Showing papers by "French Institute of Health and Medical Research published in 2023"

Gain of function <i>SCN1A</i> disease‐causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication

Abstract: Objective This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype–genotype relationship and functional consequences of SCN1A variants in a cohort of patients. Methods Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. Results Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. Significance The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication.

Participation in breast cancer screening and its influence on other cancer screening invitations: study in women aged 56 years old in four French departments

Abstract: Background Today, women 50 years of age are offered three types of cancer screening in France. However, participation is not optimal. The aim was to describe (1) participation in organised breast cancer screening (OS) of women aged 56 years old, and the influence of this participation on colorectal and cervical cancer screening, (2) the reasons for non-participation in breast cancer OS, and (3) the reasons for screening before age 50. Methods A questionnaire was sent to 56-year-old women in four French departments to identify their participation behaviour in three breast cancer OS invitations and their reasons for non-participation. Three groups were determined according to the number of participations in breast cancer OS (3, 1–2 and 0). We described the quantitative responses and grouped the qualitative responses thematically. Results A total of 4634 women responded to the questionnaire. Seventy-six percent had undergone all three breast cancer OS, 16% irregular and 7% non-participant. Among women who irregularly perform breast cancer OS, 50.5% also irregularly perform colorectal cancer OS. Women who participated in all three invitations for the breast cancer OS performed more smear tests than women in the other groups. Many of the irregular participants or non-participants underwent opportunistic screening, often initiated before the age of 50. The reasons for non-participation in breast cancer OS were mainly medical or participation in opportunistic screening. Conclusion There is no fundamental opposition to participation in breast cancer screening. However, it remains of the utmost importance that women should be better informed about OS and its benefits.

Chronic Low Back Pain: A Narrative Review of Recent International Guidelines for Diagnosis and Conservative Treatment

Abstract: Chronic low back pain (cLBP) is a public and occupational health problem that is a major professional, economic and social burden. We aimed to provide a critical overview of current international recommendations regarding the management of non-specific cLBP. We conducted a narrative review of international guidelines for the diagnosis and conservative treatment of people with non-specific cLBP. Our literature search yielded five reviews of guidelines published between 2018 and 2021. In these five reviews, we identified eight international guidelines that fulfilled our selection criteria. We added the 2021 French guidelines into our analysis. Regarding diagnosis, most international guidelines recommend searching for so-called yellow, blue and black flags, in order to stratify the risk of chronicity and/or persistent disability. The relevance of clinical examination and imaging are under debate. Regarding management, most international guidelines recommend non-pharmacological treatments, including exercise therapy, physical activity, physiotherapy and education; however, multidisciplinary rehabilitation, in selected cases, is the core treatment recommended for people with non-specific cLBP. Oral, topical or injected pharmacological treatments are under debate, and may be offered to selected and well-phenotyped patients. The diagnosis of people with cLBP may lack precision. All guidelines recommend multimodal management. In clinical practice, the management of individuals with non-specific cLBP should combine non-pharmacological and pharmacological treatments. Future research should focus on improving tailorization.

Non‐Contrast‐Enhanced Functional Lung <scp>MRI</scp> to Evaluate Treatment Response of Allergic Bronchopulmonary Aspergillosis in Patients With Cystic Fibrosis: A Pilot Study

Abstract: Background Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients is associated with severe lung damage and requires specific therapeutic management. Repeated imaging is recommended to both diagnose and follow-up response to treatment of ABPA in CF. However, high risk of cumulative radiation exposure requires evaluation of free-radiation techniques in the follow-up of CF patients with ABPA. Purpose To evaluate whether Fourier decomposition (FD) functional lung MRI can detect response to treatment of ABPA in CF patients. Study Type Retrospective longitudinal. Population Twelve patients (7M, median-age:14 years) with CF and ABPA with pre- and post-treatment MRI. Field Strength/Sequence 2D-balanced-steady-state free-precession (bSSFP) sequence with FD at 1.5T. Assessment Ventilation-weighted (V) and perfusion-weighted (Q) maps were obtained after FD processing of 2D-coronal bSSFP time-resolved images acquired before and 3–9 months after treatment. Defects extent was assessed on the functional maps using a qualitative semi-quantitative score (0 = absence/negligible, 1 = <50%, 2 = >50%). Mean and coefficient of variation (CV) of the ventilation signal-intensity (VSI) and the perfusion signal-intensity (QSI) were calculated. Measurements were performed independently by three readers and averaged. Inter-reader reproducibility of the measurements was assessed. Pulmonary function tests (PFTs) were performed within 1 week of both MRI studies as markers of the airflow-limitation severity. Statistical Tests Comparisons of medians were performed using the paired Wilcoxon-test. Reproducibility was assessed using intraclass correlation coefficient (ICC). Correlations between MRI and PFT parameters were assessed using the Spearman-test (rho correlation-coefficient). A P-value <0.05 was considered as significant. Results Defects extent on both V and Q maps showed a significant reduction after ABPA treatment (4.25 vs. 1.92 for V-defect-score and 5 vs. 2.75 for Q-defect-score). VSI_mean was significantly increased after treatment (280 vs. 167). Qualitative analyses reproducibility showed an ICC > 0.90, while the ICCs of the quantitative measurements was almost perfect (>0.99). Changes in VSI_cv and QSI_cv before and after treatment correlated inversely with changes of FEV1%p (rho = −0.68 for both). Data Conclusion Non-contrast-enhanced FD lung MRI has potential to reproducibly assess response to treatment of ABPA in CF patients and correlates with PFT obstructive parameters. Evidence Level 4 Technical Efficacy Stage 3

Traffic-Related Air Pollution and Breast Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies

Abstract: Current evidence of an association of breast cancer (BC) risk with air pollution exposure, in particular from traffic exhaust, remains inconclusive, and the exposure assessment methodologies are heterogeneous. This study aimed to conduct a systematic review and meta-analysis on the association between traffic-related air pollution (TRAP) and BC incidence (PROSPERO CRD42021286774). We systematically reviewed observational studies assessing exposure to TRAP and BC risk published until June 2022, available on Medline/PubMed and Web of Science databases. Studies using models for assessing exposure to traffic-related air pollutants or using exposure proxies (including traffic density, distance to road, etc.) were eligible for inclusion. A random-effects meta-analysis of studies investigating the association between NO2/NOx exposure and BC risk was conducted. Overall, 21 studies meeting the inclusion criteria were included (seven case–control, one nested case–control, 13 cohort studies); 13 studies (five case–control, eight cohort) provided data for inclusion in the meta-analyses. Individual studies provided little evidence of an association between TRAP and BC risk; exposure assessment methods and time periods of traffic emissions were different. The meta-estimate on NO2 exposure indicated a positive association (pooled relative risk per 10 µg/m3 of NO2: 1.015; 95% confidence interval, CI: 1.003; 1.028). No association between NOx exposure and BC was found (three studies). Although there was limited evidence of an association for TRAP estimated with proxies, the meta-analysis showed a significant association between NO2 exposure, a common TRAP pollutant marker, and BC risk, yet with a small effect size. Our findings provide additional support for air pollution carcinogenicity.

The Ethical Implications of Tissue Engineering for Regenerative Purposes: A Systematic Review

Abstract: Tissue Engineering (TE) is a branch of Regenerative Medicine (RM) that combines stem cells and biomaterial scaffolds to create living tissue constructs to restore patients' organs after injury or disease. Over the last decade, emerging technologies such as 3D bioprinting, biofabrication, supramolecular materials, induced pluripotent stem cells, and organoids have entered the field. While this rapidly evolving field is expected to have great therapeutic potential, its development from bench to bedside presents several ethical and societal challenges. To make sure TE will reach its ultimate goal of improving patient welfare, these challenges should be mapped out and evaluated. Therefore, we performed a systematic review of the ethical implications of the development and application of TE for regenerative purposes, as mentioned in the academic literature. A search query in PubMed, Embase, Scopus, and PhilPapers yielded 2451 unique articles. After systematic screening, 237 relevant ethical and biomedical articles published between 2008 and 2021 were included in our review. We identified a broad range of ethical implications that could be categorized under 10 themes. Seven themes trace the development from bench to bedside: (1) animal experimentation, (2) handling human tissue, (3) informed consent, (4) therapeutic potential, (5) risk and safety, (6) clinical translation, and (7) societal impact. Three themes represent ethical safeguards relevant to all developmental phases: (8) scientific integrity, (9) regulation, and (10) patient and public involvement. This review reveals that since 2008 a significant body of literature has emerged on how to design clinical trials for TE in a responsible manner. However, several topics remain in need of more attention. These include the acceptability of alternative translational pathways outside clinical trials, soft impacts on society and questions of ownership over engineered tissues. Overall, this overview of the ethical and societal implications of the field will help promote responsible development of new interventions in TE and RM. It can also serve as a valuable resource and educational tool for scientists, engineers, and clinicians in the field by providing an overview of the ethical considerations relevant to their work. Impact statement To our knowledge, this is the first time that the ethical implications of Tissue Engineering (TE) have been reviewed systematically. By gathering existing scholarly work and identifying knowledge gaps, this review facilitates further research into the ethical and societal implications of TE and Regenerative Medicine (RM) and other emerging biomedical technologies. Moreover, it will serve as a valuable resource and educational tool for scientists, engineers, and clinicians in the field by providing an overview of the ethical considerations relevant to their work. As such, our review may promote successful and responsible development of new strategies in TE and RM.

Response to Chemoimmunotherapy Is Associated With Expansion of Systemic Antitumor CD4+ Th1 Response in Metastatic Non–Small Cell Lung Cancer

Abstract: Limited data have reported the evolution of antitumor immune responses under chemoimmunotherapy (chemo-IO) in patients with metastatic non-small cell lung cancer. In this concise study, we performed dynamic monitoring of antitumor CD4+ T helper 1 (Th1) response in peripheral blood from 12 patients receiving a first-line chemo-IO. Tumor-reactive CD4+ Th1 cells were assessed within blood lymphocytes using interferon-gamma enzyme-linked immunospot assay to detect telomerase (TERT)-specific T cells at baseline, 3 and 12 months after treatment. An induction of circulating anti-TERT CD4+ Th1 response were found in 6 of 12 patients at 3 months after chemo-IO. In contrast, 3 patients had a substantial decrease in their preexisting response and 3 remained nonimmune responders. Among patients with chemo-IO-induced immune response, half achieved an objective clinical response and had long-lasting circulating anti-TERT CD4+ Th1 cells detected for at least 1 year. In contrast, no objective response was documented in nonimmune responders and a link between the loss of anti-TERT CD4+ Th1 responses were observed in patients with progressive disease. This preliminary work supports a relationship between the efficacy of combinatorial chemo-IO and circulating anti-TERT CD4+ Th1 responses and highlights the interest to implement blood-based monitoring of tumor-reactive CD4+ T cells that could be additional help for patient management.

Recent Trends in Antimicrobial Resistance among Anaerobic Clinical Isolates

Abstract: Anaerobic bacteria are normal inhabitants of the human commensal microbiota and play an important role in various human infections. Tedious and time-consuming, antibiotic susceptibility testing is not routinely performed in all clinical microbiology laboratories, despite the increase in antibiotic resistance among clinically relevant anaerobes since the 1990s. β-lactam and metronidazole are the key molecules in the management of anaerobic infections, to the detriment of clindamycin. β-lactam resistance is usually mediated by the production of β-lactamases. Metronidazole resistance remains uncommon, complex, and not fully elucidated, while metronidazole inactivation appears to be a key mechanism. The use of clindamycin, a broad-spectrum anti-anaerobic agent, is becoming problematic due to the increase in resistance rate in all anaerobic bacteria, mainly mediated by Erm-type rRNA methylases. Second-line anti-anaerobes are fluoroquinolones, tetracyclines, chloramphenicol, and linezolid. This review aims to describe the up-to-date evolution of antibiotic resistance, give an overview, and understand the main mechanisms of resistance in a wide range of anaerobes.

Intraoperative Electroencephalography Alpha-Band Power Is a Better Proxy for Preoperative Low MoCA Under Propofol Compared With Sevoflurane

Abstract: BACKGROUND: Preoperative abnormal cognitive status is a risk factor for postoperative complications yet remains underdiagnosed. During propofol general anesthesia, intraoperative electroencephalography (EEG) variables, such as alpha band power (α-BP), correlate with cognitive status. This relationship under sevoflurane is unclear. We investigated whether EEG biomarkers of poor cognitive status found under propofol could be extended to sevoflurane. METHODS: In this monocentric prospective observational study, 106 patients with intraoperative EEG monitoring were included (propofol/sevoflurane = 55/51). We administered the Montreal Cognitive Assessment (MoCA) scale to identify abnormal cognition (low MoCA) 1 day before intervention. EEG variables included delta to beta frequency band powers. Results were adjusted to age and drug dosage. We assessed depth of anesthesia (DoA) using the spectral edge frequency (SEF95) and maintained it within (8–13) Hz. RESULTS: The difference in α-BP between low and normal MoCA patients was significantly larger among propofol patients (propofol: 4.3 ± 4.8 dB versus sevoflurane: 1.5 ± 3.4 dB, P = .022). SEF95 and age were not statistically different between sevoflurane and propofol groups. After adjusting to age and dose, low α-BP was significantly associated with low MoCA under propofol (odds ratio [OR] [confidence interval {CI}] = 0.39 [0.16–0.94], P = .034), but not under sevoflurane, where theta-band power was significantly associated with low MoCA (OR [CI] = 0.31 [0.13–0.73], P = .007). CONCLUSIONS: We suggest that intraoperative EEG biomarkers of abnormal cognition differ between propofol and sevoflurane under general anesthesia.

The Loss of the E3 ubiquitin ligase TRIP12 inhibits Pancreatic Acinar Cell Plasticity and Tumor Cell Metastatic Capacity

Abstract: Background & Aims: Although specialized and dedicated to the production of digestive enzymes, pancreatic acinar cells harbor a high plasticity and are able to modify their identity. They undergo reversible acinar-to-ductal cell metaplasia (ADM) through epigenetic silencing of the acinar lineage gene program mainly controlled by PTF1a (Pancreas Transcription Factor 1a). ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. We investigated the role of the E3 ubiquitin ligase Thyroid hormone Receptor Interacting Protein 12 (TRIP12), involved in PTF1a degradation, in pancreatic carcinogenesis. Methods: We used genetically engineered mouse models of pancreas-selective Trip12 deletion, mutant Kras (G12D) and mutant Trp53 (R172H). We performed RNA sequencing analysis from acinar cells and cell lines derived from mice models tumors. We investigated the impact of TRIP12 deficiency on acute pancreatitis, tumor formation and metastasis development. Results: TRIP12 is overexpressed in human pancreatic preneoplastic lesions and tumors. We show that a conditional deletion of TRIP12 in the pancreas during murine embryogenesis alters pancreas homeostasis and acinar cell genes expression patterns in adults. EGF induced-ADM is suppressed in TRIP12-depleted pancreatic acini. In vivo, a loss of TRIP12 prevents acini to develop ADM in response to pancreatic injury, the formation of Kras-induced pancreatic preneoplastic lesions, and impairs tumors and metastasis formation in the presence of mutated Trp53. TRIP12 is required for Claudin18.2 isoform expression in pancreatic tumors cells. Conclusions: Our study identifies TRIP12 as a novel regulator of acinar fate in the adult pancreas with an important dual role in pancreatic carcinogenesis, in initiation steps and in metastatic behavior of tumor cells.

Novel Therapeutic Targets in Melanoma

Abstract: Melanoma is the most aggressive skin cancer type and ranks amongst the deadliest cancers due to its ability to develop resistance to current therapies [...].

Mechanical Thrombectomy in Late-Time Windows: Time to Treat More Patients

Abstract: HomeStrokeVol. 54, No. 3Mechanical Thrombectomy in Late-Time Windows: Time to Treat More Patients Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMechanical Thrombectomy in Late-Time Windows: Time to Treat More Patients Guillaume Turc, MD, PhD Guillaume TurcGuillaume Turc Correspondence to: Guillaume Turc, MD, PhD, GHU Paris Psychiatrie et Neurosciences, 1 Rue Cabanis, 75014 Paris, France. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5059-4095 Department of Neurology, GHU Paris Psychiatrie et Neurosciences, France; Université Paris Cité, France; INSERM U1266, Paris, France; and FHU NeuroVasc, Paris, France. Search for more papers by this author Originally published31 Jan 2023https://doi.org/10.1161/STROKEAHA.122.041420Stroke. 2023;54:731–732This article is a commentary on the followingMechanical Thrombectomy Versus Best Medical Treatment in the Late Time Window in Non-DEFUSE-Non-DAWN Patients: A Multicenter Cohort StudyOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 31, 2023: Ahead of Print The DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) and DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trials, published in 2018, have led to a revolution in acute stroke care, demonstrating for the first time that some patients can benefit from mechanical thrombectomy up to 24 hours after last seen well.1,2 These trials provided compelling evidence that (at least in late time windows) tissue is more important than time. However, the patients enrolled in these pivotal trials were highly selected based on the results of advanced imaging with perfusion computed tomography/magnetic resonance imaging or diffusion weighted magnetic resonance imaging. This resulted in a very strong treatment effect, even superior to that observed in trials conducted in early time windows.3 Major guidelines now recommend mechanical thrombectomy in patients who meet the inclusion criteria of DAWN or DEFUSE-3.4,5 However, only a minority of patients meet these stringent criteria. Whether mechanical thrombectomy is beneficial in patients with less favorable imaging profiles is currently uncertain.See related article, p 722In this issue of Stroke, Dittrich et al report the timely results of a retrospective analysis comparing mechanical thrombectomy with usual care in 190 patients with anterior circulation large vessel occlusion presenting in the late time window and not fulfilling the DAWN and DEFUSE-3 inclusion criteria.6 Compared with usual care, mechanical thrombectomy was associated with better functional outcomes at 3 months (adjusted common OR for lower modified Rankin Scale [mRS] scores: 1.46 [95% CI, 1.02–2.10]). The proportion of patients with functional independence (mRS 0–2) was not significantly different between the 2 groups, but the effect size was similar, suggesting insufficient statistical power for this outcome. Interestingly, mechanical thrombectomy was associated with lower odds of all-cause mortality, consistent with results of randomized trials conducted in early time windows.7 No conclusions could be drawn regarding the risk of symptomatic intracerebral hemorrhage due to a very small number of events.One question that immediately comes to mind when reading results reporting a positive treatment effect is whether they can be reasonably trusted. The study has notable strengths, including the use of prospectively collected data on consecutive patients from the Swiss stroke registry and the centralized assessment of perfusion mismatch with automated software. As in all observational studies, the decision to perform mechanical thrombectomy was not due to chance, and thus important imbalances between treatment groups were observed at baseline. To reduce the risk of confounding by indication, the authors used nonparsimonuous propensity score weighting, but residual imbalances in ischemic core and hypoperfusion volumes remained. Furthermore, unmeasured confounding is plausible, and the assessment of 3-month mRS was not blinded to treatment, precluding definite conclusions.DAWN and DEFUSE-3 left many questions unanswered, leaving behind patients with mild stroke, pre-stroke dependency, M2 occlusion, lack of perfusion or clinical mismatch, and large core. This retrospective study provides insight into a handful of these clinical scenarios. Although the sample size precluded meaningful subgroup analyses, 40% of the patients enrolled had M2 occlusion and 20% had a pre-stroke mRS of 3 or greater. However, all patients underwent perfusion imaging, and the median infarct core volume was only 8 mL. In contrast, the median perfusion volume was 67 mL, suggesting that most patients were selected based on the presence of salvageable penumbral tissue. Publication of the results of the positive MR-CLEAN LATE (Multicenter Randomized Clinical Trial of Endovascular Stroke Treatment in The Netherlands for Late Arrivals) randomized trial, which had more liberal inclusion criteria than DAWN and DEFUSE-3,8 will soon shed new light on the best patient selection strategies for late-time window acute ischemic stroke.Article InformationDisclosures Dr Turc receives lecture fees from Guerbet France.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.This article was sent to Hanne Christensen, Senior Guest Editor, for review by expert referees, editorial decision, and final disposition.For Disclosures, see page 732.Correspondence to: Guillaume Turc, MD, PhD, GHU Paris Psychiatrie et Neurosciences, 1 Rue Cabanis, 75014 Paris, France. Email g.[email protected]frReferences1. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, Yavagal DR, Ribo M, Cognard C, Hanel RA, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct.N Engl J Med. 2018; 378:11–21. doi: 10.1056/NEJMoa1706442CrossrefMedlineGoogle Scholar2. Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, McTaggart RA, Torbey MT, Kim-Tenser M, Leslie-Mazwi T, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging.N Engl J Med. 2018; 378:708–718. doi: 10.1056/nejmoa1713973CrossrefMedlineGoogle Scholar3. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Davalos A, Majoie CB, van der Lugt A, de Miquel MA, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.Lancet. 2016; 387:1723–1731. doi: 10.1016/S0140-6736(16)00163-XCrossrefMedlineGoogle Scholar4. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2019; 50:e344–e418. doi: 10.1161/STR.0000000000000211LinkGoogle Scholar5. Turc G, Bhogal P, Fischer U, Khatri P, Lobotesis K, Mazighi M, Schellinger PD, Toni D, de Vries J, White P, et al. European Stroke Organisation (ESO) – European Society for Minimally Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical Thrombectomy in Acute Ischaemic Stroke Endorsed by Stroke Alliance for Europe (SAFE).Eur Stroke J. 2019; 4:6–12. doi: 10.1177/2396987319832140CrossrefMedlineGoogle Scholar6. Dittrich TD, Sporns PB, Kriemler LF, Rudin S, Nguyen A, Zietz A, Polymeris AA, Tränka C, Thilemann S, Wagner B, et al. Mechanical thrombectomy versus best medical treatment in the late time window in non-DEFUSE-non-DAWN patients: a multicenter cohort study.Stroke. 2023; 54:722-730. doi: 10.1161/STROKEAHA.122.039793LinkGoogle Scholar7. Katsanos AH, Malhotra K, Goyal N, Palaiodimou L, Schellinger PD, Caso V, Cordonnier C, Turc G, Magoufis G, Arthur A, et al. Mortality risk in acute ischemic stroke patients with large vessel occlusion treated with mechanical thrombectomy.J Am Heart Assoc. 2019; 8:e014425. doi: 10.1161/JAHA.119.014425LinkGoogle Scholar8. Pirson F, Hinsenveld WH, Goldhoorn RB, Staals J, de Ridder IR, van Zwam WH, van Walderveen MAA, Lycklama ANGJ, Uyttenboogaart M, Schonewille WJ, et al. MR CLEAN-LATE, a multicenter randomized clinical trial of endovascular treatment of acute ischemic stroke in The Netherlands for late arrivals: study protocol for a randomized controlled trial.Trials. 2021; 22:160. doi: 10.1186/s13063-021-05092-0CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesMechanical Thrombectomy Versus Best Medical Treatment in the Late Time Window in Non-DEFUSE-Non-DAWN Patients: A Multicenter Cohort StudyTolga D. Dittrich, et al. Stroke. 2023;54:722-730 March 2023Vol 54, Issue 3 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.122.041420PMID: 36718750 Originally publishedJanuary 31, 2023 Keywordsthrombectomybrain ischemiaperfusionEditorialspropensity scoreretrospective studiesPDF download Advertisement SubjectsIschemic Stroke

Effect of Cadence on Physiological and Perceptual Responses during Eccentric Cycling at Different Power Outputs

Abstract: The effect of cadence in eccentric (ECC) cycling on physiological and perceptual responses is, to date, poorly understood. This study aimed to evaluate the effect of cadence during ECC cycling on muscular activation (EMG), oxygen consumption (V̇O 2 ), and perceived effort (PE) for two different levels of power output.Seventeen participants completed four sessions 1 wk apart: 1) determination of the maximal concentric peak power output (PPO) and familiarization with ECC cycling at five cadences (30, 45, 60, 75, and 90 rpm); 2) second familiarization with ECC cycling; 3) and 4) ECC cycling exercise consisting of 5 min at the five different cadences at either 40% or 60% PPO. PE was reported, and V̇O 2 and EMG of seven muscles were calculated over the exercise's last minute.PE, V̇O 2 , and global lower limb muscles activation (EMG ALL ) showed an effect of cadence ( P < 0.001) and followed a curvilinear function. Both low and high cadences increased PE and V̇O 2 responses compared with intermediate cadences. Although muscle activation of vastus lateralis follows a U-shaped curve with cadence, it was greater at low cadence for rectus femoris and biceps femoris, greater at high cadence for tibialis anterior and gastrocnemius medialis, and was not altered for soleus. The estimated optimal cadence was greater (all P < 0.01) for V̇O 2 (64.5 ± 7.9 rpm) than PE (61.7 ± 9.4 rpm) and EMG ALL (55.9 ± 9.3 rpm), but power output had no effect on the optimal cadences.The physiological and perceptual responses to changes in cadence during ECC cycling followed a U-shaped curve with an optimal cadence depending on the parameter considered.

Asthma burden according to treatment steps in the French population-based cohort CONSTANCES

Abstract: Data on health care consumption and costs of asthma in the French population are scarce.The study objective was to describe the burden of asthma according to GINA treatment steps in the CONSTANCES cohort.Data from 162,725 participants included between 2012 and 2019 were extracted. Participants were considered as current asthmatics if asthma was reported at inclusion and asthma symptoms and/or treatments were reported in 2019. Participants were classified in three categories according to GINA treatment steps. The results were compared to non-asthmatic participants matched with a propensity score calculated on age, sex, region of residence, precariousness score and year of inclusion.Among 162,725 participants aged 18-69 years, 6783 asthmatics (1566 not treated for asthma, 2444 + 251 GINA steps 1 + 2, 1054 + 1315 GINA steps 3 + 4, and 153 GINA step 5) were matched with 6783 controls. Average annual ambulatory cost and average annual hospitalization cost were respectively €1925 and €719 for asthmatics versus €1376 and €511 for participants without asthma (p < 0,0001). Cardiovascular risk factors, co-morbidities, visits and hospitalizations were higher for asthma participants as compared to controls and increased with GINA steps, as well as inpatient and outpatient costs. However, for cardiovascular risk factors and co-morbidities, differences were non-significant in multivariate analyses. Pharmacy costs were ten times higher for GINA step 5 participants than for GINA steps 1-2 participants: €3187 versus €393 (p < 0,0001).mean cost of asthma was estimated at €757 per patient/year and increased with GINA treatment step.

Benefit of medial retropharyngeal nodal region sparing in nasopharyngeal carcinoma patients: the final answer?

Abstract: Comment on Mao YP, Wang SX, Gao TS, et al. Medial retropharyngeal nodal region sparing radiotherapy versus standard radiotherapy in patients with nasopharyngeal carcinoma: open label, non-inferiority, multicentre, randomised, phase 3 trial. BMJ. 2023 Feb 6;380:e072133. The retropharyngeal lymph node region is considered, together with the level II lymph nodes, to be the first echelon nodes of the nasopharyngeal lymphatic drainage, as they are involved in approximately 70% of patients with lymph node metastases.1 Covering the whole retropharyngeal in radiotherapy volumes has been considered to be the standard in the nasopharyngeal carcinoma treatment,2 although there is some evidence to suggest that the rate of lymph node involvement in the medial part of the retropharyngeal region (MRLN), between the pharyngeal constrictor muscles and the prevertebral fascia, is very low, if not negligible, compared to the lateral retropharyngeal region. In a prospective study including 3100 patients, Wang and colleagues observed only 6 patients with involved lymph nodes in the MRLN (0.2%) among the 2679 (86.4%) patients who presented involved lymph nodes.3 Tang and colleagues reported no involved medial retropharyngeal lymph nodes in a retrospective cohort of 924 consecutive patients, while 73.5% (679 of 924 patients) presented a lateral retropharyngeal lymph node metastasis at the initial presentation.4 In another study, Lin and colleagues reported only 5 patients out of 959 patients (0.3%) with lymph node metastases located in the MRLN.5 Despite these rather reassuring data, only one retrospective study evaluating the feasibility of the omission of the MRLN existed until recently.6 In this retrospective case-control study, Pan and colleagues have observed no significant difference between the 2 groups of 183 patients in terms of 5 years-local relapse-free survival LRFS (94.8% vs 94.2%), regional relapse-free survival RRFS (98.3% vs 97.1%),distant metastasis-free survival DMFS (88.5% vs 86.7%), and overall survival OS (85.5% vs 84.7%) for the study group and the control groups respectively, and a significant reduction of the incidence of grade III acute oral mucositis in the study group.6 Mao and colleagues are to be commended for their randomized non-inferiority phase III trial that provided new and strong evidence regarding the pending question of the possible omission of MRLN radiotherapy and the potential benefits in terms of reduced toxicity and improved quality of life in patients with nasopharyngeal cancers.7 This study provides us with a number of valuable information, confirming the pre-existing data. In this well-designed trial, 568 patients were recruited between November 2017, and December 2018, and randomly allocated to the MRLN sparing radiotherapy group (n = 285 patients) and the standard radiotherapy group (n = 283). Radiotherapy delineation, plan, dose and schedule were performed according to the consensus guideline (70 Gy (2.12 Gy/fraction) to the planning target volume (PTV) of the gross tumor at the primary site and the involved regional lymph nodes, 66–70 Gy to the PTV of the involved cervical lymph nodes, 60–62 Gy to the PTV of the high risk clinical target volume (CTV), and 54–56 Gy to the PTV of the low risk CTV. The characteristics of the study population were wide. Stage III and IVa represented respectively 43% and 41% of the patients in the MRLN sparing radiotherapy group,and 46% and 44% in the standard radiotherapy group. Concurrent chemoradiotherapy and Induction chemotherapy followed by concurrent chemoradiotherapy represented respectively 34% and 58% of the patients in the MRLN sparing radiotherapy group, and 32% and 59% in the standard radiotherapy group. A pre-treatment EBV DNA test was available for 88% and 89% patients in the MRLN sparing group and the standard group respectively. The primary endpoint was the three year local relapse-free survival defined as any relapse in the primary site and in the retropharyngeal lymph node region, or death from any cause. Sparing the MRLN allowed to decrease the dose to the superior and middle pharyngeal constrictors. The authors have reached their primary objective and have shown that MRLN sparing radiotherapy is non-inferior to standard radiotherapy, with a three year local relapse-free survival of 95.3% (95% confidence interval 92.8 to 97.8) in the MRLN sparing radiotherapy group, and 95.5% (93.0 to 98.0) in the standard radiotherapy group (estimated absolute difference –0.2% (lower boundary of the one-sided 97.5% confidence interval of –3.6, which is not greater than the predefined non-inferiority margin of –8%). This result was consistent in multivariate and subgroup analyses taking into account the stage of the disease, the type of chemotherapy regimen, and the quantification of EBV DNA at baseline. Only six patients (1.1%) presented a lymph node recurrence in the retropharyngeal region, but none in the MRLN. OS, DMFS, and RRFS were not significantly different between the MRLN sparing radiotherapy group and the standard radiotherapy group (95.2% vs 96.4%, 89.7% vs 92.3%, 96.9% vs 94.0% respectively). The lower DMFS observed in the sparing radiotherapy group while the RRFS seemed better (HR 0.67, P = 0.28) may probably be explained by randomness. Finally, sparing MRLN has shown to decrease the incidence of grade ≥1 acute dysphagia (25.5% v 35.1%, P = 0.01) and late dysphagia (24.0% v 34.3%, P = 0.008), and to significantly improve quality of life on multiple domains such as global health status, role functioning, social functioning, fatigue and swallowing. Overall, this study provides a high level of evidence regarding the feasibility of sparing MRLN and the potential benefit on patient quality of life by reducing treatment toxicity. These results thus make it possible to envisage a new lever of action for radiation oncologists, making it possible to improve the tolerance of the treatment, which is important in this population where the prognosis is rather good, and the survival rather long. They are part of the de-escalation approach along with the studies showing the possibility to spare the level IV and Vb of the uninvolved neck of N0-N1 nasopharyngeal cancer patients8 or the studies showing the benefit of elective irradiation to neck level Ib.9 This study has the added advantage of showing the possibility of omitting MRLN irradiation in virtually all patients with cavum cancer, regardless of their stage. Some few questions are still pending such as the generalizability of these findings to a non-endemic nasopharyngeal carcinoma cohort population, and the compatibility of the MRLN sparing with other de-escalate approaches such as dose de-escalation. However, we do believe that the results provided by Mao and colleagues’ study need to be consider in future guidelines of nasopharyngeal non-keratinising carcinoma. In the future, the implementation of even more conformal radiotherapy techniques, such as proton therapy, will certainly allow to gain more benefit of the sparing of MRLN through further dose reduction to the swallowing structures.

Validation of the French version of the Emotion and Regulation Beliefs Scale (ERBS) and Dissociation Belief Scale (DBS)

Abstract: Dissociation is a recurrent symptom of post-traumatic stress disorder (PTSD) and is associated with emotional dysregulation. Beliefs about emotions seem to be involved in emotional dysregulation but have not been studied in relation to dissociation. Likewise, there is currently little empirical evidence of beliefs about dissociation. The aims of the study were to validate psychometric tools assessing these beliefs, to assess their role in dissociation, and to explore the mediating role of emotional dysregulation and beliefs about dissociation in the relationship between beliefs about emotion and dissociation.We recruited a sample from the general population (n=1009) and a sample of patients with PTSD (n=90). All participants completed self-report questionnaires to evaluate symptoms of PTSD (PTSD Checklist/Impact of Event Scale, PCL-5/IES-6), dissociation (Dissociative Experiences Scale, DES), difficulties in emotion regulation (Difficulties in Emotion Regulation Scale, DERS), beliefs about dissociation (Dissociation Beliefs Scale, DBS), and beliefs about emotion (Emotion and Regulation Beliefs Scale, ERBS).The questionnaires used to assess the beliefs about emotion (ERBS) and dissociation (DBS) had good psychometric properties. Dissociation was positively associated with positive and negative beliefs about dissociation and with negative beliefs about emotions in both the clinical and non-clinical groups. The relationship between beliefs about emotions and dissociation was mediated by emotional dysregulation and positive beliefs about dissociation in both groups.The ERBS and DBS are effective tools to assess beliefs. Beliefs about emotion and dissociation seem to be involved in dissociative manifestations in both clinical and non-clinical individuals.

Insulin analogs as an add-on to metformin after failure to oral treatment in type 2 diabetic patients increase diastole duration. The INSUlin Regimens and VASCular Functions (INSUVASC) study

Abstract: Fast acting insulin analogues are known to improve arterial stiffness. The combination of metformin with insulin represents a widely used therapeutic strategy in diabetes. We hypothesized that insulin treatment in patients with type 2 diabetes (T2D) with long-acting, fast-acting or basal bolus insulin as an add-on to metformin would provide additional improvement of arterial stiffness.The INSUlin Regimens and VASCular Functions (INSUVASC) study is a pilot, randomized, open label three-arms study that included 42 patients with type 2 diabetes (T2D) in primary prevention, after a failure to oral antidiabetic agents. Arterial stiffness measurements were performed at fasting and after a standardized breakfast. During the first visit (V1) pre-randomization, participants took only metformin to perform the tests. The same tests were repeated after 4 weeks of insulin treatment during the second visit (V2).Data were available for final analysis in 40 patients, with a mean age of 53.6±9.7 years and a mean duration of diabetes of 10.6±5.6 years. Twenty-one were females (52.5%), hypertension and dyslipidemia were present in 18 (45%) and 17 patients (42.5%), respectively. After insulin treatment, the metabolic control was associated to a decrease in oxidative stress and improvement of endothelial functions, with a post prandial diastole duration increased and a decrease of the peripheral arterial stiffness, with a better post prandial pulse pressure ratio and ejection duration after insulin. In hypertensive patients, insulin treatment provided positive effects by decreasing the pulse wave velocity and improving reflection time.A short time treatment by insulin in addition to metformin improved myocardial perfusion. Moreover, insulin treatment in hypertensive patients provides a better hemodynamic profile in large arteries.

Comment on “Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015”

Abstract: To the Editor: We read with interest the article by Tan et al “Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015.”1Tan S.Y. Buzney E. Mostaghimi A. Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015.J Am Acad Dermatol. 2018; 79: 672-679Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Although US data from the early 2000s suggested that phototherapy was in decline,2Housman T.S. Rohrback J.M. Fleischer A.B. Feldman S.R. Phototherapy utilization for psoriasis is declining in the United States.J Am Acad Dermatol. 2002; 46: 557-559Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar the authors observed that the overall volume of phototherapy services billed to Medicare during 2000-2015 increased by 5% annually. Despite several innovations in the phototherapy field, fears surrounding the introduction of biologic agents in 2000 have been thought to have decreased demand for phototherapy. However, this hypothesis was not confirmed in our recent study3Aubin F. Courtois J. Puzenat E. et al.Phototherapy in France: quantitative data (2007-2016) from the National Health Insurance Register.J Eur Acad Dermatol Venereol. 2018; 32: e224-e225Crossref PubMed Scopus (2) Google Scholar that was based on data from the National Health Insurance Register (Caisse Nationale d’Assurance Maladie) in France. In France, to be reimbursed, each medical treatment must be declared to the National Health Insurance Register. Systemic phototherapy is registered with the unique code QZRP003 (19.2€), which includes both systemic psoralen plus ultraviolet (UV) A and UVB therapies. We first observed an increase in both the number of UV treatments (12%) and UV-treated patients (11.5%) during 2007-2010.4Aubin F. Weill A. Allemand H. Phototherapy in France: quantitative data from the National Health Insurance register.Br J Dermatol. 2012; 167: 215-216Crossref PubMed Scopus (2) Google Scholar Then, both decreased; the number of UV treatments performed yearly in France decreased from 473,269 in 2010 to 382,733 in 2016 (–23.6%), and the number of UV-treated patients decreased from 28,183 in 2010 to 21,997 in 2016 (–21.9%). After a 4-year increase,4Aubin F. Weill A. Allemand H. Phototherapy in France: quantitative data from the National Health Insurance register.Br J Dermatol. 2012; 167: 215-216Crossref PubMed Scopus (2) Google Scholar our results confirmed the recent decline of phototherapy in France.3Aubin F. Courtois J. Puzenat E. et al.Phototherapy in France: quantitative data (2007-2016) from the National Health Insurance Register.J Eur Acad Dermatol Venereol. 2018; 32: e224-e225Crossref PubMed Scopus (2) Google Scholar We do not have clear explanations for the discrepancy between our data and the recent US data.1Tan S.Y. Buzney E. Mostaghimi A. Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015.J Am Acad Dermatol. 2018; 79: 672-679Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Both studies share similar limitations including the lack of information about the diagnoses and the type of phototherapy (UVB or psoralen plus UVA) used. Different hypotheses may be suggested. In our study, we do not include local phototherapy or Excimer Laser Service, whose use has grown most rapidly (by 29% annually), accounting for 22% of overall phototherapy volume by 2015 in the United States.1Tan S.Y. Buzney E. Mostaghimi A. Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015.J Am Acad Dermatol. 2018; 79: 672-679Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Patients may be also different between both countries. In the US study,1Tan S.Y. Buzney E. Mostaghimi A. Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015.J Am Acad Dermatol. 2018; 79: 672-679Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Medicare-eligible patients do not reflect the general population; their age, comorbidities, polypharmacy, and greater time flexibility to attend phototherapy sessions might bias them toward phototherapy over other systemic treatment options. In France, phototherapy is mainly prescribed and performed by dermatologists. Nurse practitioners and physician assistants who billed Medicare for 5% of the total phototherapy volume cannot perform phototherapy in France. In addition, variable compensation for phototherapy to providers and the out-of-pocket costs for patients might lead to different utilization among private payers. In our study,3Aubin F. Courtois J. Puzenat E. et al.Phototherapy in France: quantitative data (2007-2016) from the National Health Insurance Register.J Eur Acad Dermatol Venereol. 2018; 32: e224-e225Crossref PubMed Scopus (2) Google Scholar all treated patients benefit from the National Health Insurance Register whatever their income. Out-of-pocket costs are possible, but most of the time, patients were reimbursed by private insurance companies. In France, all treatments are available and reimbursed for all patients. The variable compensation is thus not a limiting factor for phototherapy in France. Additional evaluation is required to determine the effect of new systemic treatments and training gaps on the long-term accessibility of phototherapy, which still remains an important cost-effective therapeutic modality for psoriasis and other dermatoses, such as atopic dermatitis.5Staidle J.P. Dabade T.S. Feldman S.R. A pharmacoeconomic analysis of severe psoriasis therapy: a review of treatment choices and cost efficiency.Expert Opin Pharmacother. 2011; 12: 2041-2054Crossref PubMed Scopus (57) Google Scholar The authors thank Elisabeth Homassel. Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015Journal of the American Academy of DermatologyVol. 79Issue 4PreviewPhototherapy is a cost-effective treatment for many dermatoses, yet the emergence of alternative therapies such as biologics led many to think that phototherapy utilization was declining. Full-Text PDF ReplyJournal of the American Academy of DermatologyVol. 88Issue 1PreviewTo the Editor: We thank Aubin et al1 for their commentary regarding our article.2 Aubin et al1 share some thoughtful theories for the contrast between declining ultraviolet A light/ultraviolet B light (UVA/UVB) phototherapy use in France compared with the relative rise among the Medicare population in the United States. Full-Text PDF

Visual activity enhances neuronal excitability in thalamic relay neurons

Abstract: Abstract The dorsal lateral geniculate nucleus (dLGN) has long been held to act as a basic relay for visual information travelling from the retina to cortical areas, but recent findings suggest a largely underestimated functional plasticity of dLGN neurons. However, the cellular mechanisms supporting this functional plasticity have not been yet explored. In particular, it remains to elucidate whether intrinsic neuronal excitability change upon visual stimuli. We show here that monocular deprivation for 10 days reduces the intrinsic excitability of dorsal LGN relay cells. Furthermore, dLGN neurons exhibit long-term potentiation of their intrinsic excitability (LTP-IE) when suprathreshold afferent retinal inputs are stimulated at 40 Hz or when spikes are induced with direct somatic current injection to reproduce patterns of retinal activity. LTP-IE is observed after eye opening and requires calcium influx mediated by L-type calcium channels. It involves activation of PKA and is expressed through the down-regulation of Kv1 potassium channels. In conclusion, our study provides the first evidence for intrinsic plasticity in dLGN relay cells, thus further pointing the role of thalamic neurons in activity-dependent visual plasticity and amblyopia.

Tixagevimab-cilgavimab as an Early Treatment for COVID-19 in Kidney Transplant Recipients

Abstract: The concomitant use of the monoclonal antibodies (mAbs) tixagevimab-cilgavimab has been originally authorized for pre-exposure prophylaxis of COVID-19.1 Although limited by a weak neutralizing activity,2 tixagevimab-cilgavimab has been the only efficient combination available in France during the BA.1 and BA.2 breakthrough. The aim of this single-center retrospective study is to describe the use of tixagevimab-cilgavimab as an early treatment for COVID-19 in kidney transplant recipients (KTRs). The study cohort consisted of all adult KTRs diagnosed with COVID-19 from December 22, 2021, to April 27, 2022 (ie, during the BA.1 and BA.2 breakthrough). Tixagevimab-cilgavimab (600 mg) was given intravenously. Participants were retrospectively divided into 2 groups according to their risk to develop moderate-to-severe COVID-19. Patients with at least 1 comorbid condition (ie, age >60 y, diabetes, obesity, or a history of cardiovascular disease) who were unvaccinated or showed a weak vaccine-induced humoral response (<264 BAU/mL after the last dose vaccine and before mAb administration) were considered at high risk. The remaining participants were deemed to be at low risk. A total of 197 KTRs with COVID-19 were identified. Of them, 63 were excluded for the following reasons: treatment with sotrovimab (n = 31), administration of mAbs on hospitalization or in a late phase after symptom onset (ie, >8 d, n = 17), and missing information (n = 15). No adverse effect was observed at follow-up in any patient. Among high-risk KTRs (n = 61), 26 received tixagevimab-cilgavimab within a median of 3 d (range: 2–4.75 d) from symptom onset. The remaining 35 patients were not treated with tixagevimab-cilgavimab for the following reasons: late notification of diagnosis (n = 19), clinical management in a different hospital (n = 4), COVID-19 infection before tixagevimab-cilgavimab availability (n = 7), patient refusal (n = 2), and unknown reasons (n = 3). Patients who received tixagevimab-cilgavimab benefited more frequently from early immunosuppressive therapy reduction (Table 1). COVID-19–related hospitalizations (3.8% versus 34%, respectively, P = 0.006; Figure 1A) and oxygen need (3.8% versus 23%, respectively, P = 0.04; Figure 1B) were significantly less frequent in KTRs treated with tixagevimab-cilgavimab. Similar, albeit not significant, trends were observed for intensive care unit admissions (3.8% versus 14.3%, respectively, P = 0.17; Figure 1C) and mortality (0 versus 3 patients, respectively, P = 0.13; Figure 1D). Of the low-risk KTRs (n = 73), 10 received tixagevimab-cilgavimab as an early treatment (Table 1). Three were hospitalized and 1 required oxygen treatment. No patient required intensive care unit admission or showed COVID-19–related mortality (Figure 1E). TABLE 1. - General characteristics of kidney transplant recipients at high risk and low risk of moderate-to-severe COVID-19 according to early treatment with tixagevimab-cilgavimab High-risk group (n = 61) Patient who did not receive curative tixagevimab-cilgavimab (n = 35) Patient who received curative tixagevimab-cilgavimab (n = 26) P value Statistical test Low-risk group (n = 73) Patient who did not receive curative tixagevimab-cilgavimab (n = 63) Patient who received curative tixagevimab-cilgavimab (n = 10) P value Statistical test Age, y 61.0 [52.0–71.0] 60 [52–71.5] 65.5 [51.2–70.8] 0.75 Welch test 49.0 [38–57] 49 [38–57.5] 49.5 [41.5–55.5] 0.83 Welch test Men, n, %) 42 (69%) 25 (71%) 17 (65%) 0.61 χ2 49 (67%) 44 (70%) 5 (50%) 0.28 Fisher exact test BMI, kg/m2 28.4 [25.0–30.9] 27.6 [24.9–30.6] 28.5 [25.3–31.6] 0.74 Welch test 25.1 [22.0–29.7] 25.3 [22.1–30] 24.9 [21.7–27.1] 0.47 Welch test Serum creatinine, μmol/L 133 [115–173] 140 [116–186] 125 [98–159] 0.22 Mann-Whitney U test 115 [96–146] 121 [96.0–146] 98.5 [85.3–195] 0.46 Mann-Whitney U test Cardiovascular disease, n, % 21 (34%) 8 (23%) 13 (50%) 0.03 χ2 14 (19%) 14 (22%) 0 (0%) 0.19 Fisher exact test Diabetes, n, % 34 (56%) 20 (57%) 14 (54%) 0.8 χ2 18 (25%) 18 (29%) 0 (0%) 0.06 Fisher exact test High blood pressure, n, % 50 (82%) 29 (83%) 21 (81%) 1 Fisher exact test 61 (84%) 53 (84%) 8 (80%) 0.67 Fisher exact test First kidney transplantation, n, % 54 (89%) 33 (94%) 21 (81%) 0.13 Fisher exact test 62 (85%) 54 (86%) 8 (80%) 0.64 Fisher exact test Time from kidney transplantation, y 4.50 [1.75–8.73] 2.9 [1.39–5.65] 7.49 [266–12.5] 0.02 Mann-Whitney U test 7.06 [4.14–11.8] 7.06 [3.46–11.0] 7.28 [5.40–17.6] 0.5 Mann-Whitney U test Immunosuppressive drugs at diagnosis, n, % Tacrolimus 40 (66%) 23 (66%) 17 (65%) 0.98 χ2 48 (66%) 41 (65%) 7 (70%) 1 Fisher exact test Cyclosporine 14 (23%) 7 (20%) 7 (27%) 0.52 χ2 20 (27%) 17 (27%) 3 (30%) 1 Fisher exact test MMF/MPA 53 (87%) 33 (87%) 23 (85%) 1 Fisher exact test 60 (82%) 53 (84%) 7 (70%) 0.37 Fisher exact test mTOR inhibitors 7 (11%) 4 (11%) 3 (12%) 1 Fisher exact test 8 (11%) 7 (11%) 1 (10%) 1 Fisher exact test Steroids 45 (74%) 26 (74%) 19 (73%) 0.92 χ2 50 (68%) 44 (70%) 6 (60%) 0.72 Fisher exact test Belatacept 7 (11%) 5 (14%) 2 (7.7%) 0.69 Fisher exact test 4 (5.5%) 4 (6.3%) 0 (0%) 1 Fisher exact test Azathioprine 0 0 0 5 (6.8%) 4 (6.3%) 1 (10%) 0.53 Fisher exact test COVID-19 prevention, n, % Vaccination 57 (93%) 32 (91%) 25 (96%) 0.64 Fisher exact test 69 (95%) 60 (95%) 9 (90%) 0.45 Fisher exact test Pre-exposure tixagevimab-cilgavimab prophylaxis 24 (39%) 19 (54%) 5 (19%) <0.01 χ2 7 (9.6%) 7 (11%) 0 (0%) 0.58 Fisher exact test Pre-exposure casirivimab-imdevimab prophylaxis 28 (46%) 16 (46%) 12 (46%) 0.97 χ2 8 (11%) 6 (9.5%) 2 (20%) 0.3 Fisher exact test Antibody titer, BAU/mL a 33 [1–117] 8 [0–70] 47 [16–133] 0.12 Mann-Whitney U test 710 [240–1627] 945 [285–1722] 281 [47–407] 0.02 Mann-Whitney U test History of COVID-19, n, % 3 (4.9%) 2 (5.7%) 1 (3.8%) 1 Fisher exact test 7 (9.6%) 7 (11%) 0 (0%) 0.58 Fisher exact test COVID-19 presentation and clinical evolution, n, % Symptomatic COVID-19 55 (92%) 32 (94%) 23 (88%) 0.64 Fisher exact test 58 (88%) 51 (88%) 9 (90%) 1 Fisher exact test COVID-19–related hospitalization 13 (21%) 12 (34%) 1 (3.8%) <0.01 Log-rank 3 (4.1%) 2 (3.2%) 1 (10%) 0.31 Log-rank Oxygen need 9 (5%) 8 (23%) 1 (3.8%) 0.04 Log-rank 1 (1.4%) 0 (0%) 1 (10%) 0.69 Log-rank ICU admission 6 (9.8%) 5 (14.3%) 1 (3.8%) 0.17 Log-rank 0 (0%) 0 (0%) 0 (0%) 1 Log-rank Death 3 (4.9%) 3 (8.6%) 0 (0%) 0.13 Log-rank 0 (0%) 0 (0%) 0 (0%) 1 Log-rank COVID-19 management, n, % Dexamethasone 7 (11%) 6 (17%) 1 (3.8%) 0.22 Fisher exact test 1 (1.4%) 1 (1.6%) 0 (0%) 1 Fisher exact test Immunosuppressive therapy reduction 24 (41%) 12 (36%) 12 (46%) 0.45 χ2 7 (9.9%) 4 (6.6%) 3 (30%) 0.06 Fisher exact test Early immunosuppressive therapy reduction b 15 (24.6%) 4 (1.1%) 11 (42.3%) 0.006 χ2 5 (8.1%) 2 (5.7%) 3 (30%) 0.016 Fisher exact test Continuous variables are presented as medians (interquartile ranges), whereas categorical variables are presented as counts (percentages).aOnly for patients not previously treated with casirivimab-imdevimab or tixagevimab-cilgavimab for pre-exposure prophylaxis.bPatients who benefitted from a reduction of immunosuppression on hospitalization were excluded.BAU, binding antibody unit; BMI, body mass index; ICU, intensive care unit; MMF, mycophenolate mofetil; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin. FIGURE 1.: Kaplan-Meier plots of hospitalization-free survival (A), oxygen need-free survival (B), ICU admission-free survival (C), and survival (D) in high-risk patients stratified according to the use (yes vs no) of tixagevimab-cilgavimab as an early treatment for COVID-19. Kaplan-Meier plots of hospitalization-free survival in low-risk patients stratified according to the use (yes vs no) of tixagevimab-cilgavimab as an early treatment for COVID-19 (E). ICU, intensive care unit.Our data suggest that early administration of monoclonal anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, in combination with reduction of immunosuppression, may be clinically useful in high-risk KTRs with COVID-19. This is also supported by the observation that peak tixagevimab-cilgavimab concentrations are reached at 1 h after intravenous administration and are followed by rapid action.3 In contrast, our data provide an argument against the necessity to treat low-risk patients in the Omicron era. This is supported by the favorable clinical course observed in our study participants, and so even in the absence of treatment. As mAbs could drive the emergence of SARS-CoV-2 variants,4 we believe that their use should be limited to high-risk cases. However, our results should be interpreted in light of several limitations. This is a retrospective nonrandomized single-center study with a relatively limited sample size. Although the emergence of new variants (eg, BQ.1 and XBB), which are resistant to neutralization by most of the currently available mAbs (including tixagevimab-cilgavimab), puts this strategy into question,2 sotrovimab maintains a weak activity and can be used in high-risk patients as a curative strategy at the beginning of infection.2 This approach can also undergo future adaptations according to SARS-CoV-2 evolution and the in vitro efficacy of mAbs against novel variants. Fortunately, antiviral drugs continue to retain their activity against all variants and can provide an alternative strategy for the protection of KTRs. However, it should be kept in mind that the use of nirmatrelvir-ritonavir is challenging in patients being treated with calcineurin inhibitors and/or mammalian target of rapamycin inhibitors, and that remdesivir is contraindicated in patients with an estimated glomerular filtration rate <30 mL/min.5 A benefit-risk assessment tailored to the individual patient should be considered to guide the choice of the most appropriate option. ACKNOWLEDGMENTS The authors thank the clinical research team (Danielle Roy, Annie Menguy, and Fanny Husselstein) and the nursing staff (Sandra Ludwiller, Lucile Steinmetz, Christelle Appenzeller, and Fanny Petitjean) for their contribution to the study.

Common femoral artery endarterectomy by eversion versus prosthetic patch angioplasty: a propensity-matched study

Abstract: BACKGROUND: Endarterectomy with prosthetic patch angioplasty is the preferred treatment for common femoral artery occlusive disease. Eversion endarterectomy was described as a promising alternative. the aim of this study was to compare the eversion endarterectomy and patch angioplasty outcomes for patients with de novo femoral bifurcation atherosclerotic lesions. this study was a single-center, retrospective analysis of prospectively collected registry data, non-randomized cohort. Patients treated by eversion endarterectomy and patch angioplasty for de novo femoral bifurcation atheromatous lesions were evaluated.METHODS: Between January 2016 and June 2019, all patients with de novo femoral bifurcation atheromatous lesions with a stenosis ≥70% were included in a prospective single-center database. Patients undergoing eversion endarterectomy and patch angioplasty were propensity-matched by age, sex, preexisting comorbidities, and lesion characteristics.RESULTS: There were 51 eversion endarterectomy and 137 patch angioplasty cases. One-to-one propensity matching yielded 51 pairs of patients. In the matched population, intermittent claudication was the most common clinical presentation (68% for both groups; P=0.83). There was no difference in femoral bifurcation lesion types between the two groups (P=0.11). Univariate analysis found no significant difference between the groups in terms of 30-d morbidity and mortality (10% and 16%; P=0.55). At 24 months, there was no significant difference in primary sustained clinical improvement (72% and 86%; P=0.22), primary patency rate (90% and 98%; P=0.48), and freedom from target lesion revascularization (100% and 98%; P=0.31) between the groups.CONCLUSIONS: This propensity-score analysis did not show any advantage for the EE. The EPPA should be the first line treatment of de novo femoral tripod occlusive disease. Results show that patch angioplasty treatment for de novo femoral bifurcation atheromatous could improve the daily practice with a good clinical improvement and primary patency.

Higher-order epistasis shapes natural variation in germ stem cell niche activity

Abstract: Abstract To study how natural allelic variation explains quantitative developmental system variation, we characterized natural differences in germ stem cell niche activity, measured as progenitor zone (PZ) size, between two Caenorhabditis elegans isolates. Linkage mapping yielded candidate loci on chromosomes II and V, and we found that the isolate with a smaller PZ size harbours a 148 bp promoter deletion in the Notch ligand, lag-2/Delta , a central signal promoting germ stem cell fate. As predicted, introducing this deletion into the isolate with a large PZ resulted in a smaller PZ size. Unexpectedly, restoring the deleted ancestral sequence in the isolate with a smaller PZ did not increase—but instead further reduced—PZ size. These seemingly contradictory phenotypic effects are explained by epistatic interactions between the lag-2/Delta promoter, the chromosome II locus, and additional background loci. These results provide first insights into the quantitative genetic architecture regulating an animal stem cell system.

Mitigating the Risk of t-MNs Development: TP53 or Not TP53?

Abstract: Therapy-related myeloid neoplasms (t-MNs) are severe consequences of cytotoxic therapies used to treat solid tumors, nonmyeloid hematological cancers, or autoimmune disorders.1 They consist of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and associate to poor prognostic features. The majority of t-MNs are believed to arise from pre-existing mutant hematopoietic stem cell (HSC) clones which do not undergo apoptosis in response to cytotoxic therapies and are thus favored under this selective pressure. Albeit numerous evidence demonstrated that the clonal hematopoiesis of indeterminate potential (CHIP) constitutes the soil for t-MNs development, it remains to be fully elucidated how individual therapies shape the selection and the evolution of specific mutant HSC clones. Understanding this aspect could enable modulating therapeutic regimens based on their effects on pre-existing mutant HSCs and thus reducing the risk of t-MNs development. In a recent Blood article, Sperling and colleagues provided interesting clinical and experimental evidence to tackle this aspect.2 The researchers first performed a mutational analysis of 416 patients diagnosed with t-MNs, including 40% of AML cases and 60% of MDS patients. This revealed the predominance of mutations in genes involved in DNA damage responses such as TP53 and PPM1D, which were followed by common CHIP-associated mutations such as TET2, DNMT3A, ASL1, and SRF2. PPM1D and TP53 mutations occurred more frequently in t-MNs compared to AML-MDS cases without prior exposure to chemoradiation therapies. TP53 mutations, moreover, significantly associated to prior exposure to lenalidomide, hence suggesting that this drug could directly promote the development of t-MNs by selecting TP53 mutant HSCs. To investigate this hypothesis, the authors performed competitive transplant assays using a murine model deficient for Trp53 and sensitive to thalidomide analogs such as lenalidomide and pomalidomide. This revealed an outgrowth of Trp53 knock-out HSCs over wild-type cells, which occurred only following exposure to lenalidomide but not to pomalidomide. To explain these findings on a mechanistic level, the authors built on their previous findings, reasoning that lenalidomide selective toxicity on wild-type HSCs could derive from its exclusive ability to degrade casein kinase alpha (CK1α), a phenomenon that triggers p53-mediated apoptosis.3 Supporting this hypothesis, HSCs haploinsufficient for Csnk1a (the gene coding for CK1α) were out-competed by wild-type cells in competitive transplant assays when exposed to lenalidomide. However, they did not show a competitive disadvantage upon treatment with pomalidomide or iberdomide, 2 thalidomide analogs which do not degrade CK1α. These data suggest an interesting model linking lenalidomide and t-MNs bearing TP53 mutations. In this model (Figure 1), CK1α degradation, selectively induced by lenalidomide but not by other thalidomide analogs, induces p53-mediated apoptosis in wild-type cells but not in TP53 mutant HSCs, hence positively selecting them. Although the researchers provided some experimental evidence excluding the possibility that lenalidomide could select for HSCs bearing other CHIP-associated mutations (ie, Dnmt3A, Tet2, Asxl, Pmp1d, Ezh2), it remains to be investigated whether this holds true for other thalidomide analogs. Further investigating these aspects will be important to define whether the careful choice of thalidomide analogs in chemotherapy regimens may allow to mitigate the risk of developing t-MNs.Figure 1.: By degrading CK1α, lenalidomide induces p53-dependent apoptosis in wild-type hematopoietic stem cells but not in TP53 mutant clones, hence favoring their positive selection and, ultimately, the development of t-MNs. CK1α = casein kinase alpha; t-MNs = therapy-related myeloid neoplasms.As the patients analyzed in Sperling’s study included multiple myeloma cases, the vast majority of which were exposed to both lenalidomide and proteasome inhibitors, one may argue that the expansion of TP53 mutant HSC clones may result from the combined exposure of both drugs. The clinical and experimental evidence provided by the authors, however, do not support this possibility. On one side, the multivariate analysis the authors performed to adjust for the confounding effects of multiple exposure confirmed the significant association of TP53 mutation and lenalidomide exposure. On the other side, in vitro long-term competitive experiments using an immortalized murine hematopoietic stem/progenitors line showed that proteasome inhibitors such as bortezomib or carfilzomib conferred only a mild proliferative advantage to Trp53 mutant cells in contrast to the pronounced proliferative advantage provided by lenalidomide exposure. To conclude, the study by Sperling and colleagues provided an interesting molecular and functional characterization of the interplay linking patients genotype and specific cytotoxic drugs in driving the selection of premalignant clones. This has important consequences as it suggest at least 2 strategies to possibly reduce the risk of developing t-MNs, namely screening patients undergoing lenalidomide-based therapies for TP53 mutant CHIP and/or adapting chemotherapy regimens by choosing the appropriate thalidomide analog. DISCLOSURES The author has no conflicts of interest to disclose.