Centre Hospitalier Universitaire de Grenoble

Rationale: Treatment-emergent central sleep apnea (TE-CSA) is the most common indication for adaptive servo-ventilation (ASV). Evidence on the effects of TE-CSA treatment on quality of life (QoL) is limited. Objectives: To test the hypotheses that patients with TE-CSA who have cardiovascular disease (CVD) would be less symptomatic than those with CVD, and that the beneficial effects of ASV on QoL/sleepiness might be smaller in individuals with versus without CVD. Methods: ASV-naïve adults with TE-CSA and an ASV prescription were included in this analysis of the Registry on the Treatment of Central and Complex Sleep-Disordered Breathing with ASV (READ-ASV). QoL (Functional Outcomes of Sleep Questionnaire [FOSQ] and daytime sleepiness (Epworth Sleepiness Scale [ESS]) were assessed at baseline and 12-month follow-up. Measurements and main results: Of 452 TE-CSA patients, 81% had CVD. Before treatment initiation FOSQ and ESS scores were better in those with versus without CVD. On ASV, in the CVD and no CVD subgroups, median [interquartile range] FOSQ score significantly increased (+0.72 [-0.20; +1.98], p<0.001 and +0.90 [-0.12; +2.29], p<0.001, respectively) and the ESS score significantly decreased (-2.00 [-5.00; 0.00], p<0.001 and -3.00 [-6.75; 0.00], p<0.001); improvement magnitude was similar in both subgroups (p=0.454 and p=0.120). Conclusions: The majority of individuals with TE-CSA and an ASV therapy prescription had CVD. Although those with TE-CSA and CVD were less symptomatic than those without CVD, ASV had a positive effect on QoL and sleepiness in these individuals, as well as those without CVD.

There are very limited data regarding the outcomes of elderly patients with acute lymphoblastic leukemia (ALL) who undergo allogeneic hematopoietic stem cell transplantation (alloHSCT). A total of 316 ALL patients aged ≥ 60 years who underwent alloHSCT between 2010 to 2022 were identified in the SFGM‐TC registry. The primary objective was to evaluate progression‐free survival (PFS), non‐relapse mortality (NRM), relapse incidence (RI), and graft‐versus‐host disease (GvHD)‐free relapse‐free survival (GRFS), as well as their risk factors. The median age was 63.8 years (range 60–75.8), 49.8% of patients had Philadelphia‐positive B‐ALL (Ph + ALL), and 70.9% were in first complete remission (CR1) at transplantation. The donor was an unrelated donor in 52.1%, a matched related donor (MRD) in 26.3%, and a haplo‐identical donor in 17.7%. Reduced‐intensity conditioning (RIC) was administered to 64.6% of patients, while total body irradiation (TBI) was used in 35.8%. The 3‐year overall survival (OS) was 46% (95% CI 40%–53%). The 3‐year PFS, NRM, RI, and GRFS were 41% (95% CI 35%–48%), 23% (95% CI 18%–28%), 36% (95% CI 31%–42%), and 30% (95% CI 25%–37%), respectively. Multivariable analyses confirmed poorer OS and PFS in patients with advanced disease, with an HR of 1.79 (95% CI 1.22–2.64), p = 0.0032. Additionally, the ALL subtype significantly impacted outcomes, with an HR of 1.99 (95% CI 1.42–2.79) for non‐Ph + ALL. This study suggests that alloHSCT is a viable option for elderly ALL patients, as age itself did not impact outcomes. However, advanced disease and non‐Ph + ALL were associated with significantly worse survival.

Background To determine whether hierarchical unsupervised cluster analysis identifies a phenotypic distinction in adult patients with primary CNS vasculitis (PCNSV). Methods An agglomerative hierarchical cluster analysis based on the Ward method was conducted, including 153 patients with complete baseline phenotypic characterization in the COVAC' registry. Results The hierarchical analysis identified two main clusters. In Cluster 1 (n = 109 patients, 71%), patients more frequently had a motor deficit (p = 0.039), ≥ 1 acute brain infarct (p < 0.001), and ≥ 1 intracranial stenosis on CT or MR angiogram (p < 0.001) than patients in Cluster 2 (n = 44 patients, 29%). Conversely, patients in Cluster 2 more frequently had seizures (p < 0.001), cognitive impairment (p = 0.002), gadolinium‐enhanced parenchymal lesions (p < 0.001), leptomeningeal enhancement (p < 0.001), ≥ 1 cerebral microbleed (p < 0.001), and intracranial hemorrhage(s) (p < 0.001). In multivariable logistic regression, gadolinium‐enhanced parenchymal lesions were significantly associated with Cluster 2 lesions (OR = 35.53 [95% CI: 3.91–322.81], p = 0.002). Conversely, ≥ 1 acute brain infarct was significantly associated with Cluster 1 (OR = 0.003 [95% CI: 0.01–0.03], p < 0.001). A CNS biopsy was positive in 11/40 (28%) patients from Cluster 1 and 35/37 (95%) patients from Cluster 2 (p < 0.001). At 12 months, functional independence (modified Rankin scale score ≤ 2) did not differ between the two groups (p = 0.17). Relapse and mortality rates did not differ between the clusters (p = 0.17 and p = 0.23, respectively). Conclusion This unsupervised analysis of a large PCNSV cohort identified two different clinical and radiological phenotypes with different diagnostic work‐ups, which confirms the relevance of distinguishing PCNSV phenotypes according to the sizes of affected vessels.

Objectives Although rare, sacrococcygeal teratoma is the most common type of fetal tumor. It requires close antenatal monitoring to anticipate complications. We sought to determine whether the tumor growth rate was predictive of complications. The objective was to investigate the association between the growth rate of tumor volume, tumor diameter and the ratio of tumor volume to head circumference and extended perinatal morbidity and mortality. Secondly, we proposed a growth threshold predictive of poor outcome. Methods We conducted a retrospective multicenter observational study of ultrasound data from fetuses with an antenatal diagnosis of sacrococcygeal teratoma between 2011 and 2021 in France. Results Among the 28 cases, fetuses that died or required transfusion/vasopressors at birth presented with a higher growth rate for all three parameters. After adjusting by multivariate analysis, only a higher tumor volume growth rate ( p = 0.043) was significantly associated with extended perinatal morbidity and mortality. A tumor volume growth rate > 18.01 cm ³ /week and a volume > 245 cm ³ at any stage of pregnancy were associated with a poor perinatal outcome. Conclusions The volume growth rate is associated with extended perinatal morbidity and mortality. Tumor volume, per se, seems to play an important role in this association.

Male fertility declines during aging. This process mainly affects spermatogonia and Sertoli cells, leading to impaired spermatogenesis and poor‐quality sperm production. Circular RNAs (circRNAs) are covalently closed RNA molecules produced by backsplicing. In the field of male reproduction, circRNAs boast great potential in the regulation of spermatogenesis and sperm morpho‐functional skills. However, their potential role in age‐related male reproductive anomalies remains largely elusive. Here, we analyzed the reproductive phenotype of the aged male mouse experimental model, pointing our attention to a putative functional link between circRNAs and Sertoli cell survival. Our results confirm several testicular age‐related defects including: (i) altered morphology of the seminiferous epithelium; (ii) affected spermatogenesis; and (iii) decreased sperm production. In particular, aged spermatozoa (SPZ) were decreased in number in association with low motility and abnormal morphology (sperm head anomalies and tail bents). The expression analysis of selective spermatic circRNAs demonstrated a de‐regulated expression profile in Aged versus Young SPZ. Among them, we turned the lens on circAbcb9 as a spermatic circRNA potentially involved in the Sertoli cell senescence pathway via the circRNA/miRNA/mRNA network (ceRNET). Indeed, a significant shutdown of circAbcb9‐dependent network associated with a prominent increase in Sertoli cell senescence occurred in Aged testis. Interestingly, circAbcb9 was also expressed in human SPZ at decreased levels in Aged men, suggesting a conserved role. Collectively, our study stimulates greater interest in circRNAs as involved in the molecular mechanisms behind the age‐related effect on Sertoli cell survival, also providing new implications for fused protein in sarcoma (FUS) protein in sertolian circRNA biogenesis.

Objective To compare outcomes of nephrectomy for left‐sided (n = 70) vs right‐sided (n = 118) renal tumours with caval thrombi. Methods In this retrospective analysis (June 2008–February 2023), we evaluated peri‐operative variables, 30‐day complications, estimated glomerular filtration rate (eGFR), and survival rates. Results Patients in the left‐sided renal tumour group experienced significantly longer operating times (240 vs 193 min; P < 0.001), greater blood loss (1700 vs 1000 mL, P = 0.042), and more complications (53% vs 35%, P = 0.015). Postoperative renal function was worse in the left‐sided vs the right‐sided renal tumour group, with lower immediate postoperative eGFR (P = 0.035) and a higher dialysis rate (17% vs 6.8%, P = 0.026). However, overall survival and recurrence‐free survival were similar (P = 0.8 and P = 0.43, respectively). Conclusions Left‐sided renal tumours with caval thrombi present a higher risk of complications and acute kidney injury requiring dialysis, potentially due to left renal vein ischaemia during surgery and anatomical proximity to the superior mesenteric artery. Thorough preoperative planning and limited clamping time are essential.

Intensive chemotherapy (IC) combined with broad-spectrum antibiotics for acute myeloid leukemia (AML) leads to gut microbiota dysbiosis, promoting pathological conditions and an increased incidence of complications, possibly limiting eligibility to allogenic hematopoietic cell transplantation (alloHCT). The purpose of this dose-ranging phase I study (CIMON) was to evaluate the first-in-man use of MaaT033, a pooled, allogeneic, lyophilized, and standardized fecal microbiotherapeutic product, formulated as a delayed-release capsule for oral administration. Primary objectives of the study were to evaluate the maximum tolerable dose of MaaT033 in 21 AML patients having undergone IC and antibiotics. Secondary objectives were to assess MaaT033 safety, its efficacy in restoring the patients' gut microbiome using shotgun sequencing in order to evaluate the recommended dose regimen, and patient compliance (ClinicalTrials.gov number: NCT04150393). MaaT033 was shown to be safe and effective for gut microbiota restoration in AML patients receiving IC and antibiotics, with an excellent gut microbiota reconstruction based on diversity indices at the species level, and restoration of microbial communities close to the composition of the drug product. Moreover, inflammatory markers (C-reactive protein, interleukin-6) decrease with treatment, while short-chain fatty acids increase over time. A randomized, placebo-controlled phase IIb trial, in recipients of alloHCT patients in ongoing.

Deep Brain Stimulation (DBS) is a therapeutic option for treatment resistant (TR) obsessive-compulsive disorder (OCD). The OCD network comprises different sub-networks with homeostatic functions, altered under disease and modifiable with DBS. Connectomic analyses of DBS data sets have defined fiber selections explaining anti-OCD efficacy. This is a retrospective stimulation and outcome derived anatomical overlay analysis of 26 TR-OCD patients who received DBS at two academic centers. Grenoble, 14 anteromedial subthalamic nucleus (amSTN); Freiburg, 12 superolateral medial forebrain bundle (slMFB). Yale-Brown Obsessive Compulsive Scale improvement at 24 months served as outcome parameter. Structural proximity and outcomes were correlated using individual volumes of activated tissue for STN, slMFB, ORT (average OCD response tract) and further structures based on atlases or established connectomes. Connectomes (slMFB, ORT) were inspected for structural congruences. Normative connectomic data served to investigate cortical fiber penetration for the two target regions. Cortical sub-network conjugations were evaluated as peak levels. Our analyses revealed that ORT represents a fiber selection from the slMFB. DBS of amSTN and slMFB each address distinctive sub-networks while deep amSTN DBS can also address slMFB. Sub-network conjugations project amongst other regions onto the dorsomedial prefrontal cortex (dmPFC). The average ORT fiber selection is an integral part of the generic slMFB. Anti-OCD effects of amSTN DBS are not entirely explained by ORT overlay. The slMFB is dispersed and encompasses all OCD sub-networks and might qualify as a common DBS target when stimulated close to the ventral tegmental area. The dmPFC emerges as an interesting conjugation/hub between OCD sub-networks.

Deviations in the diversity and composition of the gut microbiota are called “gut dysbiosis”. They have been linked to various chronic diseases including cancers and resistance to immunotherapy. Stool shotgun based-metagenomics informs on the ecological composition of the gut microbiota and the prevalence of homeostatic bacteria such as Akkermansia muciniphila (Akk), while determination of the serum addressin MAdCAM-1 instructs on endothelial gut barrier dysfunction. Here we examined patient survival during chemo-immuno-therapy in 955 cancer patients across four independent cohorts of non-small cell lung (NSCLC), genitourinary (GU) and colorectal (CRC) cancers, according to hallmarks of gut dysbiosis. We show that Akk prevalence represents a stable and favorable phenotype in NSCLC and CRC cancer patients. Over-dominance of Akk above the healthy threshold was observed in dismal prognosis in NSCLC and GU and mirrored an immunosuppressive gut ecosystem and excessive intestinal epithelial exfoliation in NSCLC. In CRC, the combination of a lack of Akk and low sMAdCAM-1 levels identified a subset comprising 28% of patients with reduced survival, independent of the immunoscore. We conclude that gut dysbiosis hallmarks deserve integration within the diagnosis toolbox in oncological practice.

Background Plastic surgery residency training in France presents unique challenges and opportunities, with a highly competitive environment and a growing demand for academic plastic surgeons. Understanding the factors influencing residents’ career decisions is essential for optimizing training programs and fostering academic interest. Methods A cross-sectional study was conducted using a self-administered questionnaire comprising 14 questions distributed via RedCAP between January and June 2023. The study included all residents and young attendings in all 21 French University Hospital Centers nationwide, from year 1 to postgraduate year 2. Results Among 204 contacted participants, 106 responses were obtained. All responses were complete. First-year residents represented 9.4% of respondents, whereas residents in the “deepening” and “consolidation phases” represented 41.5% and 25.6%, respectively. Senior residents such as “junior doctors” and young attendings represented 25.5% of survey respondents. Although most residents expressed interest in private practice, mentorship from academic surgeons emerged as a significant influencer toward academic pursuits. Despite the prevalence of academic mentors (38% of identified mentors), a discrepancy was found between perceived academic orientation and actual research opportunities, indicating a need for improved awareness and exposure to academic possibilities during residency. Financial considerations, including salary differentials and job security, also seemed to play a substantial role in career decision-making. Conclusions Cultivating a deeper understanding of academic careers’ multifaceted nature and enhancing the appeal of academic pursuits are essential for nurturing the next generation of academic plastic surgeons. It is hoped that this study will help enhance the appeal of academic vocations in plastic surgery residents.

Purpose PPM1D, a central regulator of the DNA damage response, is commonly mutated in therapy-related clonal hematopoiesis, acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS). PPM1D mutations have been shown to expand under the selective pressure of DNA-damaging chemotherapy. However, whether PPM1D mutations promote the development of hematologic malignancies remains unclear. Experimental Design We characterized the clinical and genomic profiles of 112 PPM1D-mutated patients across the spectrum of myeloid disorders using a combination of bulk and single-cell analyses on diagnostic and longitudinal samples. Results Among all patients, 78% had a history of primary cancer, with DNMT3A and TP53 being the most frequently comutated genes. In 10 patients with high-grade serous ovarian cancer, longitudinal analysis showed variable dynamics of PPM1D-mutant clones, with 81% of clones expanding during exposure to alkylating agents. Clonal hierarchy estimation revealed that 44% of patients with PPM1D-mutated AML had a PPM1D mutation in the founder clone, with rare TP53 comutations. Both patients with TP53 wild-type and TP53-mutated AML had poor overall survival. Single-cell DNA and surface protein analysis in seven patients confirmed that PPM1D mutations can arise in the founding clone and are associated with the expression of leukemic markers. Conclusions PPM1D mutations found in clonal hematopoiesis can spontaneously regress after treatment discontinuation; however, they can also be found in the dominant clone in AML/MDS.

The SARS-CoV-2 pandemic revealed the rapid evolution of circulating strains. This led to new variants carrying mostly mutations within the receptor binding domain, which is immunodominant upon immunization and infection. In order to steer the immune response away from RBD epitopes to more conserved domains, we generated S glycoprotein trimers without RBD and stabilized them by formaldehyde cross-linking. The cryoEM structure demonstrated that SΔRBD folds into the native prefusion conformation, stabilized by one specific cross-link between S2 protomers. SΔRBD was coated onto lipid vesicles, to produce synthetic virus-like particles, SΔRBD-LV, which were utilized in a heterologous prime-boost strategy. Immunization of cynomolgus macaques either three times with the mRNA Comirnaty vaccine or two times followed by SΔRBD-LV showed that the SΔRBD-LV boost induced similar antibody titers and neutralization of different variants, including omicron. Upon challenge with omicron XBB.3, both the Comirnaty only and Comirnaty/SΔRBD-LV vaccination schemes conferred similar overall protection from infection for both the Comirnaty only and Comirnaty/SΔRBD-LV vaccination schemes. However, the SΔRBD-LV boost indicated better protection against lung infection than the Comirnaty strategy alone. Together our findings indicate that SΔRBD is highly immunogenic and provides improved protection compared to a third mRNA boost indicative of superior antibody-based protection.

Epidemiology of cerebral palsy (CP) aims to describe the frequency of the condition in a population and to monitor its changes over time, and a guide to the management of patients. Classification of CP is an important step toward describing more homogenous subgroups of persons with CP. Several classifications exist based on neurological signs and topography, on motor function loss, associated impairments, severity of the clinical pattern and on the neuroimaging findings. Caution should be paid when interpreting changes in prevalence rates since factors that may influence these estimates are numerous. The diagnosis may be made in infants as early as 4 months of age through a combination of neurological examination, prenatal findings, recognition of clinical risk factors and neuroimaging findings. Over the last 20 years, various other screening tests, developmental and neurological examination methods have been developed. For the fourth edition, the chapter has been reviewed/revised by the Book Editor.

Background/Objectives: Artificial intelligence (AI), particularly large language models (LLMs), has demonstrated versatility in various applications but faces challenges in specialized domains like neurology. This study evaluates a specialized LLM’s capability and trustworthiness in complex neurological diagnosis, comparing its performance to neurologists in simulated clinical settings. Methods: We deployed GPT-4 Turbo (OpenAI, San Francisco, CA, US) through Neura (Sciense, New York, NY, US), an AI infrastructure with a dual-database architecture integrating “long-term memory” and “short-term memory” components on a curated neurological corpus. Five representative clinical scenarios were presented to 13 neurologists and the AI system. Participants formulated differential diagnoses based on initial presentations, followed by definitive diagnoses after receiving conclusive clinical information. Two senior academic neurologists blindly evaluated all responses, while an independent investigator assessed the verifiability of AI-generated information. Results: AI achieved a significantly higher normalized score (86.17%) compared to neurologists (55.11%, p < 0.001). For differential diagnosis questions, AI scored 85% versus 46.15% for neurologists, and for final diagnosis, 88.24% versus 70.93%. AI obtained 15 maximum scores in its 20 evaluations and responded in under 30 s compared to neurologists’ average of 9 min. All AI-provided references were classified as relevant with no hallucinatory content detected. Conclusions: A specialized LLM demonstrated superior diagnostic performance compared to practicing neurologists across complex clinical challenges. This indicates that appropriately harnessed LLMs with curated knowledge bases can achieve domain-specific relevance in complex clinical disciplines, suggesting potential for AI as a time-efficient asset in clinical practice.

Background There is an increasing global concern about the use of synthetic cathinones (SCs). Detecting these drugs in human urine samples can be difficult, particularly in emergency settings. Cross-reactivity has been described for several immunoassays. We evaluated the analytical interference caused by common SCs in MDMA and amphetamine assays that use the EMIT® Atellica CH (Siemens Healthineers) with both clinical and in vitro experimental data. Methods Drug-free urine samples were spiked with various concentrations (5 to 100 µg/mL) of 2-methylmethcathinone (MMC), 3-MMC, 4-MMC, 3-chloromethcathinone (CMC), methylone and alpha-PHP and tested using EMIT® assays. The percentage of false-positive results was determined in urine samples from patients above 18 years of age admitted to the ICU or emergency department who underwent routine toxicology screening and urine immunoassays over a 4-year period. Confirmatory analyses of SC were performed by mass spectrometry techniques. Results False-positive results occurred for the MDMA assay with methylone (10 µg/mL) and 3-CMC (100 µg/mL) and for the amphetamine test with 2-MMC (50 µg/mL). We studied 2033 urine samples from 1812 patients (mean age 39 years, 61.8% male), of which 49 tested positive for amphetamine and 76 for MDMA. SCs were responsible for a false-positive rate of 16.3% for the amphetamine tests and 17.1% for the MDMA tests. Most of the false-positive tests occurred among young male patients (mean age 38 years, 92.8% male). Conclusions This study demonstrates that SC intoxication may be underreported in immunoassay toxicology testing. Due to a lack of specificity of screening immunoassay methods, positive results for amphetamine-type stimulants should be confirmed by specific MS methods.

In the phase 3 POLARIX study, polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) improved progression-free survival (PFS) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This post hoc subgroup analysis of POLARIX evaluated the efficacy and safety of Pola-R-CHP versus R-CHOP in elderly patients ≥60, ≥65, ≥70, and ≥75 years. As of June 15, 2022 (median follow-up 40 months), 629 patients ≥60 years were included (Pola-R-CHP, n = 311; R-CHOP, n = 318). Clinically meaningful improvements in PFS with Pola-R-CHP versus R-CHOP were observed across all age groups, particularly in patients ≥70 years whereby the risk of disease progression, relapse or death was reduced by 37% (unstratified hazard ratio [HR] 0.63; 95% confidence interval [CI]: 0.41-0.96). In patients ≥ 60 years, overall survival was similar with Pola-R-CHP versus R-CHOP (unstratified HR 0. 99; 95% CI: 0.67 -1.47 ). Safety profiles were similar for Pola-R-CHP versus R-CHOP among patients ≥60 years, including rates of grade 3-4 adverse events (AEs; 62.7% vs 61.5%), grade 3-5 infections (15.0% vs 12.9%), and grade 5 AEs (3.6% vs 3.2%); no novel toxicities were reported. Incidence of grade 3-4 febrile neutropenia was higher with Pola-R-CHP than R-CHOP (16.3% vs 7.6%), highlighting the importance of G-CSF prophylaxis in elderly patients receiving Pola-R-CHP. The benefit-risk profile favored Pola-R-CHP versus R-CHOP in elderly patients with previously untreated DLBCL. This trial was registered at ClinicalTrials.gov as #NCT03274492.