Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy

Timing of initiation of oral anticoagulants in patients with acute ischemic stroke and atrial fibrillation comparing posterior and anterior circulation strokes

Background: The aim of this study in patients with acute posterior ischemic stroke (PS) and atrial fibrillation (AF) were to evaluate the risks of recurrent ischemic event and severe bleeding and these risks in relation with oral anticoagulant therapy (OAT) and its timing. Methods: Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of: stroke recurrence, TIA, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. Results: A total of 2,470 patients were available for the analysis: 473 (19.1%) with PS and 1,997 (80.9%) AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39-2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16-1.80). Conclusions: Patients with posterior or anterior stroke and AF appear to have similar risks of ischemic or hemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT

Rationale for BepiColombo Studies of Mercury's Surface and Composition

BepiColombo has a larger and in many ways more capable suite of instruments relevant for determination of the topographic, physical, chemical and mineralogical properties of Mercury's surface than the suite carried by NASA's MESSENGER spacecraft. Moreover, BepiColombo's data rate is substantially higher. This equips it to confirm, elaborate upon, and go beyond many of MESSENGER's remarkable achievements. Furthermore, the geometry of BepiColombo's orbital science campaign, beginning in 2026, will enable it to make uniformly resolved observations of both northern and southern hemispheres. This will offer more detailed and complete imaging and topographic mapping, element mapping with better sensitivity and improved spatial resolution, and totally new mineralogical mapping. We discuss MESSENGER data in the context of preparing for BepiColombo, and describe the contributions that we expect BepiColombo to make towards increased knowledge and understanding of Mercury's surface and its composition. Much current work, including analysis of analogue materials, is directed towards better preparing ourselves to understand what BepiColombo might reveal. Some of MESSENGER's more remarkable observations were obtained under unique or extreme conditions. BepiColombo should be able to confirm the validity of these observations and reveal the extent to which they are representative of the planet as a whole. It will also make new observations to clarify geological processes governing and reflecting crustal origin and evolution. We anticipate that the insights gained into Mercury's geological history and its current space weathering environment will enable us to better understand the relationships of surface chemistry, morphologies and structures with the composition of crustal types, including the nature and mobility of volatile species. This will enable estimation of the composition of the mantle from which the crust was derived, and lead to tighter constraints on models for Mercury's origin including the nature and original heliocentric distance of the material from which it formed.Peer reviewe

Anticoagulation After Stroke in Patients With Atrial Fibrillation : To Bridge or Not With Low-Molecular-Weight Heparin?

Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.Peer reviewe

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Key factors for successful outcomes of abdominal wall reconstruction with biologic implant

We read with interest the article by Fayezizadeh and colleagues titled “Outcomes of Retromuscular Porcine Biologic Mesh Repairs Using Transversus Abdominis Release Reconstruction.”1 In a consecutive series of 77 patients undergoing abdominal wall reconstruction (AWR), the authors reported a surgical site infection rate of 28.6% and hernia recurrence in rate of 12.5% (8 of 64 patients). These results are certainly favorable and we agree with the authors when they suppose that the restoration of linea alba, performing transversus abdominis release reconstruction when necessary, and retrorectus placement of biologic implant appear paramount to successful outcomes. In our comment to Abdelfatah and colleagues’ report,2,3 we stressed the superiority of sublay repair when compared with underlay or bridging repairs, especially when biologic implants are required. In fact, the retromuscular plane offers a much more vascularized anatomic environment than the intraperitoneal space, and provides the basis for implant’s ingrowth and integration. 4 But operative technique and mesh positioning are not the only key factors for successful outcomes of AWR with biologics. Indications and selection of the proper implant are equally important. Our experience with AWR with biologics started in 2005. The use of biologic implants did not modify the surgical technique (Rives-Stoppa procedure plus posterior component separation when necessary) we have been using routinely since the mid 1980s. In other words, in patients at risk for wound infection, we changed the mesh but not the surgical technique

Comment on: Comparative analysis of biologic versus synthetic mesh outcomes in contaminated hernia repairs

We read with great interest the article by Majumder et al.1 The authors performed a multicenter, retrospective review of 126 patients undergoing prosthetic sublay abdominal wall reconstruction (AWR) in cleancontaminated/ contaminated field. They concluded that the use of polypropylene or polyester mesh resulted in a significantly lower wound morbidity and more durable outcomes compared with a similar cohort patients in whom non–cross-linked porcine acellular dermal matrix (PADM) was used. Surgical site infections (SSIs) and recurrence (mean follow-up >12 months, <22 months) were less frequent in the synthetic group (12.3% and 8.9%, respectively) than in the biologic group (31.9% and 26.3%, respectively), with one incidence of partial mesh explantation in each group. At the end of the study, the authors challenged the advantage of biologics in patients at risk of wound infection. According to our experience with biologics, the results of complex AWR were different. Between 2005 and 2014, 49 patients underwent elective AWR using biologic mesh in our tertiary referral center for complex hernias. Patient demographics, comorbidities, risk infection, according to the modifiedWorking Ventral Hernia Group,2 and hernia characteristics did not significantly differ from Majumder’s review. All patients underwent sublay repair using PADM processed with 2 different cross-linking agents, group A (hexamethylene diisocyanate: 36 implants) and group B (carbodiimide: 13 implants), with posterior component separation when necessary. Patients were collected in a database and submitted to clinical exam and computed tomography scan every year. Our SSI rate was 19%, taking into account group A only. No implant needed to be removed, including one case with early sigmoid perforation, which was conservatively treated with success. In June 2016, the database analysis of group A showed an overall recurrence rate of 2.8%, with a medium follow-up >5 years (17– 132 months). Group A proved that the putative advantages of biologics were true. Outcomes of group B were instead less favorable (SSI 31%, recurrence 23%). These results, along with those of Majumder’s non–cross-linked PADM series, confirm that all biologics are not equal.3 The authors assert that the operative technique and mesh site of the implant play a primary role. We completely agree and add that these are especially important when using biologics. 4 Selection of the proper implant is also crucial. The choice of a cross-linked, proper-sized PADM represented the key factor of our success. In fact, no implant was removed due to infection, and the long-term recurrence rate was significantly lower than that achieved by Majumder, both in the biologic and the synthetic group. Results of prospective, randomized trials comparing monofilament synthetic meshes with biologics in sublay AWR are needed before advocating the purported advantages of biologic implants in contaminated AWRs. Which biologic should be proposed for this study? On the basis of our experience, we suggest the proper one from the cross-linked meshes family

Surveillance of Surgical Meshes in Ventral Hernias and Unpredictability of the Their History

: The authors read the article "The importance of registries in the postmarketing surveillance of surgical meshes" by Kockerling et al, and they completely agree on the role of a clinical follow-up of surgical meshes even if they suggest that a surveillance longer than one year is advisable, particularly in IPOM repair, to collect not only late complications but also more serious adverse events. This seems be the only way to properly assess the safety of the mesh

Factors influencing recurrence in abdominal wall reconstruction (awr) in biologic implants

Background: Interest about use of biologie implants (cross- linked or not) in complex abdominal wall reconstruction has grown up in the last years, supp01ted by literature. From literature review, recurrence rate using non cross-linked biologics ranges from 14.7 to 59% and surgical site infection rate ranges from 28.6 to 3 1.9%. We present recurrence rate and surgical site infection in our experience with cross- linked implants (2005-20 16). Methods: From 2005, we treated 49 patients (Grade 2 or 3, according to Ventral Hernia Working Group) with complex abdominal wall reconstruction by retro-muscolar repair, and posterior component separation when necessary, using a porcine cross- linked acellular derma] matrix. Implants were processed with 2 different cross-linking agents, hexamethylene di isocyanate (group A, n.36) or carbodiimide (group B, n.1 3). Ali patients underwent annua] fo llow-up, including clinical evaluation and computed tomography/MRl scan with Valsalva maneuver. Results: The overall recurrence rate was 8.2% (at a mean follow-up of 59.3 months), with a significantly lower rate in group A (2.8%) vs group B (23%, p < 0.05). No implant was removed. Surgical site infection was not signiticantly different in the 2 groups ( 19 vs 26%, p = 0.8). Conclusion: In our experie nce of complex abdominal wall reconstruction, overall rates of recurrence and surgical site infection using porcine cross- linked acellular dermal matrix are notably lower than those previously reported in literature using a non-cross linked biologie mesh. These results stress the role of proper indications (never in grade 4), mesh selection and site of the implant. These factors appear to play a key role in A WR using biologics