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Background: Although the benefit of supportive care in the postcancer period is now well demonstrated, its implementation in the patient journey remains challenging. This article describes the development, since 2015 and in routine care, of supportive postcancer care comprising a multidisciplinary rehabilitation programme (MRP) based on exercise for patients with early breast cancer., Methods: As part of quality control, we reviewed all patient files since the programme was implemented. Patient data regarding the type of cancer, clinical and pathological factors, and treatment were recorded in a computerised database., Results: From April 2015 to January 2024, 655 patients participated in the MRP. The programme lasts for 14 weeks, totalling 126 hours of face-to-face programme, with a maximum of 8 patients per group, in 5 different centres. A multidisciplinary professional team provide supportive care. The MRP is mainly based on supervised physical exercise and patients also participate in social, psychological, dietary support and educational sessions. Supervised physical exercise includes cardiorespiratory endurance work through specific sessions on ergometers or outdoor walking and adapted physical activity sessions to improve muscular capacities (endurance, strength and flexibility)., Conclusion: We describe here the practical implementation of a routine multidisciplinary supportive care programme, based mainly on physical activity, for post-treatment breast cancer patients. We report almost 9 years of experience with the programme. We show that offering this programme in the postcancer setting and in clinical routine practice is feasible and can be maintained in the long term., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Context and Aims: Eribulin is used in taxane and anthracycline refractory HER2-negative metastatic breast cancers (MBC). Patients treated in pivotal clinical trials achieved low survival rates, therefore, the identification of prognostic criteria for long progression-free survival (PFS) is still an unmet medical need. In this study, we sought to determine potential prognostic criteria for long-term eribulin response in HER2-negative MBC., Methods: Our retrospective cohort includes female patients with HER2-negative MBC treated with eribulin in Franche-Comté, France. We defined a long-term response as at least 6 months of eribulin treatment. The primary endpoint was the analysis of criteria that differ according to the progression-free survival. Secondary outcomes concerned overall survival and response rate., Results: From January 2011 to April 2020, 431 patients treated with eribulin were screened. Of them, 374 patients were included. Median PFS was 3.2 months (2.8-3.7). Eighty-eight patients (23.5%) had a long-term response to eribulin. Four discriminant criteria allowed to separate PFS in 2 arms (PFS < 3 months or > 6 months) with a 78% positive predictive value: histological grade, absence of meningeal metastasis, response to prior chemotherapy, and OMS status. We have developed a nomogram combining these 4 criteria. Median overall survival was 8.5 months (7.0-9.5)., Conclusion: Eribulin response in MBC can be driven by clinical and biological factors. Application of our nomogram could assist in the prescription of eribulin., 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The global increase in the aging population has led to a rise in many age-related diseases with continuing unmet therapeutic needs. Research into the molecular mechanisms underlying both aging and neurodegeneration has identified promising therapeutic targets, such as the oxytosis/ferroptosis cell death pathway, in which mitochondrial dysfunction plays a critical role. This study focused on sterubin and fisetin, two flavonoids from the natural pharmacopeia previously identified as strong inhibitors of the oxytosis/ferroptosis pathway. Here, we investigated the effects of the compounds on the mitochondrial physiology in HT22 hippocampal nerve cells under oxytotic/ferroptotic stress. We show that the compounds can restore mitochondrial homeostasis at the level of redox regulation, calcium uptake, biogenesis, fusion/fission dynamics, and modulation of respiration, leading to the enhancement of bioenergetic efficiency. However, mitochondria are not required for the neuroprotective effects of sterubin and fisetin, highlighting their diverse homeostatic impacts. Sterubin and fisetin, thus, provide opportunities to expand drug development strategies for anti-oxytotic/ferroptotic agents and offer new perspectives on the intricate interplay between mitochondrial function, cellular stress, and the pathophysiology of aging and age-related neurodegenerative disorders.

While the transmembrane glycoprotein mucin 1 (MUC1) is clustered at the apical borders of normal epithelial cells, with transformation and loss of polarity, MUC1 is found at high levels in the cytosol and is uniformly distributed over the entire surface of carcinoma cells, where it can promote tumor progression and adversely affects the response to therapy. Clear cell renal cell carcinoma (ccRCC), the main histotype of kidney cancer, is typically highly resistant to conventional and targeted therapies for reasons that remain largely unknown. In this context, we investigated whether MUC1 also plays a pivotal role in the cellular and molecular events driving ccRCC progression and chemoresistance. We showed, using loss- and gain-of-function approaches in ccRCC-derived cell lines, that MUC1 not only influences tumor progression but also induces a multi-drug-resistant profile reminiscent of the activation of ABC drug efflux transporters. Overall, our results suggest that targeting MUC1 may represent a novel therapeutic approach to limit ccRCC progression and improve drug sensitivity.

Non-small cell lung cancer is characterized by a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Therefore, the identification of new molecular determinants underlying sensitivity of cancer cells to existing therapy is of particular importance to develop new effective combinatorial treatment strategy. MicroRNAs (miRNAs), a class of small non-coding RNAs, have been established as master regulators of a variety of cellular processes that play a key role in tumor initiation, progression and metastasis. This, along with their widespread deregulation in many distinct cancers, has triggered enthusiasm for miRNAs as novel therapeutic targets for cancer management, in particular in patients with refractory cancers such as those harboring KRAS mutations. In this study, we performed a loss-of-function screening approach to identify miRNAs whose silencing promotes sensitivity of lung adenocarcinoma (LUAD) cells to cisplatin. Our results showed in particular that antisense oligonucleotides directed against miR-92a-3p, a member of the oncogenic miR-17 ~ 92 cluster, caused the greatest increase in the sensitivity of KRAS-mutated LUAD cells to cisplatin. In addition, we demonstrated that this miRNA finely regulates the apoptotic threshold and the proliferative capacity of various tumor cell lines with distinct genetic alterations. Collectively, these data suggest that targeting miR-92a-3p may serve as an effective strategy to overcome treatment resistance of solid tumors., (© 2023. The Author(s).)

Background: Up to 70% of breast cancer patients report symptoms of insomnia during and after treatment. Despite the ubiquity of insomnia symptoms, they are under-screened, under-diagnosed and poorly managed in breast cancer patients. Sleep medications treat symptoms but are ineffective to cure insomnia. Other approaches such as cognitive behavioral therapy for insomnia, relaxation through yoga and mindfulness are often not available for patients and are complex to implement. An aerobic exercise program could be a promising treatment and a feasible option for insomnia management in breast cancer patients, but few studies have investigated the effects of such a program on insomnia., Methods: This multicenter, randomized clinical trial evaluate the effectiveness of a moderate to high intensity physical activity program (45 min, 3 times per week), lasting 12 weeks, in minimizing insomnia, sleep disturbances, anxiety/depression, fatigue, and pain, and in enhancing cardiorespiratory fitness. Patients with breast cancer be recruited from six hospitals in France and randomly allocated to either the "training" or the "control" group. Baseline assessments include questionnaires [Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index questionnaire (PSQI), Hospital Anxiety Depression Scale (HADS), Epworth Sleepiness Scale (ESS)], home polysomnography (PSG), and 7-day actigraphy coupled with completion of a sleep diary. Assessments are repeated at the end of training program and at six-month follow-up., Discussion: This clinical trial will provide additional evidence regarding the effectiveness of physical exercise in minimizing insomnia during and after chemotherapy. If shown to be effective, exercise intervention programs will be welcome addition to the standard program of care offered to patients with breast cancer receiving chemotherapy., Trial Registration: National Clinical Trials Number (NCT04867096)., (© 2023. The Author(s).)

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment.

Until recently, the first-line treatments used in metastatic renal cell carcinoma were based on first-generation anti-VEGFR (vascular endothelial growth factor receptor) tyrosine kinase inhibitors (TKIs) as monotherapy. Trials combining immunotherapy (IO) (anti-CTLA4 + anti-PD-1) or immunotherapy with TKIs showed striking results in the first-line setting with improvement in overall response rates, progression-free survival and overall survival versus sunitinib. This allowed the combinations to gain registration in the US and Europe in the first-line advanced or metastatic clear-cell renal cell carcinoma setting. However, this improved activity comes at the cost of increased toxicity. Immunotherapy-related toxicities usually occur earlier within the first six months. With immunotherapy came a new range of toxicities making it more necessary to work with networks of specialists to better address autoimmune toxicity in particular. The safety profile is also impacted by the type of TKI used. In most cases, health-related quality of life (HRQoL) favours combinations over the comparator sunitinib. This article aims to review and assess the safety and HRQoL data on these new combinations., (Copyright © 2022 Elsevier Masson SAS. Tous droits réservés.)

Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional therapies and known for abnormal lipid accumulation. In this context, we focused our attention on miR-21, an oncogenic miRNA overexpressed in ccRCC, and peroxysome proliferator-activated receptor-α (PPAR- α), one master regulator of lipid metabolism targeted by miR-21. First, in a cohort of 52 primary ccRCC samples, using RT-qPCR and immunohistochemistry, we showed that miR-21 overexpression was correlated with PPAR-α downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-α overexpression (i) decreased miR-21 expression, AP-1 and NF-κB transcriptional activity, and the binding of AP-1 and NF-κB to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-α expression and transcriptional activity mediated by PPAR-α, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-α expression, but also the expression of its targets involved in fatty acid oxidation. In this study, we showed a double-negative feedback interaction between miR-21 and PPAR-α. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.

This paper surveys the "Dutch disease" literature in developing and emerging countries. It describes the original model of Dutch disease and some main extensions proposed in the theoretical literature, focusing on the ones that match developing countries' conditions. It then reviews various empirical studies that have been conducted and provides evidence that the Dutch disease is still an issue for many developing countries. Finally, it discusses the gaps in the theoretical and empirical literature for understanding the suitable policy instruments to cope with Dutch disease., (© Association for Comparative Economic Studies 2021.)

Background: Postoperative intracerebral haematomas represent a serious complication following stereotactic biopsy. We investigated the possible underlying causes - poor planning or poor execution - of postoperative intracerebral haematomas following stereotactic biopsies., Methods: We performed a technical investigation using a retrospective single-centre consecutive series of robot-assisted stereotactic biopsies for a supratentorial diffuse glioma in adults. Each actual biopsy trajectory was reviewed to search for a conflict with an anatomical structure at risk., Results: From 379 patients, 12 (3.2%) presented with a postoperative intracerebral haematoma ≥20 mm on postoperative CT-scan (3 requiring surgical evacuation); 11 of them had available intraoperative imaging (bi-planar stereoscopic teleangiography x-rays at each biopsy site). The actual biopsy trajectory was similar to the planned biopsy trajectory in these 11 cases. In 72.7% (8/11) of these cases, the actual biopsy trajectory was found to contact a structure at risk (blood vessel and cerebral sulcus) and identified as the intracerebral haematoma origin., Conclusions: Robot-assisted stereotactic biopsy is an accurate procedure. Postoperative intracerebral haematomas mainly derive from human-related errors during trajectory planning., (© 2021 John Wiley & Sons Ltd.)

Introduction: We describe the clinical features and inpatient trajectories of older adults hospitalized with COVID-19 and explore relationships with frailty., Methods: This retrospective observational study included older adults admitted as an emergency to a University Hospital who were diagnosed with COVID-19. Patient characteristics and hospital outcomes, primarily inpatient death or death within 14 days of discharge, were described for the whole cohort and by frailty status. Associations with mortality were further evaluated using Cox Proportional Hazards Regression (Hazard Ratio (HR), 95% Confidence Interval)., Results: 214 patients (94 women) were included of whom 142 (66.4%) were frail with a median Clinical Frailty Scale (CFS) score of 6. Frail compared to nonfrail patients were more likely to present with atypical symptoms including new or worsening confusion (45.1% vs. 20.8%, p < 0.001) and were more likely to die (66% vs. 16%, p = 0.001). Older age, being male, presenting with high illness acuity and high frailty were independent predictors of death and a dose-response association between frailty and mortality was observed (CFS 1-4: reference; CFS 5-6: HR 1.78, 95% CI 0.90, 3.53; CFS 7-8: HR 2.57, 95% CI 1.26, 5.24)., Conclusions: Clinicians should have a low threshold for testing for COVID-19 in older and frail patients during periods of community viral transmission, and diagnosis should prompt early advanced care planning.

Gadolinium-based contrast agents (GBCAs) are used in up to 35% of magnetic resonance imaging (MRI) examinations and are associated with an excellent safety profile. Nevertheless, two main issues have arisen in the last two decades: the risk of nephrogenic systemic fibrosis and the risk of gadolinium deposition and retention. As a first step, this article reviews the different categories of GBCAs available in neuroradiology, their issues, and provides updates regarding the use of these agents in routine daily practice. Recent advances in MRI technology, as well as the development of new MRI sequences, have made GBCA injection avoidable in many indications, especially in patients with chronic diseases when iterative MRIs are required and when essential diagnostic information can be obtained without contrast enhancement. These recent advances also lead to changes in recommended MRI protocols. Thus, in a second step, this review focuses on consensus concerning brain MRI protocols in 10 common situations (acute ischemic stroke, intracerebral hemorrhage, cerebral venous thrombosis, multiple sclerosis, chronic headache, intracranial infection, intra- and extra-axial brain tumors, vestibular schwannoma and pituitary adenoma). The latter allowing the standardization of practices in neuroradiology. Recommendations were also made concerning the use of GBCAs in neuroradiology, based on evidence in the literature and/or by consensus between the different coauthors., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background Brain MRI parenchymal signal abnormalities have been associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Purpose To describe the neuroimaging findings (excluding ischemic infarcts) in patients with severe coronavirus disease 2019 (COVID-19) infection. Materials and Methods This was a retrospective study of patients evaluated from March 23, 2020, to April 27, 2020, at 16 hospitals. Inclusion criteria were ( a ) positive nasopharyngeal or lower respiratory tract reverse transcriptase polymerase chain reaction assays, ( b ) severe COVID-19 infection defined as a requirement for hospitalization and oxygen therapy, ( c ) neurologic manifestations, and ( d ) abnormal brain MRI findings. Exclusion criteria were patients with missing or noncontributory data regarding brain MRI or brain MRI showing ischemic infarcts, cerebral venous thrombosis, or chronic lesions unrelated to the current event. Categorical data were compared using the Fisher exact test. Quantitative data were compared using the Student t test or Wilcoxon test. P < .05 represented a significant difference. Results Thirty men (81%) and seven women (19%) met the inclusion criteria, with a mean age of 61 years ± 12 (standard deviation) (age range, 8-78 years). The most common neurologic manifestations were alteration of consciousness (27 of 37, 73%), abnormal wakefulness when sedation was stopped (15 of 37, 41%), confusion (12 of 37, 32%), and agitation (seven of 37, 19%). The most frequent MRI findings were signal abnormalities located in the medial temporal lobe in 16 of 37 patients (43%; 95% confidence interval [CI]: 27%, 59%), nonconfluent multifocal white matter hyperintense lesions seen with fluid-attenuated inversion recovery and diffusion-weighted sequences with variable enhancement, with associated hemorrhagic lesions in 11 of 37 patients (30%; 95% CI: 15%, 45%), and extensive and isolated white matter microhemorrhages in nine of 37 patients (24%; 95% CI: 10%, 38%). A majority of patients (20 of 37, 54%) had intracerebral hemorrhagic lesions with a more severe clinical presentation and a higher admission rate in intensive care units (20 of 20 patients [100%] vs 12 of 17 patients without hemorrhage [71%], P = .01) and development of the acute respiratory distress syndrome (20 of 20 patients [100%] vs 11 of 17 patients [65%], P = .005). Only one patient had SARS-CoV-2 RNA in the cerebrospinal fluid. Conclusion Patients with severe coronavirus disease 2019 and without ischemic infarcts had a wide range of neurologic manifestations that were associated with abnormal brain MRI scans. Eight distinctive neuroradiologic patterns were described. © RSNA, 2020.

Objective: To describe neuroimaging findings and to report the epidemiologic and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with neurologic manifestations., Methods: In this retrospective multicenter study (11 hospitals), we included 64 patients with confirmed COVID-19 with neurologic manifestations who underwent a brain MRI., Results: The cohort included 43 men (67%) and 21 women (33%); their median age was 66 (range 20-92) years. Thirty-six (56%) brain MRIs were considered abnormal, possibly related to severe acute respiratory syndrome coronavirus. Ischemic strokes (27%), leptomeningeal enhancement (17%), and encephalitis (13%) were the most frequent neuroimaging findings. Confusion (53%) was the most common neurologic manifestation, followed by impaired consciousness (39%), presence of clinical signs of corticospinal tract involvement (31%), agitation (31%), and headache (16%). The profile of patients experiencing ischemic stroke was different from that of other patients with abnormal brain imaging: the former less frequently had acute respiratory distress syndrome ( p = 0.006) and more frequently had corticospinal tract signs ( p = 0.02). Patients with encephalitis were younger ( p = 0.007), whereas agitation was more frequent for patients with leptomeningeal enhancement ( p = 0.009)., Conclusions: Patients with COVID-19 may develop a wide range of neurologic symptoms, which can be associated with severe and fatal complications such as ischemic stroke or encephalitis. In terms of meningoencephalitis involvement, even if a direct effect of the virus cannot be excluded, the pathophysiology seems to involve an immune or inflammatory process given the presence of signs of inflammation in both CSF and neuroimaging but the lack of virus in CSF., Clinicaltrialsgov Identifier: NCT04368390., (© 2020 American Academy of Neurology.)

Background: Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs)., Methods: We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification., Results: Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of "rare adult IDH mutations" (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance., Conclusions: HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background Metastatic Squamous cell Penile Carcinoma (mSCPC) is an orphan disease with a virally induced oncogenesis. PD-L1 expression rate is around 60% with a strong correlation between PD-L1 in the primary tumour and metastases. The first line systemic treatment relies on platinum-based chemotherapies with a median progression free survival and overall survival around 7.5 and 16 months, respectively. Immunotherapies targeting PD-1/PD-L1 axis are effective in other squamous cell or HPV related cancers. Methods PULSE is a prospective multicenter open label single arm phase II study. Thirty-two patients will be enrolled after a radiological assessment showing a non-progressive disease after 3 to 6 cycles of a first line platinum-based polychemotherapy. Patients will receive Avelumab injections 10mg/ kg every two weeks until progression or unacceptable toxicity. The primary endpoint will be the progression free survival (PFS) according to RECIST v1.1 criteria. Secondary endpoints will include PFS according to iRECIST criteria, overall survival, quality of life, safety. Ancillary explorations will include assessing blood and tissue biomarkers for association with clinical benefit. Discussion After the first line, the prognosis remains poor with no consensus on a second line systemic treatment in locally advanced or mSCPC. PULSE trial is the first study that assess an anti PD-L1 immunotherapy in maintenance among patients with locally advanced or mSCPC. NCT NUMBER : NCT03774901., (Copyright © 2020 Société Française du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Background: Patients with severe renal impairment or undergoing hemodialysis are usually excluded from clinical trials. Available data regarding safety and activity of systemic therapies (ST) in hemodialyzed patients are scarce., Methods: Clinical data were searched through PubMed database until April 2020 according to PRISMA criteria. Efficacy, safety and pharmacokinetic (PK) assessment of ST were reported., Results: Among 270 references, 56 reports were evaluated in full text: 41 were included for efficacy and 42 for safety analysis (sunitinib n = 68, bevacizumab n = 6, everolimus n = 28, temsirolimus n = 17, sorafenib n = 55, axitinib n = 13, pazopanib n = 13, nivolumab n = 18, cabozantinib n = 0, lenvatinib n = 0, and ipilimumab n = 0). Twelve of the reports included PK assessment among dialyzed patients. Hemodialysis did not seem to modify the expected efficacy and safety of each compound among patients undergoing hemodialysis. PK assessments were not modified in comparison with a population not undergoing dialysis., Conclusion: Targeted and Immune therapies seem to be effective and can be used among patients undergoing hemodialysis. Due to frailty and comorbidities associated to chronic hemodialysis enhanced vigilance for these therapies within this specific population is recommended. Dedicated prospective clinical trials would definitely help to obtain data with a higher level of evidence., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Klajer E.: Pfizer and Ipsen Garnier L.: No conflict of interest Goujon M.: BMS and Ipsen Schurmann-Constans F.: Ipsen, Novartis, PfizerMery B.: No conflict of interest N Guyen Tan Hon: No conflict of interest Mouillet G: BMS Ipsen, Novartis, Pfizer, and Roche, (Copyright © 2020 Elsevier Inc. All rights reserved.)

The first example of a ruthenium-catalyzed C-H bond alkylation via six-membered ruthenacycles is presented. This is disclosed for the C-H bond alkylation of biologically relevant cyclic amides with maleimide derivatives. The cyclic tertiary amide core acted as a directing group (DG) enabling formation of six-membered cycloruthenated species responsible for the control of the regio- and site selectivity of the reaction as well as the excellent functional group tolerance. Unexpectedly, cyclic amides were found to be better DGs than pyridine-containing ones or cyclic imides for this type of C-H bond functionalization.

Objective: Our aim was to compare the clinical outcome of patients with ischaemic stroke with anterior large vessel occlusion treated with stent retrievers and/or contact aspiration mechanical thrombectomy (MT) under general anaesthesia (GA) or conscious sedation non-GA through a systematic review and meta-analysis., Methods: The literature was searched using PubMed, Embase and Cochrane databases to identify studies reporting on anaesthesia and MT. Using fixed or random weighted effect, we evaluated the following outcomes: 3-month mortality, modified Rankin Score (mRs) 0-2, recanalisation success (thrombolysis in cerebral infarction (TICI) ≥2b) and symptomatic intracerebral haemorrhagic (sICH) transformation., Results: We identified seven cohorts (including three dedicated randomised controlled trials), totalling 1929 patients (932 with GA). Over the entire sample, mortality, mRs 0-2, TICI≥2b and sICH rates were, respectively 17.5% (99% CI 9.7% to 29.6%; Q-value: 60.1; I 2 : 93%, 1717 patients), 42.1% (99% CI 33.3% to 51.7%; Q-value: 41.3; I 2 : 87.9%), 82.9% (99% CI 74.0% to 89.1%; Q-value: 20.7; I 2 : 80.6%, 1006 patients) and 5.5% (99% CI 2.8% to 10.8%; Q-value: 18.6; I 2 : 78.5%). MT performed in non-GA patients was associated with better 3-month functional outcome (pooled OR, 1.35; 99% CI 1.04 to 1.76; Q-value: 24.0; I 2 : 9.2%, 1845 patients) and lower 3-month mortality rate (pooled OR, 0.70; 99% CI 0.49 to 0.98; Q-value: 1.4; I 2 : 0%, 1717 patients; fixed weighted effect model) compared with GA. MT performed under conscious sedation non-GA had significantly shorter onset-to-recanalisation and onset-to-groin delay compared with GA, and recanalisation success and sICH were similar., Conclusion: Non-GA during MT for anterior acute ischaemic stroke with current-generation stent retriever/aspiration devices is associated with better 3-month functional outcome and lower mortality rates. These unadjusted estimates are subject to biases and should be interpreted with caution., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose- We assessed whether the presence, number, and distribution of cerebral microbleeds (CMBs) on pre-intravenous thrombolysis MRI scans of acute ischemic stroke patients are associated with an increased risk of intracerebral hemorrhage (ICH) or poor functional outcome. Methods- We performed an individual patient data meta-analysis, including prospective and retrospective studies of acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Using multilevel mixed-effects logistic regression, we investigated associations of pre-treatment CMB presence, burden (1, 2-4, ≥5, and >10), and presumed pathogenesis (cerebral amyloid angiopathy defined as strictly lobar CMBs and noncerebral amyloid angiopathy) with symptomatic ICH, parenchymal hematoma (within [parenchymal hemorrhage, PH] and remote from the ischemic area [remote parenchymal hemorrhage, PHr]), and poor 3- to 6-month functional outcome (modified Rankin score >2). Results- In 1973 patients from 8 centers, the crude prevalence of CMBs was 526 of 1973 (26.7%). A total of 77 of 1973 (3.9%) patients experienced symptomatic ICH, 210 of 1806 (11.6%) experienced PH, and 56 of 1720 (3.3%) experienced PHr. In adjusted analyses, patients with CMBs (compared with those without CMBs) had increased risk of PH (odds ratio: 1.50; 95% confidence interval: 1.09-2.07; P=0.013) and PHr (odds ratio: 3.04; 95% confidence interval: 1.73-5.35; P<0.001) but not symptomatic ICH. Both cerebral amyloid angiopathy and noncerebral amyloid angiopathy patterns of CMBs were associated with PH and PHr. Increasing CMB burden category was associated with the risk of symptomatic ICH ( P=0.014), PH ( P=0.013), and PHr ( P<0.00001). Five or more and >10 CMBs independently predicted poor 3- to 6-month outcome (odds ratio: 1.85; 95% confidence interval: 1.10-3.12; P=0.020; and odds ratio: 3.99; 95% confidence interval: 1.55-10.22; P=0.004, respectively). Conclusions- Increasing CMB burden is associated with increased risk of ICH (including PHr) and poor 3- to 6-month functional outcome after intravenous thrombolysis for acute ischemic stroke.

The availability of comprehensive information about enzymes plays an important role in answering questions relevant to interdisciplinary fields such as biochemistry, enzymology, biofuels, bioengineering and drug discovery. At the EMBL European Bioinformatics Institute, we have developed an enzyme portal (http://www.ebi.ac.uk/enzymeportal) to provide this wealth of information on enzymes from multiple in-house resources addressing particular data classes: protein sequence and structure, reactions, pathways and small molecules. The fact that these data reside in separate databases makes information discovery cumbersome. The main goal of the portal is to simplify this process for end users.

Unlabelled: Iterative similarity searches with PSI-BLAST position-specific score matrices (PSSMs) find many more homologs than single searches, but PSSMs can be contaminated when homologous alignments are extended into unrelated protein domains-homologous over-extension (HOE). PSI-Search combines an optimal Smith-Waterman local alignment sequence search, using SSEARCH, with the PSI-BLAST profile construction strategy. An optional sequence boundary-masking procedure, which prevents alignments from being extended after they are initially included, can reduce HOE errors in the PSSM profile. Preventing HOE improves selectivity for both PSI-BLAST and PSI-Search, but PSI-Search has ~4-fold better selectivity than PSI-BLAST and similar sensitivity at 50% and 60% family coverage. PSI-Search is also produces 2- for 4-fold fewer false-positives than JackHMMER, but is ~5% less sensitive., Availability and Implementation: PSI-Search is available from the authors as a standalone implementation written in Perl for Linux-compatible platforms. It is also available through a web interface (www.ebi.ac.uk/Tools/sss/psisearch) and SOAP and REST Web Services (www.ebi.ac.uk/Tools/webservices).

The EMBL-EBI provides access to various mainstream sequence analysis applications. These include sequence similarity search services such as BLAST, FASTA, InterProScan and multiple sequence alignment tools such as ClustalW, T-Coffee and MUSCLE. Through the sequence similarity search services, the users can search mainstream sequence databases such as EMBL-Bank and UniProt, and more than 2000 completed genomes and proteomes. We present here a new framework aimed at both novice as well as expert users that exposes novel methods of obtaining annotations and visualizing sequence analysis results through one uniform and consistent interface. These services are available over the web and via Web Services interfaces for users who require systematic access or want to interface with customized pipe-lines and workflows using common programming languages. The framework features novel result visualizations and integration of domain and functional predictions for protein database searches. It is available at http://www.ebi.ac.uk/Tools/sss for sequence similarity searches and at http://www.ebi.ac.uk/Tools/msa for multiple sequence alignments.

The EB-eye is a fast and efficient search engine that provides easy and uniform access to the biological data resources hosted at the EMBL-EBI. Currently, users can access information from more than 62 distinct datasets covering some 400 million entries. The data resources represented in the EB-eye include: nucleotide and protein sequences at both the genomic and proteomic levels, structures ranging from chemicals to macro-molecular complexes, gene-expression experiments, binary level molecular interactions as well as reaction maps and pathway models, functional classifications, biological ontologies, and comprehensive literature libraries covering the biomedical sciences and related intellectual property. The EB-eye can be accessed over the web or programmatically using a SOAP Web Services interface. This allows its search and retrieval capabilities to be exploited in workflows and analytical pipe-lines. The EB-eye is a novel alternative to existing biological search and retrieval engines. In this article we describe in detail how to exploit its powerful capabilities.

The European Bioinformatics Institute (EMBL-EBI) provides public access to patent data, including abstracts, chemical compounds and sequences. Sequences can appear multiple times due to the filing of the same invention with multiple patent offices, or the use of the same sequence by different inventors in different contexts. Information relating to the source invention may be incomplete, and biological information available in patent documents elsewhere may not be reflected in the annotation of the sequence. Search and analysis of these data have become increasingly challenging for both the scientific and intellectual-property communities. Here, we report a collection of non-redundant patent sequence databases, which cover the EMBL-Bank nucleotides patent class and the patent protein databases and contain value-added annotations from patent documents. The databases were created at two levels by the use of sequence MD5 checksums. Sequences within a level-1 cluster are 100% identical over their whole length. Level-2 clusters were defined by sub-grouping level-1 clusters based on patent family information. Value-added annotations, such as publication number corrections, earliest publication dates and feature collations, significantly enhance the quality of the data, allowing for better tracking and cross-referencing. The databases are available format: http://www.ebi.ac.uk/patentdata/nr/.

The European Bioinformatics Institute (EMBL-EBI) has been providing access to mainstream databases and tools in bioinformatics since 1997. In addition to the traditional web form based interfaces, APIs exist for core data resources such as EMBL-Bank, Ensembl, UniProt, InterPro, PDB and ArrayExpress. These APIs are based on Web Services (SOAP/REST) interfaces that allow users to systematically access databases and analytical tools. From the user's point of view, these Web Services provide the same functionality as the browser-based forms. However, using the APIs frees the user from web page constraints and are ideal for the analysis of large batches of data, performing text-mining tasks and the casual or systematic evaluation of mathematical models in regulatory networks. Furthermore, these services are widespread and easy to use; require no prior knowledge of the technology and no more than basic experience in programming. In the following we wish to inform of new and updated services as well as briefly describe planned developments to be made available during the course of 2009-2010.