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Atypical femoral fractures (AFFs) are rare adverse effects of bisphosphonate therapy. We report an unusual case of bilateral diaphyseal AFFs in an antiresorptive-naïve Singaporean Chinese female with Graves’ disease. She presented with complete right AFF requiring surgical fixation, and persistent left incomplete AFF for over four years. Femoral bowing, varus femoral geometry, and ethnic influence likely contributed to the AFFs’ formation. This case may provide insights into the pathogenesis of AFFs in high-risk Asian populations.

Abstract Background Immunotherapy alone or in combination has clearly improved the survival of patients with lung cancer. However, it may also be responsible for adverse events impacting these patients' quality of life. The ToxImmune study aims to identify prognostic factors that can help to predict immune‐related adverse events. Methods We included all patients aged 18 years and older who had received at least one dose of immune checkpoint inhibitors, with or without other therapy, between June 2015 and December 2020 and were diagnosed with nonsmall cell lung cancer or small‐cell lung cancer. Patients' baseline demographic characteristics, biological blood markers, and imaging by PET‐scanner were collected from electronic medical records. All adverse events (AEs) and immune‐related AEs (irAEs) were recorded (Common Terminology Criteria For Adverse Events V.5.0). Results Sixty‐four patients were included, of whom 60 (94%) presented at least one irAE. The incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 and grade 3–4 was 34% and 8% respectively. Female sex, Primitive Tumor Standardized Uptake Value Max (SUVmax)

Hereditary erythrocytosis is a rare hematologic disorder characterized by an excess of red blood cell production. Here we describe a European collaborative study involving a collection of 2,160 patients with erythrocytosis sequenced in ten different laboratories. We focused our study on the EGLN1 gene and identified 39 germline missense variants including one gene deletion in 47 probands. EGLN1 encodes the PHD2 prolyl 4-hydroxylase, a major inhibitor of hypoxia-inducible factor. We performed a comprehensive study to evaluate the causal role of the identified PHD2 variants: (i) in silico studies of localization, conservation, and deleterious effects; (ii) analysis of hematologic parameters of carriers identified in the UK Biobank; (iii) functional studies of the protein activity and stability; and (iv) a comprehensive study of PHD2 splicing. Altogether, these studies allowed the classification of 16 pathogenic or likely pathogenic mutants in a total of 48 patients and relatives. The in silico studies extended to the variants described in the literature showed that a minority of PHD2 variants can be classified as pathogenic (36/96), without any differences from the variants of unknown significance regarding the severity of the developed disease (hematologic parameters and complications). Here, we demonstrated the great value of federating laboratories working on such rare disorders in order to implement the criteria required for genetic classification, a strategy that should be extended to all hereditary hematologic diseases.

Background: Kidney transplant recipients (KTRs) are likely to develop severe COVID-19 and are less well-protected by vaccines than immunocompetent subjects. Thus, the use of neutralizing anti–SARS-CoV-2 monoclonal antibodies (mAbs) to confer a passive immunity appears attractive in KTRs. Methods: This retrospective monocentric cohort study was conducted between 1 January 2022 and 30 September 2022. All KTRs with a weak antibody response one month after three doses of mRNA vaccine (anti spike IgG < 264 (BAU/mL)) have received tixagevimab-cilgavimab in pre-exposure (group 1), post-exposure (group 2) or no specific treatment (group 3). We compared COVID-19 symptomatic hospitalizations, including intensive care unit hospitalizations, oxygen therapy, and death, between the three groups. Results: A total of 418 KTRs had SARS-CoV-2 infection in 2022. During the study period, we included 112 KTRs in group 1, 40 KTRs in group 2, and 27 KTRs in group 3. The occurrence of intensive care unit hospitalization, oxygen therapy, and COVID-19 death was significantly increased in group 3 compared to group 1 or 2. In group 3, 5 KTRs (18.5%) were admitted to the intensive care unit, 7 KTRs (25.9%) needed oxygen therapy, and 3 KTRs (11.1%) died. Patients who received tixagevimab-cilgavimab pre- or post-exposure had similar outcomes. Conclusions: This retrospective real-life study supports the relative effectiveness of tixagevimab-cilgavimab on COVID-19 infection caused by Omicron, used as a pre- or post-exposure therapy. The continued evolution of Omicron variants has made tixagevimab-cilgavimab ineffective and reinforces the need for new therapeutic monoclonal antibodies for COVID-19 active on new variants.

Patients admitted to the intensive care unit (ICU) often experience endotoxemia, nosocomial infections and sepsis. Polymorphonuclear and monocytic myeloid-derived suppressor cells (PMN-MDSCs and M-MDSCs) can have an important impact on the development of infectious diseases, but little is known about their potential predictive value in critically ill patients. Here, we used unsupervised flow cytometry analyses to quantify MDSC-like cells in healthy subjects challenged with endotoxin and in critically ill patients admitted to intensive care units and at risk of developing infections. Cells phenotypically similar to PMN-MDSCs and M-MDSCs increased after endotoxin challenge. Similar cells were elevated in patients at ICU admission and normalized at ICU discharge. A subpopulation of M-MDSC-like cells expressing intermediate levels of CD15 (CD15int M-MDSCs) was associated with overall mortality (p = 0.02). Interestingly, the high abundance of PMN-MDSCs and CD15int M-MDSCs was a good predictor of mortality (p = 0.0046 and 0.014), with area under the ROC curve for mortality of 0.70 (95% CI = 0.4–1.0) and 0.86 (0.62–1.0), respectively. Overall, our observations support the idea that MDSCs represent biomarkers for sepsis and that flow cytometry monitoring of MDSCs may be used to risk-stratify ICU patients for targeted therapy.

Research aim and purposeThe benefits of Electronic Patient -Reported Outcomes (e-PRO) for telemonitoring are well established, allowing early detection of illnesses and continuous monitoring of patients. The primary objective of the PROTECTY study was to assess the compliance with patient use of the telemonitoring platform Cureety. An exploratory objective was to assess if the first-month health status is a prognostic factor of progression free-survival (PFS) and overall survival (OS) for prostate cancer patient.MethodsThis prospective study was conducted at the Military Hospital Bégin on prostate cancer patients. Patients were allowed to respond to a symptomatology questionnaire based on CTCAE v.5.0, personalized to their pathology and treatment. An algorithm evaluates the health status of the patient based on the reported adverse events, with a classification into 2 different states: Good Health Status (GHS) and Poor Health status (PHS).ResultsSixty-one patients were enrolled between July 1st, 2020 and September 30th, 2021. The median age was 74.0 (range 58.0–94.0). 78% presented a metastatic stage, and the most represented cancer was mHSPC. Overall, 2,457 questionnaires were completed by the patients, 4.0% resulted in a health classification in to monitor or critical state. 87% of patients were classified in the GHS group. The compliance was 72% in the overall population during the first month, 71% in GHS group and 75% in PHS group. The median follow-up was 8 months. PFS at 6 months was 84% in GHS group vs. 57% in PHS group, p = 0.19. OS at 6 months was 98% in GHS group vs. 83% in PHS group, p = 0.31.ConclusionsOur study showed that compliance was satisfactory. The feasibility of remote monitoring for prostate cancer patients means that they should benefit from its implementation. Our study is also the first to assess the correlation between treatment tolerance and survival. The initial results suggest that e-PRO assessment could help identify in the early stages the patients that require further health assessment and potential therapeutic changes. While further follow-up of more patients will be required, our study highlights the importance of e-PRO in cancer patient care.

Author(s): Frantisek Duska [sup.1] [sup.2], Maurizio Cecconi [sup.1] [sup.3] [sup.4], Frantisek Duska, Mauricio Cecconi, Mo Al-Haddad, Frauke Weidanz, Anne Le Roy, Raj Saha, Anne Mecklenburg, Eumorfia Kondil, Nathan Nielsen, María [...]

Background: Vitamin D (VD) deficiency is common among patients with atopic dermatitis (AD) and often associated with severity. However, randomized trials of VD supplementation in AD have had equivocal results, and there is little information regarding the effect of VD supplementation on type 2 immunity in AD patients. Objectives: To investigate the efficacy of VD supplementation to decrease severity of AD and to alter type 2 immunity biomarkers. Methods: We performed a randomized, double‐blind, placebo‐controlled trial. We randomly assigned 101 children with AD to weekly oral vitamin D3 (VD3) or placebo for 6 weeks. The primary outcome was the change in the Severity Scoring of AD (SCORAD). Results: Mean age of subjects was 6.3 ± 4.0 years, and baseline SCORAD was 32 ± 29. At baseline, 57% of children were VD deficient, with no difference between groups. Change in 25(OH)D was significantly greater with VD3 than placebo (+43.4 ± 34.5 nmol/L vs. +2.3 ± 21.2 nmol/L, p < 0.001). SCORAD change at 6 weeks was not different between VD and placebo (−5.3 ± 11.6 vs. −5.5 ± 9.9, p = 0.91). There were no significant between‐group differences in change of eosinophil counts, total IgE, Staphylococcal enterotoxin specific IgE, CCL17, CCL22, CCL27, LL‐37 or Staphylococcus aureus lesional skin colonization. Vitamin D receptor (VDR) gene single nucleotide polymorphisms FokI, ApaI and TaqI did not modify subjects' response to VD supplementation. Conclusions: Among children with AD, weekly VD supplementation improved VD status but did not modify AD severity or type 2 immunity biomarkers compared to placebo (ClinicalTrials.gov NCT01996423). [ABSTRACT FROM AUTHOR]

Mainland France is part of a plate interior with a strong structural heritage, undergoing a low rate of deformation, where destructive earthquakes can nevertheless occur. In this paper, we emphasize that the knowledge of active faults is still largely fragmentary, and that significant efforts are needed to generate robust data, in particular on the numerous faults, that still lack any study. This is the aim of the “Failles ACTives France” (FACT) axis launched in the framework of the Transverse Seismicity Action (ATS) of the Resif-Epos consortium. We present some recent investigations carried out along suspected active faults in mountainous areas, their forelands and remote lowlands, which implement new approaches and new tools, and allow characterizing their Quaternary activity.

Objectives: Physiotherapy leads to improvements in critically ill patients who receive mechanical ventilation. However, cancer patients have not been included in previous studies on this subject. This study explored the feasibility and safety of physiotherapy in the intensive care unit for patients with malignancy. Design: Observational prospective single-centre study, comparing cancer and control patients. Patients: All consecutive patients admitted to the intensive care unit who needed invasive mechanical ventilation for more than 2 days with no contraindication to physiotherapy were included in the study. Methods: The main outcome was the proportion of physiotherapy sessions at the prescribed level in each group. Results: A total of 60 patients were included within 1 year. A total of 576 days were screened for physiotherapy sessions and 367 physiotherapy-days were analysed (137 days for control patients and 230 days for cancer patients). The ratio of physiotherapy sessions performed/prescribed did not differ between groups: 0.78 (0.47–1) in the control group vs 0.69 (0.6–1) in the cancer group (odds ratio 1.18 (IC95% 0.74–1.89); p = 0.23). A sensitivity analysis including patient effect as random variable confirmed those results (odds ratio 1.16 (0.56–2.38), p = 0.69). Adverse events occurred with the same frequency in cancer patients and non-cancer patients. Conclusion: Physiotherapy in cancer patients who require intubation is feasible and safe. However, only two-thirds of prescribed physiotherapy sessions were performed. Studies are warranted to explore the barriers to physiotherapy in the intensive care unit setting. LAY ABSTRACT Mobilization for intubated patients improves outcomes. However, patients with malignancy have not been included in previous studies exploring mobilization in the intensive care unit (ICU). This study explored the feasibility and safety of mobilization for intubated patients with malignancy. Intubated patients with and without cancer were included in an observational study. Each day, a mobilizing team, including a physiotherapist, decide on the mobilization level for individual patients, according to their awakening and motor status. The physiotherapist performed the physiotherapy sessions. The level obtained during physiotherapy sessions was compared with the prescribed level. A physiotherapy session was considered successful when the prescribed level was obtained. Statistical analysis of 27 non-cancer patients and 33 cancer patients did not reveal any differences in terms of the feasibility and safety of physiotherapy sessions. However, in this study, only two-thirds of prescribed physiotherapy sessions were performed. Barriers to the use of physiotherapy in the ICU for patients with malignancy should be explored.

Gain-of-function mutations in the EPAS1/HIF2A gene have been identified in patients with hereditary erythrocytosis that can be associated with the development of paraganglioma, pheochromocytoma and somatostatinoma. In the present study, we describe a unique European collection of 41 patients and 28 relatives diagnosed with an erythrocytosis associated with a germline genetic variant in EPAS1. In addition we identified two infants with severe erythrocytosis associated with a mosaic mutation present in less than 2% of the blood, one of whom later developed a paraganglioma. The aim of this study was to determine the causal role of these genetic variants, to establish pathogenicity, and to identify potential candidates eligible for the new hypoxia-inducible factor-2 α (HIF-2α) inhibitor treatment. Pathogenicity was predicted with in silico tools and the impact of 13 HIF-2b variants has been studied by using canonical and real-time reporter luciferase assays. These functional assays consisted of a novel edited vector containing an expanded region of the erythropoietin promoter combined with distal regulatory elements which substantially enhanced the HIF-2α-dependent induction. Altogether, our studies allowed the classification of 11 mutations as pathogenic in 17 patients and 23 relatives. We described four new mutations (D525G, L526F, G527K, A530S) close to the key proline P531, which broadens the spectrum of mutations involved in erythrocytosis. Notably, we identified patients with only erythrocytosis associated with germline mutations A530S and Y532C previously identified at somatic state in tumors, thereby raising the complexity of the genotype/phenotype correlations. Altogether, this study allows accurate clinical follow-up of patients and opens the possibility of benefiting from HIF-2α inhibitor treatment, so far the only targeted treatment in hypoxia-related erythrocytosis disease.

Abstract In this study, we present an ultra‐wideband full‐duplex system constituted of a wideband 4‐element Vivaldi array and wideband microstrip‐to‐slotline baluns. The proposed system is characterised by its simplicity, high directivity, and high self‐interference cancellation levels over a wide frequency bandwidth. The system is fabricated using basic printed‐circuit board (PCB) technology and can provide at least 50 dB of self‐interference cancellation over the bandwidth of operation, 4–40 GHz, with an average gain of 7.8 dBi. The system has a size of 8 cm × 8 cm × 9.4 cm and can be used as a high data rate link between two distant wireless nodes. To assess the merits of the proposed system and compare it to other published works, a new figure of merit (FoMWFD) dedicated to wide‐band full‐duplex antenna topologies is introduced in this study.

IntroductionPruritus is a major and burdensome symptom in atopic dermatitis (AD). The number of systemic treatments available for AD has increased recently, enabling improved patient relief.ObjectiveTo evaluate the effect of AD treatments on pruritus.MethodsA systematic literature review and a meta-analysis were conducted to evaluate and compare the effects of treatment used in AD on pruritus. PubMed and Embase databases were searched to find articles published between January 1990 and December 2021. Topical and systemic treatments were studied in patients aged ≥10 years.ResultsAmong the 448 articles identified, 56 studies were retained in the systematic review. A total of 15 studies evaluated topical treatments: topical corticosteroids (TCS; 2), calcineurin inhibitors (6), PDE4 inhibitors (3), and Jak inhibitors (4). A total of five studies were included in the meta- analysis. All treatments had a positive effect on pruritus, with a mean overall reduction of 3.32/10, 95% IC [2.32–4.33]. The greatest reduction was observed with halometasone (mean: 4.75), followed by tofacitinib 2% (mean: 4.38). A total of 41 studies evaluated systemic therapies: cyclosporine (6), phototherapy (5), azathioprine (2), dupilumab (9), anti-IL 13 (5), nemolizumab (3), Jak inhibitors (9), mepolizumab (1), and apremilast (1). A total of 17 studies were included in 2 meta-analyses according to the concomitant use or not of TCS. In the meta-analysis without TCS, the overall decrease was 3.07/10, 95% IC [2.58–3.56]. The molecules with the highest efficacy on pruritus were upadacitinib 30 mg (mean: 4.90) and nemolizumab (mean: 4.81).DiscussionThe therapeutic arsenal for AD has increased rapidly, and many molecules are under development. The primary endpoint of clinical trials is most often a score that assesses the severity of AD; however, the assessment of pruritus is also essential. The majority of molecules have a positive effect on pruritus, but the improvement varies between them. Efficacy on pruritus is not always correlated with efficacy on AD lesions; therefore, these two criteria are crucial to evaluate. The limitations of this study were the heterogeneity in the assessment of pruritus, the moment of the assessment, and the concomitant application of TCS or not for studies evaluating systemics. In the future, it would be useful to use standardized criteria for assessing pruritus.

Roux-en-Y gastric bypass (RYGB) is efficient at inducing drastic albeit variable weight loss and type-2 diabetes (T2D) improvements in patients with severe obesity and T2D. We hypothesized a causal implication of the gut microbiota (GM) in these metabolic benefits, as RYGB is known to deeply impact its composition. In a cohort of 100 patients with baseline T2D who underwent RYGB and were followed for 5-years, we used a hierarchical clustering approach to stratify subjects based on the severity of their T2D (Severe vs Mild) throughout the follow-up. We identified via nanopore-based GM sequencing that the more severe cases of unresolved T2D were associated with a major increase of the class Bacteroidia, including 12 species comprising Phocaeicola dorei, Bacteroides fragilis, and Bacteroides caecimuris. A key observation is that patients who underwent major metabolic improvements do not harbor this enrichment in Bacteroidia, as those who presented mild cases of T2D at all times. In a separate group of 36 patients with similar baseline clinical characteristics and preoperative GM sequencing, we showed that this increase in Bacteroidia was already present at baseline in the most severe cases of T2D. To explore the causal relationship linking this enrichment in Bacteroidia and metabolic alterations, we selected 13 patients across T2D severity clusters at 5-years and performed fecal matter transplants in mice. Our results show that 14 weeks after the transplantations, mice colonized with the GM of Severe donors have impaired glucose tolerance and insulin sensitivity as compared to Mild-recipients, all in the absence of any difference in body weight and composition. GM sequencing of the recipient animals revealed that the hallmark T2D-severity associated bacterial features were transferred and were associated with the animals’ metabolic alterations. Therefore, our results further establish the GM as a key contributor to long-term glucose metabolism improvements (or lack thereof) after RYGB.