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Introduction: While the economic and clinical burden of chronic diseases are well documented, their environmental impact remains poorly understood. We developed a framework to estimate the environmental impact of a disease care pathway using chronic kidney disease (CKD) as an example., Methods: A life cycle assessment framework was developed for the CKD care pathway and validated by experts. Life cycle stages were characterised for resource utilisation based on a literature review and ecoinvent database inputs, in ten countries. The ReCiPe impact assessment method was used to calculate impacts across multiple environmental dimensions., Results: At CKD stage 5, kidney replacement therapies (KRT) have highest impact; emissions ranged between 3.5 and 43.9 kg carbon dioxide equivalents (CO 2 e) per session depending on dialysis modality, and 336-2022 kg CO 2 e for kidney transplant surgery, depending on donor type. Hospitalisations have a substantial environmental impact: a 1-day intensive care stay had highest impact (66.4-143.6 kg CO 2 e), followed by a 1-day hospital stay (28.8-63.9 kg CO 2 e) and an 8-h emergency room visit (14.4-27.5  kg CO 2 e). Patient transport to and from healthcare sites was a key driver of environmental impact for all life cycle stages, representing up to 99.5% of total CO 2 e emissions., Conclusion: Full care pathways should be analysed alongside specific healthcare processes. Application of this framework enables quantification of the environmental benefits of preventative medicine and effective management of chronic diseases. For CKD, early diagnosis, and proactive management to reduce the need for KRT and hospitalisations could improve patient outcomes and reduce environmental burden., Competing Interests: Declarations Conflict of Interest Katherine A. Barraclough, Aleix Cases, Roberto Pecoits-Filho, Celine Germond-Duret, Carmine Zoccali, and Matthew J. Eckelman received consulting fees for taking part in Scientific Steering Committee meetings regarding CKD environmental impact research. Aleix Cases has received research grants from CSL Vifor; consultancy fees from Astellas, Astra Zeneca, Bayer, Boehringer Ingelheim, GSK, Lilly, Novo Nordisk, Otsuka, CSL Vifor, and lecture fees from Astellas, Astra Zeneca, Amgen, Bayer, Medscape, Novo Nordisk, Sanofi (Mexico), CSL Vifor. Roberto Pecoits-Filho has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion, Akebia, AstraZeneca, Bayer, Boehringer, and Fresenius Medical Care. Juan Jose Garcia Sanchez, Salvatore Barone, Nigel Budgen, Claudia Cabrera, and Viknesh Selvarajah are employees and shareholders of AstraZeneca. Nina Embleton, Antony Wright, Luke Hubbert, and Lindsay Nicholson received consulting fees from AstraZeneca. Ethical Approval This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors., (© 2024. The Author(s).)

Competing Interests: Competing interests: MS is a consultant for Apollo Endosurgery and Anchora and has stock options from Anchora. SS is a consultant for Biolinq, Bariatek, Endo Tools Therapeutics, Nitinotes, Olympus, Pentax, and Fractyl, has research contracts from Allurion and ReBiotix and has stock options from Elira and Biolinq. IB is a consultant for Apollo Endosurgery, Boston Scientific, Nitinotes, Pentax, Cook Medical, Microtech, ERBE, Siemens, Myka labs and Endo Tools Therapeutics S.A., conducts sponsored lectures for Apollo Endosurgery, Boston Scientific, Cook Medical, Microtech, is recipient of research grant from Apollo Endosurgery, Endo Tool Therapeutics, and ERBE, and is scientific advisory board member for Nitinotes and Myka labs. All other authors have nothing to declare.

Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder. Most MG patients have autoantibodies against acetylcholine receptors (AChRs). Some have autoantibodies against muscle-specific tyrosine kinase (MuSK) or lipoprotein-receptor-related protein 4 (LRP4), and some are seronegative. Standard of care, which includes anti-cholinesterase drugs, thymectomy, corticosteroids (CS), and off-label use of non-steroidal immunosuppressive drugs (NSISTs), is bounded by potential side effects and limited efficacy in refractory generalized MG (gMG) patients. This highlights the need for new therapeutic approaches for MG. Eculizumab, a monoclonal antibody that inhibits the complement system, has been recently approved in Italy for refractory gMG. A panel of 11 experts met to discuss unmet therapeutic needs in the acute and chronic phases of the disease, as well as the standard of care for refractory patients. Survival was emphasized as an acute phase outcome. In the chronic phase, persistent remission and early recognition of exacerbations to prevent myasthenic crisis and respiratory failure were considered crucial. Refractory patients require treatments with fast onset of action, improved tolerability, and the ability to slow disease progression and increase life expectancy. The Panel agreed that eculizumab would presumably meet the therapeutic needs of many refractory gMG patients. The panel concluded that the unmet needs of current standard of care treatments for gMG are significant. Evaluating new therapeutic options accurately is essential to find the best balance between efficacy and tolerability for each patient. Collecting real-world data on novel molecules in routine clinical practice is necessary to address unmet needs., Competing Interests: Declarations Conflict of Interest RM received funding for Travel, Meeting attendance or Advisory Board participation from Alexion, Argenx, Biomarin, Catalyst, SANOFI, Regeneron and UCB.FS received public speaking honoraria from Alexion, argenx, Biogen, Genpharm, Medpharma, Medison Pharma, Mylan, Neopharm Israel, Novartis, Roche, Sanofi, Zai Lab; compensation for advisory boards from Alexion, Almirall, argenx, Astrazeneca, Avexis, Biogen, Forward Pharma, Dianthus, Lexeo Therapeutics, Merk, Novartis GmBh, Reata, Roche, Sandoz, Sanofi, Takeda; consultation fees from Alexion, Dianthus, EPG Comunication Holding ltd, Forward Pharma, Medscape, Novatek,PeerView, Vitaccess; he has been clinical trial principal investigator for Alexion, argenx, Dianthus, Immunovant, Lediant, Novartis, Prilenia, Sanofi.GA declares conference honoraria, advisory board and travel grants from Kedrion, Jannsen, Alnylam, Alexion, Argenx, Takeda.DMB declares advisory board honoraria from Argenx, Alexion, Roche; research support as PI for Roche and Alexion; speaker's Honoraria from Argenx, Alexion, UCB.AE has no competing interests to declare.FH has no competing interests to declare.RL declares lecture fees, advisory board, videointerview, fees for meeting chairing and scientific organization from Summeet, Alexion Pharma Italy, UCB Pharma, Med Stage, Amicus Therapeutics, Alfasigma, ECM network, Healthware group, PTS, Aim Education, Sanofi Genzyme Corporation.EP reports personal fees from Biogen, Roche, Novartis, Alexion and UCB Biopharma outside the submitted work. EP is part of the advisory boards for Biogen, Roche, Alexion, UCB Pharma.CR received honoraria for speaking, advisory boards and compensation for congress participations from Alexion, Argenx, and UCB, outside the submitted work.AS, MS and GP have no competing interests to declare., (© 2024. Fondazione Società Italiana di Neurologia.)

The brain remains one of the most challenging therapeutic targets due to the low and selective permeability of the blood-brain barrier and complex architecture of the brain tissue. Nanomedicines, despite their relatively large size compared to small molecules and nucleic acids, are being heavily investigated as vehicles to delivery therapeutics into the brain. Here we elaborate on how nanomedicines may be used to treat rare neurodevelopmental disorders, using Krabbe disease (globoid cell leukodystrophy) to frame the discussion. As a monogenetic disorder and lysosomal storage disease affecting the nervous system, the lessons learned from examining nanoparticle delivery to the brain in the context of Krabbe disease can have a broader impact on the treatment of various other neurodevelopmental and neurodegenerative disorders. In this review, we introduce the epidemiology and genetic basis of Krabbe disease, discuss current in vitro and in vivo models of the disease, as well as current therapeutic approaches either approved or at different stage of clinical developments. We then elaborate on challenges in particle delivery to the brain, with a specific emphasis on methods to transport nanomedicines across the blood-brain barrier. We highlight nanoparticles for delivering therapeutics for the treatment of lysosomal storage diseases, classified by the therapeutic payload, including gene therapy, enzyme replacement therapy, and small molecule delivery. Finally, we provide some useful hints on the design of nanomedicines for the treatment of rare neurological disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Due to poor data in literature, we aimed to investigate the respiratory function in a large cohort of naïve Italian adult (≥18 years) SMA patients in a multi-centric cross-sectional study. The following respiratory parameters were considered: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and need for non-invasive ventilation (NIV). We included 145 treatment-naïve adult patients (SMA2=18, SMA3=125; SMA4=2), 58 females (40 %), with median age at evaluation of 37 years (range 18-72). Fifty-six (37 %) and 41 (31 %) patients had abnormal (<80 %) values of FVC and FEV1, respectively. Fourteen (14 %) patients needed NIV, started at median age of 21 (range 4-68). Motor function, measured by Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module as well as SMA2, loss of walking ability, surgery for scoliosis, use of NIV, and cough assisting device (CAD) were all significantly associated to lower FVC and FEV1 values, while no association with age at baseline, disease duration, gender or 6 min walking test was observed, except for a correlation between FVC and age in SMA3 walkers (p < 0.05). In conclusion, respiratory function in adult SMA patients is relatively frequently impaired, substantially stable, and significantly correlated with motor function and disease severity., Competing Interests: Declaration of Competing Interest The authors do not declare any financial and personal relationships with other people or organizations that could inappropriately influence their work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab., Methods: In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD)., Results: Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms., Conclusions: SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response., Trial Registration Number: NCT03144947, and EudraCT number: 2016-000435-41., Competing Interests: Competing interests: BP reports research grants from Lilly, Pfizer, Novartis; and personal fees from MSD outside the submitted work. EC reports travel grants from Pfizer and Ipsen outside the submitted work. EB reports research grants from Roche, AstraZeneca; personal fees from MSD, AstraZeneca, BMS, Roche, Novartis, Pfizer, Lilly; and travel grants from Roche and AstraZeneca outside the submitted work. LC reports personal fees from AstraZeneca, Novartis and Lilly outside the submitted work. LG reports personal fees from Daiichi, Seagen; and travel grants from Ipsen, Novartis, Pfizer outside the submitted work. AZ reports personal fees from AstraZeneca, Lilly, Pfizer, Daiichi, MSD, Roche, Seagen, Exact Sciences, Gilead and Istituto Gentili outside the submitted work. FM reports personal fees from Roche, Novartis, AstraZeneca, Daiichi, Seagen, MSD, Lilly, Pfizer, Pierre Fabre; and travel grants from Roche and AstraZeneca outside the submitted work; from May 15th 2023, FM is Roche employee. AM reports research grants from Lilly; personal fees from Seagen, Daiichi, Gilead, Novartis, AstraZeneca; and travel grants from Gilead and Novartis outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Late-Onset Neonatal Sepsis (LOS) is a rare condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not completely preventable, identifying susceptibility factors is critical to characterizing the pathophysiology and developing interventions. Prior studies demonstrated both genetics and infant sex influence susceptibility. Our study was designed to identify LOS associated genetic variants., Methods: We performed an exploratory genome wide association study (GWAS) with 224 LOS cases and 273 controls from six European countries. LOS was defined as sepsis presenting from 3 to 90 days of age; diagnosis was established by clinical criteria consensus guidelines. We tested for association with both autosomal and X-chromosome variants in the total sample and in sex-stratified analyses., Results: In total, 71 SNPs associated with neonatal sepsis at p < 1 × 10 -4 in at least one analysis. Most importantly, sex-stratified analyses revealed associations with multiple SNPs (28 in males and 16 in females), but no variants from single-sex analyses associated with sepsis in the other sex. Pathway analyses showed NOTCH signaling is over-represented among genes linked to these SNPS., Conclusion: Our results indicate genetic susceptibility to LOS is sexually dimorphic and corroborate that NOTCH signaling plays a role in determining risk., Impact: Genes associate with late onset neonatal sepsis. Notch pathway genes are overrepresented in associations with sepsis. Genes associating with sepsis do not overlap between males and females. Sexual dimorphism can lead to sex specific treatment of sepsis., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: The purpose of this study was to assess the rate and type of infections in gynecological cancer patients. We also performed an economic analysis to provide an overview of costs related to healthcare associated infections., Methods: We retrospectively collected data from culture samples at the site of infection from patients undergoing surgery or chemotherapy, admitted to the Gynecologic Oncology Unit, Fondazione Policlinico Agostino Gemelli IRCCS, from January 2017 to December 2018. We performed univariate and multivariate analyses to calculate potential risk factors for prolonged length of hospitalization. The average cost per patient was calculated, including the cost of hospital stay, operating room, medications, and diagnostic and invasive procedures., Results: Among 5682 patients, 322 (5.6%) gynecological cancer patients with healthcare associated infections were identified. A total of 249 patients (77.3%) had undergone surgery in the previous 30 days and 73 (22.7%) patients were receiving chemotherapy. In the whole population, the most common healthcare associated infections were urinary infections (58%) and surgical wound infections (42.1%). In addition, 14.5% of patients had central venous catheter infections and 21.7% had blood stream infections. Median length of stay was 20 days (range 1-100). Among surgical patients, advanced age (odds ratio (OR) 1.233, 95% confidence interval (CI) 1.001 to 1.519, p=0.049), bowel resection (OR 2.659, 95% CI 1.493 to 4.735, p=0.001), surgical site infection (OR 10.447, 95% CI 1.143 to 95.5, p=0.038), and central venous catheter infection (OR 9.856, 95% CI 1.139 to 85.319, p=0.038) were independently associated with an increased risk of prolonged hospital stay (>20 days). The overall direct cost of healthcare associated infections was $6 273 852 per year., Conclusions: The infection rate in our population was 5.6%. The most common healthcare associated infections were urinary and surgical wound infections. Among surgical patients, advanced age, bowel resection, surgical site, and central venous catheter infection were associated with an increased length of hospitalization. Healthcare associated infections cause an increase in the length of stay after surgery and hospital costs., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Rituximab (RTX) efficacy in patients with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorders (MOGADs) is still poorly understood, though it appears to be lower than in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders (AQP4-IgG+NMOSDs). The aim of this systematic review and meta-analysis is to assess the efficacy and safety profile of RTX in patients with MOGAD and to compare RTX efficacy between MOGAD and AQP4-IgG+NMOSD., Methods: We searched original English-language articles published between 2012 and 2021 in MEDLINE, Cochrane, Central Register of Controlled Trials and clinicaltrials.gov, reporting data on RTX efficacy in patients with MOGAD. The main outcome measures were annualised relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score mean differences (MDs) after RTX. The meta-analysis was performed with a random effects model. Covariates associated with the outcome measures were analysed with a linear meta-regression., Results: The systematic review included 315 patients (138 women, mean onset age 26.8 years) from 32 studies. Nineteen studies (282 patients) were included in the meta-analysis. After RTX, a significant decrease of ARR was found (MD: -0.92, 95% CI -1.24 to -0.60, p<0.001), markedly different from the AQP4-IgG+NMOSD (MD: -1.73 vs MOGAD -0.92, subgroup difference testing: Q=9.09, p=0.002). However, when controlling for the mean ARR pre-RTX, this difference was not significant. After RTX, the EDSS score decreased significantly (MD: -0.84, 95% CI -1.41 to -0.26, p=0.004). The frequency of RTX-related adverse events was 18.8% (36/192) and overall RTX-related mortality 0.5% (1/192)., Conclusions: RTX showed effective in MOGAD, although to a lesser extent than in AQP4-IgG+NMOSD, while the safety profile warrants some caution in its prescription. Randomised-controlled trials are needed to confirm these findings and provide robust evidence to improve treatment strategies in patients with MOGAD., Prospero Registration Number: CRD42020175439., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To study the natural history of optical coherence tomography (OCT) imaging-based findings seen in non-exudative age-related macular degeneration (neAMD) and model their relative likelihood in predicting development of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), complete retinal pigment epithelium and outer retinal atrophy (cRORA), and neovascular AMD (nAMD)., Methods: Retrospective chart review was performed at two academic practices. Patients diagnosed with neAMD for whom yearly OCT scans were obtained for at least 4 consecutive years were included. Baseline demographic, visual acuity, AREDS staging, and OCT data were collected. OCTs were assessed for the presence or absence of eleven features previously individually associated with progression of neAMD, both at baseline, and on all subsequent follow-up scans. Likewise, charts were reviewed to assess visual acuity and staging of NEAMD at all follow-up visits. A multivariate regression analysis was constructed to determine predictors of iRORA, cRORA, and nAMD., Results: A total of 107 eyes of 88 patients were evaluated. Follow-up included yearly OCTs obtained over at least 4 consecutive years follow-up (range: 50-94 months). During the follow-up period, 17 eyes progressed to iRORA while 25 progressed to cRORA and 16 underwent conversion to nAMD. Predictors of conversion to iRORA and cRORA included integrity of the external limiting membrane (p = 0.02), the ellipsoid zone (p = 0.01), and the cone outer segment line (p = 0.003) and the presence of intraretinal hyporeflective spaces (p = 0.009), drusen ooze (p = 0.05), and drusen collapse (p = 0.001). OCT features predictive of conversion to nAMD included outer nuclear layer (ONL) loss (p = 0.01), presence of intraretinal (p = 0.001) and subretinal (p = 0.005) hyporeflective spaces, and drusen collapse (p = 0.003)., Conclusion: Of these multiple factors predictive of progression of neAMD, the OCT feature most strongly correlated to progression to iRORA/cRORA was drusen collapse, and the feature most predictive of conversion to nAMD was the presence of intraretinal hyporeflective spaces., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Cancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy., Design: A collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance., Results: Here we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy., Conclusions: While PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Life-threatening streptococcal sepsis nowadays represents an uncommon event in previously healthy infants and children. Critically ill patients suffering from severe streptococcal sepsis complications may present with pre-antibiotic era clinical pictures and require a timely clinical approach to achieve restitutio ad integrum., Results: We report a series of four patient groups affected by an uncommon life-threatening streptococcal sepsis, each of them exhibiting some distinct features. Streptococcus Agalactiae sepsis was associated with cerebral thrombotic/ischaemic lesions, whereas severe cardiogenic shock was prominent in the Streptococcus Viridans group; Streptococcus Faecalis and β-hemolytic group A Streptococcus patients mostly reported lung complications., Conclusions: Previous antibiotic treatments should not delay aggressive treatment in the intensive care setting. Early diagnostic suspicion, as well as appropriate and aggressive treatment provided within an intensive care setting are crucial for the clinical outcome., (© 2021. The Author(s).)

Objective: To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab., Methods: A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m 2 ) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints., Results: From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1-40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported., Conclusions: Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors., Trial Registration Number: EudraCT 2012-003043-29; NCT01706120., Competing Interests: Competing interests: Dr Daniele reports travel and accommodations from Roche, outside the submitted work. Dr Raspagliesi reports grants from Roche, grants from GSK, grants from MSD, grants from Pharmamar, outside the submitted work. Dr Colombo reports personal fees from Roche, personal fees from Pharmamar, personal fees from AstraZeneca, personal fees from MSD, personal fees from Tesaro, personal fees from GSK, personal fees from Clovis, personal fees from Amgen, personal fees from Pfizer, personal fees from Biogen, personal fees from BIOCAD, outside the submitted work. Dr De Giorgi reports personal fees from Astellas - Pharma, personal fees from Bayer, personal fees and non-financial support from Bristol Myers-Squibb, personal fees and non-financial support from Ipsen, personal fees and non-financial support from Janssen, personal fees and non-financial support from Pfizer, grants and personal fees from Sanofi, personal fees from Novartis, personal fees from MSD, grants and non-financial support from Roche, grants from AstraZeneca, personal fees from Pharmamar, outside the submitted work. Dr Lorusso reports grants, personal fees and non-financial support from Pharmamar, grants and personal fees from MSD, grants and personal fees from Clovis, grants, personal fees and non-financial support from GSK, personal fees and non-financial support from AstraZeneca, personal fees from Merck Serono, personal fees from Amgen, non-financial support from Roche, outside the submitted work. Dr Salutari reports personal fees from MSD, personal fees from GSK, personal fees from Tesaro, personal fees from AstraZeneca, personal fees from Roche, personal fees from Eisai, personal fees from Clovis, outside the submitted work. Dr Piccirillo reports personal fees from Daichii Sankyo, personal fees from GSK, personal fees from MSD, grants from Roche, grants and personal fees from AstraZeneca, non-financial support from Bayer, outside the submitted work. Dr Perrone reports grants from Roche, during the conduct of the study; grants, personal fees and non-financial support from Bayer, personal fees from Sandoz, grants and personal fees from Incyte, personal fees from Celgene, grants and personal fees from AstraZeneca, personal fees from Pierre Fabre, personal fees from Janssen Cilag, grants from Roche, grants from Pfizer, outside the submitted work. Dr Pignata reports grants from Roche, during the conduct of the study; personal fees from AZ, personal fees from MSD, personal fees from Clovis, personal fees and non-financial support from Tesaro GSK, personal fees from Roche, outside the submitted work. The other authors do not declare conflicts of interests., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Guidelines and expert consensus are lacking on fertility preservation in BRCA mutation carriers and in patients with Lynch syndrome. The safety of fertility preservation in this setting is still a topic of debate and multiple factors need to be carefully considered. The aim of this review was to analyze the reproductive potential of women harboring a genetic mutation affecting the DNA repair system and explore the efficacy and safety of existing fertility preservation strategies in these patients., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is no consensus on the appropriate treatment of lymphedema. Proposed techniques include lymphaticovenous anastomosis (LVA), vascularized lymph nodes transfer (VLNT), and suction lipectomy (SL). The benefit of combined procedures has also been postulated. In this prospective study, a combined protocol is proposed as an alternative to single-procedure strategies., Methods: Between January 2016 and October 2018, we enrolled patients with secondary lymphedema of lower limbs, stage II-III according to the International Society of Lymphology, progressive swelling and skin tonicity >60. Thirty-seven consecutive patients were dichotomized into group I, undergoing VLNT, and group II undergoing VLNT and LVA. Gastroepiploic lymphnode flap was harvested through laparoscopy, and in the same operation, LVAs were performed in group II on the basis of indocyanine green lymphography and patent blue findings. Two weeks later, SL was performed in all the patients. Patients were prospectively evaluated through clinical examination, circumference measurement, and skin tonicity., Results: The average follow-up was 2 ± 0.8 years. The first consecutive 21 patients were treated with VLNT followed by SL. The next 16 patients underwent combined VLNT and LVA, followed by SL. A mean of 2.4 LVAs were performed. A significant difference in the postoperative circumference measurements was found overall (p < .05): 52.6 ± 18.9 above the knee, 42.9 ± 25 below the knee, 36.2 ± 37 at foot. The postoperative tonicity dropped by 12.7 ± 6.3% (p < .05). The episodes of cellulitis significantly decreased to 0.1 ± 0.3 (p < .05)., Conclusions: LVA, VLNT, and SL can be integrated together in a combined approach, in synergy to enhance the outcomes., (© 2020 Wiley Periodicals LLC.)

Objectives: Assessment of competence in technical skills, including point-of-care ultrasound (POCUS), is required before a novice can safely perform the skill independently. Ongoing assessment of competence is also required because technical skills degrade over time, especially when they are infrequently performed or complex. Hand-motion analysis (HMA) is an objective assessment tool that has been used to evaluate competency in many technical skills. The purpose of this study was to demonstrate the feasibility and validity of HMA as an assessment tool for competence in both simple and complex technical skills as well as skill degradation over time., Methods: This prospective cohort study included 36 paramedics with no POCUS experience and six physicians who were fellowship trained in POCUS. The novices completed a 4-hour didactic and hands-on training program for cardiac and lung POCUS. HMA measurements, objective structured clinical examinations (OSCE), and written examinations were collected for novices immediately before and after training as well as 2 and 4 months after training. Expert HMA metrics were also recorded., Results: Expert HMA metrics for cardiac and lung POCUS were significantly better than those of novices. After completion of the training program, the novices improved significantly in all HMA metrics, knowledge test scores, and OSCE scores. Novices showed skill degradation in cardiac POCUS based on HMA metrics and OSCE scores while lung POCUS image acquisition skills were preserved. Novices deemed competent by OSCE score performed significantly better in HMA metrics than those not deemed competent., Conclusion: We have demonstrated that HMA is a feasible and valid tool for assessment of competence in technical skills and can also evaluate skill degradation over time. Skill degradation appears more apparent in complex skills, such as cardiac POCUS. HMA may provide a more efficient and reliable assessment of technical skills, including POCUS, when compared to traditional assessment tools., (© 2020 by the Society for Academic Emergency Medicine.)

Objective: To retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA)., Methods: Inclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6)., Results: We included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18-72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14., Conclusions: Our data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear., Competing Interests: Competing interests: LM has received honoraria for speaking and compensation for congress participations from: Sanofi Genzyme and Biogen. LB reports speaker honoraria from PTC Therapeutics, participation in advisory boards for PTC Therapeutics and Sarepta Therapeutics and participation in research sponsored by Santhera Pharmaceuticals. SB received funds for travel and congress participation from Sanofi Genzyme and Biogen. LP has received compensation for congress participations from: Sanofi Genzyme and Biogen. MG received honoraria for speaking and grants to attend scientific meetings from Sanofi-Genzyme and Pfizer. VB compensation for congress participations from Biogen and Sanofi Genzyme. LC received compensation for congress participations from Biogen. RP has received compensation for congress participation from Sanofi Genzyme and Biogen. RT has received compensation for congress participations from Sanofi Genzyme, Biogen and Roche. ES has received compensation for congress participations from: Biogen. GR has received compensation for congress participations from Sanofi Genzyme, CSL Behring, Santhera and Biogen. RZ has received funds for travel and congress participation from Biogen. MS has received speaker’s honoraria from ITALFARMACO, PIAM, Boheringer and Novartis Pharmaceuticals. LP received compensation for congress participations from Biogen Inc, Italy. AS received honoraria for speaking and grants to attend scientific meetings from Sanofi-Genzyme, Alnylam Pharmaceuticals, Akcea Therapeutics and Pfizer. LV has received compensation for congress participation from Sanofi Genzyme and Biogen. RM received compensation for participating on advisory boards in relation to MG clinical trial design, congress participations and research support in the last 5 years from: Catalyst Pharmaceuticals, Alexion Pharmaceuticals, ARGENX Pharma, Biomarin. RL has received: Lecture fees from LT3 s.r.l., NICO s.r.l., SUMMEET s.r.l. and GALEN SYMPOSION s.r.o.; fees for consultancy (Advisory Board) from LT3 s.r.l. and PREX s.r.l.; fees for scientific meeting organization from I & C s.r.l.; Chair meeting fees from PLANNING CONGRESSI s.r.l. GC in the last two years has received compensation for advisory board compensation from: Sanofi Genzyme, Spark, Roche, Lupin and Santhera, congress participations from: Sanofi Genzyme, CSL Behring, Sarepta and Biogen. ILS received compensation for congress participation from Biogen, Italy. TM has received compensation for Scientific Board participations from Sanofi Genzyme; for congress participation from Biogen. GC received compensation for participation ad advisory board for Roche, Sarepta and Italfarmaco. EP reports personal fees from Sarepta, grants and non-financial support from Santhera, personal fees and non-financial support from PTC Pharmaceuticals, non-financial support from Genzyme, personal fees from Roche, outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The aim of this preliminary retrospective study was to assess the feasibility and accuracy of Indocyanine Green (ICG) sentinel node (SLN) sampling using a laparoscopic camera during open endometrial cancer surgery. Material and methods: Retrospective study. Fourteen women with endometrial cancer, not fit for a complete laparoscopic staging, underwent SLN mapping using the IMAGE1 camera during open surgery. Results: The median age of patients was 67 (range 33-86) years. Median BMI was 31 (range 23-58). Mean operative time 157.5 minutes and hospital stay three days. The overall detection rate of SLN mapping was 93%. Bilateral detection was 86%. No post-operative short or long-term complications were observed. Conclusions: Real-time NIR technology supported by the IMAGE1 S is a reliable system and represents a promising method for SLN mapping in selected cases with EC and severe surgical risks, during 48 traditional open approaches. The use of laparoscopy ICG in open surgery seems to be a feasible and useful tool for the detection of SLN in endometrial cancer patients with intraoperative and/or postoperative high morbidity risk. It represents a valid alternative to robotic surgery, particularly in countries and centers where the robotic platform or SPY system for open surgery are not available.

Background:  Anterior communicating artery (AComA) aneurysms are the most common intracranial aneurysm, accounting for 25 to 38% of all cases. In spite of the advent of modern neurointerventional treatments, they still represent a strong indication for clipping in certain anatomical and clinical conditions. However, AComA aneurysms are the deepest located aneurysms of the anastomotic circle of Willis, with a complex spatial orientation, and they are fed by bilateral branches of the anterior circulations. Although, on one hand, these aneurysms represent the most complex ones of the anterior circulation, on the other hand, the experience of young neurosurgeons is increasingly limited. Therefore, respecting operative guidelines is crucial to achieve the best aneurysm exclusion and avoid fatal intraoperative complications., Study Objective:  We describe the technical algorithm we use to teach young neurosurgeons how to approach AComA aneurysms and help them to develop a procedural memory needed to perform an efficient and safe surgery., Materials and Methods:  We reviewed our last 10 years of institutional experience of > 200 cases of clipping ruptured and unruptured AComA aneurysms, analyzing our technical refinements and the difficulties in teaching residents and young neurosurgeons how to establish fundamental key points and design a didactic algorithm that includes operative instructions and safety rules., Results:  We identified seven pragmatic technical key points regarding craniotomy, cisternostomy, gyrus rectus corticectomy, proximal control, perforators and Heubner preservation, aneurysm neck dissection, and clipping to use in a didactic algorithm for teaching residents and as operative instructions for inexperienced neurosurgeons., Conclusion:  In the setting of clipping AComA aneurysms, respect for surgical rules is of paramount importance to perform an efficacious and safe procedure and ensure the best aneurysm exclusion and preservation of neurovascular structures., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: Competing interests: None declared.

Objective: To evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus., Design: Randomised, double-blind, placebo-controlled clinical trial., Setting: 15 hospitals in Italy and five hospitals in the UK., Participants: 44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment., Intervention: 30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1)., Primary and Secondary Outcome Measures: The primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus., Results: The trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was -2.78 (SD: 2.64) points in the 30 mg group, -3.04 (SD: 3.06) points in the 10 mg group and -3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity., Conclusions: Orvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible., Trial Registration Number: EudraCT2013-002763-25., Competing Interests: Competing interests: MT is a current employee and ER is a past employee of NeRRe Therapeutics, and both are inventors on a granted patent on novel uses of orvepitant. BV and PG received payment from NeRRe as investigators in this study. AD received payment from NeRRe for service as the chief medical officer for this study. DJ is an employee of Cromsource, who received payment from NeRRe for statistical analysis of this study. PH has received payment from NeRRe as a consultant. MEL reports receiving personal fees from Legacy Healthcare Services, AdgeroBio Pharmaceuticals, Amryt Pharma, Celldex Therapeutics, Debiopharm, Galderma Research and Development, Johnson & Johnson, Novocure, Lindi Skin, Merck Sharp and Dohme, Helsinn Healthcare, Janssen Research & Development, Menlo Therapeutics, Novartis Pharmaceuticals, F Hoffmann-La Roche, AbbVie, Boehringer Ingelheim Pharma, Allergan, Amgen, ER Squibb & Sons, EMD Serono, AstraZeneca Pharmaceuticals, Genentech, Leo Pharma, Seattle Genetics, Bayer, Männer SAS, Lutris Pharma, Pierre Fabre, Paxman Cooler, Adjucare, Dignitana, Biotechspert, Teva Pharmaceuticals Mexico, Parexel, OnQuality Pharmaceuticals, Novartis, Our Brain Bank, Millennium Pharmaceuticals, and research funding from Berg Health, Bristol-Myers Squibb, Lutris Pharma, Novocure, Paxman, Biotest and Veloce BioPharma. GT reports no conflicts of interest. AW reports receiving payment from NeRRe as chair of the advisory board and from Advent Life Sciences for consultancy, Canbex Therapeutics as a non-executive director (past position), Calcico Therapeutics as chairman (past position) and a non-executive director (past position), and the Wellcome Trust as a member of grant committees. SS reports receiving payment from NeRRe as a member of the advisory board and from Almirall, Astellas Pharma, Beiersdorf, Celgene, Chugai Pharma, Creabilis, Daiichi Sankyo, Galderma, Helsinn, Kiniska Pharmaceuticals, Kneipp, Maruho, Merz Pharma, Novartis, Pierre Fabre Laboratories, Sienna Biopharmaceuticals and Ziarco as a member of their advisory boards and from Menlo Therapeutics as an investigator and participation as an investigator in trials sponsored by Dermascence, Trevi Therapeutics and Vanda Pharmaceuticals., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Extrusion of the scleral buckle is one of the complications patients may encounter undergoing the surgical treatment for retinal detachment. We present two cases of persistent Pseudomonas a eruginosa -related conjunctivitis which infected the silicone explant after retinal surgery. One of them is a 73-year-old Caucasian female patient with hyperaemia, intense pain and mucopurulent discharge. After the conjunctival swabs detected a P. aeruginosa infection, she started both topical and systemic treatment without any results; for this reason we opted for the buckle removal always under systemic therapy. The second case is an 84-year-old Caucasian female patient with fever, periorbital oedema, chronic ocular pain, hyperaemia and purulent discharge. P. aeruginosa has also been detected in this case. No improvement with topical and systemic treatment, so this convinced us to remove patient's buckles and to continue systemic therapy. Both cases had the complete resolution after surgery. It is important to quickly recognise exposed scleral buckles because they can be a source of infections and a rare but threatening cause of endophthalmitis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: AP worked in the Astrazeneca Medical Department until December 2018.

A 26-year-old man undergoing therapy with 45 mg ustekinumab (Stelara) for chronic psoriasis vulgaris was referred by his general practitioner to an infectious diseases department for fatigue, fever, night sweating, generalised lymphadenomegaly and unexplained weight loss. Physical examination revealed bilateral occipital, cervical, axillary and inguinal lymphadenomegalies in addition to splenomegaly. Preliminary investigation revealed elevated Plasmodium lactate dehydrogenase and an inversion of the CD4/CD8 ratio. Whole-body spiral CT scanning with and without contrast showed splenomegaly and highlighted supradiaphragmatic and subdiaphragmatic lymphadenopathies. A complete Infectious Disease Test Panel revealed high levels of anti- Toxoplasma gondii antibodies. Immunoglobulin G avidity was negative. Peripheral blood lymphocyte phenotyping was performed to exclude underlying lymphatic neoplasia. The diagnosis of severe acute toxoplasmosis infection in the setting of immune response modifiers was made. Ustekinumab was suspended indefinitely and the patient underwent monthly serological tests to monitor the immune response until all symptoms resolved and the serological testing was negative for Toxoplasma., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)