearterialization (THD) is associated with less postoperative pain and faster recovery than Ferguson hemorrhoidectomy. However, there is some uncertainty regarding the durability of the therapeutic effect in terms of recurrent disease. Objective and significance: The aim of this study will be to evaluate the outcome of THD compared to Ferguson hemorrhoidectomy in terms of recurrence rate at 1-year follow-up., Methods: This is a multicenter, parallel-arm, non-randomized prospective study comparing Ferguson hemorrhoidectomy and THD in terms of recurrence rate at one year. The primary endpoint is recurrence rate at one year defined as prolapsing internal hemorrhoids at physical examination. Secondary endpoints include the following postoperative complications: urinary retention, constipation (requiring laxative or emergency room visit), dysuria, pruritis ani, anal pain, anal stenosis, unhealed wound, fissure, fecal urgency, and flatus or stool incontinence. Adults older than 18 years with prolapsed, non-incarcerated, reducible hemorrhoids in at least 3 columns at physical examination will be included in one of the study arms: Ferguson hemorrhoidectomy and THD. Surgeons with proven expertise in hemorrhoids surgery will enroll patients undergoing Ferguson hemorrhoidectomy and THD (not both). Each participating surgeon will enroll a maximum of 10 patients. Ethics and Dissemination: This study was approved by the Institutional Review Boards of Stony Brook University (previously) and New York Medical College (currently), and registered in ClinicalTrials.gov (NCT03245086). The findings of the study will be published in a peer-reviewed journal.

This review aims to provide succinct insight into the past, present and near-future of right colon resection. The history of right colon resection as well as the evolution of a laparoscopic approach are described. Standardization of the surgical technique, indications for medial-to-lateral and lateral-to medial mobilization, D2 and D3 lymphadenectomy, iso-peristaltic and antiperistaltic anastomotic configurations, intracorporeal and extracorporeal anastomosis, totally stapled and stapled handsewn techniques, laparoscopic and robotic suturing, mucosa eversion and inversion, and specimen extraction sites are discussed. In addition, totally intracorporeal robotic right colectomy for cancer is described. This review concludes that, whether it is hindered or assisted, gasless or "con gas", multiple- or single-port, extra- or intracorporeal, iso- or anti-peristaltic, right colon resection is still evolving.

Objective: Air pollution has been recently identified as a risk factor for multiple sclerosis. Aim of this study was to investigate the immunological mechanism underlying the clinical association between air pollution, namely exposure to particulate matter 10 (PM10), and inflammatory activity of multiple sclerosis (MS) METHODS: Daily recording of PM10 was obtained by monitors depending on the residence of subjects. Expression of molecules involved in activation, adhesion, and migration of T lymphocytes were tested by flow cytometry in 57 MS patients and 19 healthy controls. We next assessed in vitro the effect of PM10 on expression of C-C chemokine receptors 6 (CCR6) by peripheral blood mononuclear cells (PBMCs), on cytokine production by monocyte-derived dendritic cells (mdDC), and on T cell polarization in PBMC/mdDC mixed cultures., Results: We identified a significant correlation between mean PM10 levels and expression of CCR6 CD4+ T circulating cells in MS patients. This was paralleled by the observation in vitro of a higher level of CCR6 expression on PBMC following treatment with increased doses of particulate matter. Moreover, in mdDC cultures, particulate matter induced the secretion by mdDC of Th17 polarizing IL1 beta, IL6, and IL23 and, in mdDC/PBMC mixed cultures, enhanced generation of IL17-producing T cells., Conclusions: Ex vivo and in vitro studies support the pro-inflammatory role of PM in MS, by upregulating expression of CCR6 on circulating CD4+ T cells and inducing in innate immune cells the production of Th17 polarizing cytokines. Therefore, we speculate that in MS respiratory exposure to PM10 may induce the production in the lung of autoreactive Th17 lymphocytes and boost their migratory properties through the blood-brain barrier.

Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS)., Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation., Design, Setting, and Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53 680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020., Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated., Main Outcomes and Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: the rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models)., Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P = .009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent., Conclusions and Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.

Background and Purpose: The literature provides contrasting results on the efficacy of levetiracetam (LEV) in multiple sclerosis (MS) patients with cerebellar signs. It was sought to evaluate the efficacy of LEV on upper limb movement in MS patients., Methods: In this multicenter double-blind placebo-controlled crossover study, MS patients with prevalently cerebellar signs were randomly allocated into two groups: LEV followed by placebo (group 1) or placebo followed by LEV (group 2). Clinical assessments were performed by a blinded physician at T0 (day 1), T1 (day 22), T2 (2-week wash-out period, day 35) and T3 (day 56). The primary outcome was dexterity in the arm with greater deficit, assessed by the nine-hole peg test (9HPT). Secondary clinical outcomes included responders on the 9HPT (∆9HPT >20%), tremor activity of the daily living questionnaire and self-defined upper limb impairment, through a numeric rating scale. Kinematic evaluation was performed using a digitizing tablet, providing data on normalized jerk, aiming error and centripetal acceleration., Results: Forty-eight subjects (45.2 ± 10.4 years) were randomly allocated into two groups (n = 24 each). 9HPT significantly improved in the LEV phase in both groups (P < 0.001). The LEV treatment phase led to a significant improvement (P < 0.01) of all clinical outcomes in group 1 and in dexterity in group 2. No significant changes were reported during both placebo phases in the two groups. Considering the kinematic analysis, only normalized jerk significantly improved after treatment with LEV (T0-T1) in group 1., Conclusions: Levetiracetam treatment seems to be effective in improving upper limb dexterity in MS patients with cerebellar signs., (© 2020 European Academy of Neurology.)

Aim: The aim of this meta-analysis was to comparatively evaluate the outcomes of primary anastomosis (PRA) and nonrestorative resection (NRR) as emergency surgery and ostomy reversal in patients with perforated diverticulitis and peritonitis., Methods: PubMed, MEDLINE via Ovid, Embase, CINAHL, Cochrane Library and Web of Science databases were systematically searched. Postoperative morbidity following emergency resection was the primary end-point. Quality assessment of the included studies was performed using the Cochrane Quality Assessment Tool including recruitment bias and crossover with intention-to-treat analysis. The Haenszel-Mantel method with odds ratios (OR, 95% CI) and the inverse variance method with mean difference (MD, 95% CI) as effect measures were utilized for dichotomous and continuous outcomes, respectively., Results: Four randomized controlled trials totaling 382 patients (180 PRA vs 204 NRR) were included. Morbidity rates following emergency resection did not differ (OR = 0.99, 95% CI 0.65, 1.51; P = 0.95; number needed to treat/harm (NNT) 96). Organ/space surgical site infection rates were 3.3% in PRA vs 11.3% in NRR (OR = 0.29, 95% CI 0.12, 0.74; P = 0.009; NNT = 13). Postoperative morbidity rates following ostomy reversal were significantly lower in PRA (OR = 0.31, 95% CI 0.15, 0.64; P = 0.001; NNT = 7). Pooled ostomy non-reversal rates were 16% in PRA vs 35.5% in NRR (OR = 0.37, 95% CI 0.22, 0.62; P = 0.0001; NNT = 6) with high heterogeneity (I 2  = 63%; τ 2  = 8.17). Meta-regression analysis revealed significant negative correlation between the PRA-to-NRR crossover rate and the ostomy non-reversal rate (P = 0.029)., Conclusion: This meta-analysis found that PRA was associated with better short- and long-term outcomes at the cost of significantly longer operating time at emergency surgery., (Colorectal Disease © 2020 The Association of Coloproctology of Great Britain and Ireland.)

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: A beneficial impact of robotic proctectomy on circumferential resection margin (CRM) is expected due to the robot's articulating instruments in the pelvis. There are however concerns about a negative impact on the quality of total mesorectal excision (TME) due to the lack of tactile feedback. The aim of this study was to assess whether surgeons' learning curve impacted CRM and TME quality., Methods: In a multicenter study, individual patient data of robotic proctectomy for resectable rectal cancer were pooled. Patients were stratified into two phases of surgeons' learning curve. Cumulative sum (CUSUM) analysis was used to determine the transition from learning phase (LP) to plateau phase (PP), which were compared. CRM was microscopically measured in mm by pathologists. TME quality was classified by pathologists as complete, nearly complete or incomplete. T-test and Chi-squared tests were used to compare continuous and categorical variables, respectively., Results: 235 patients underwent robotic proctectomy by five surgeons. 83 LP patients were comparable to 152 PP patients for age (p = 0.20), gender (67.5% vs. 65.1% males; p = 0.72), BMI (p = 0.82), cancer stage (p = 0.36), neoadjuvant chemoradiation (p = 0.13), distance of tumor from anal verge (5.8 ± 4.4 vs. 5.5 ± 3.3; p = 0.56). CRM did not differ (7.7 ± 11.4 mm vs. 8.4 ± 10.3 mm; p = 0.62). The rate of complete TME quality was significantly improved in PP patients as compared to LP patients (73.5% vs. 92.1%; p < 0.001)., Conclusion: While learning had no impact on circumferential resection margins, the quality of TME significantly improved during surgeons' plateau phase as compared to their learning phase., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)