Assistance Publique – Hôpitaux de Paris

Diagnosis of imported malaria is based on microscopic examination of blood smears (BS), detection of circulating plasmodial antigen by immunochromatography (ICT), or detection of Plasmodium spp. DNA by loop mediated isothermal amplification. We have developed duplex ( Plasmodium spp. and Plasmodium falciparum ) real-time PCR (qPCR) and species-specific qPCR assays for the identification and quantification of human Plasmodium species. Whole nucleic acids from 523 samples prospectively collected from 410 patients suspected of malaria between June 2016 and March 2021 were tested by qPCRs and compared to standard diagnostic procedures. All qPCRs were designed on 18S ribosomal ribonucleic acid. The limit of detection of duplex qPCR was 8 copies/reaction, and analytical specificity of species-specific qPCRs was 100%. Seventy-nine patients diagnosed for single species malaria involving P. falciparum , P. vivax , P. ovale, and P. malariae were positive with duplex and species-specific qPCRs. P. knowlesi qPCR detected DNA from a P. knowlesi culture. Of eight cases of mixed Plasmodium species infection, five were identified with our qPCR assays with better sensitivity as compared to BS and ICT. Eight out of 323 patients with negative BS were hospitalized for symptoms suggestive malaria after malaria-endemic area travel or known with history of malaria had a low positive duplex qPCR. Between day of diagnosis and post-treatment follow-up at D2-D4 of malaria, a 3.1-log P. falciparum load decrease was observed by qPCR. These new Plasmodium qPCRs allowing detection of human plasmodial species have excellent species specificity and allow rapid detection of P. falciparum cases, malaria with low parasitaemia, and mixed Plasmodium species infection. IMPORTANCE Malaria is a disease transmitted by a Plasmodium parasite genus. Most cases are caused by Plasmodium falciparum . Despite a significant drop of incidence and mortality since 2000, 249million cases and 608,000 deaths have been estimated in 2022, mainly in Africa. Due to the increasing number of travels to endemic areas, incidence of imported malaria is rising in Europe. Various techniques are used in European laboratories, such as microscopic examination of thin and thick smears and rapid diagnostic tests. However, these techniques require skilled operators to differentiate plasmodial species and have limited sensitivity. Actually, molecular diagnosis is carried out using point-of-care test for rapid results with excellent sensitivity but is unabled to determine involved species and assess parasitaemia. In this study, we developed a combined molecular tool based on both detection of all human plasmodial species ( Plasmodium spp.) and P. falciparum . We have also developed specific qPCRs for each human plasmodial species.

Background The newborn transphyseal fracture of the distal humerus is frequently misdiagnosed with an elbow dislocation due to the absence of the lateral condyle ossification node. No consensus has been reported either for the diagnosis or the management of these rare fractures. This study aimed to analyze a series of newborns with transphyseal distal humerus fractures. Methods All consecutive infants treated between 2005 and 2020 for a transphyseal fracture of the distal humerus before the age of 6 months were retrospectively included. All radiological examinations were analyzed (X-ray, ultrasound, and magnetic resonance imaging (MRI)) as well as the therapeutic management (orthopedic or surgical treatment). The patients were seen at outpatient clinic visits with a minimum of 2-year follow-up. Results Nine newborns were treated. The main cause was an obstetrical traumatism ( n = 8). The diagnosis was made on physical examination and addressed by obstetric departments with standard biplanar radiographs in four cases. The fracture was suspected on physical examination in the remaining five cases and confirmed by complementary imaging (ultrasound (2), MRI (1), and both (3)). A total of six patients were treated conservatively and three surgically with an open reduction. At a mean follow-up of 79 months, two complications occurred: one axillary abscess due to the cast and one cubitus varus deformity. All children had a full functional recovery. Conclusions The transphyseal fracture of the distal humerus in newborns is a rare entity that should be managed conservatively. Additional imaging examinations are recommended to clarify the diagnosis. Level of evidence Level IV, cohort study.

Antimicrobial resistance (AMR) has become a worldwide growing concern over the past decades. Thus, encouraging manufacturers to develop new antibiotics is needed. We hypothesised that transparency on the regulatory appraisals of antibiotics would provide an incentive to pharmaceutical development. We thus aimed at reporting the French health technology assessment (HTA) opinions and reimbursement decision on antibiotics to those German (G-BA) and English (NICE) HTA bodies. A qualitative analysis of the Transparency Committee of the French National Authority for Health (TC-HAS) opinions regarding antibiotics assessment between 2016 and 2020 was performed. Decisions of reimbursement by TC-HAS were compared to those from G-BA and NICE when available. TC-HAS recognized a clinical benefit (CB) for 15/15 evaluated indications, a clinical added value for 9/15, and a public health interest for 8/15. Among the valued antibiotics by HAS, 5 were recommended for restricted use as a “reserve” to protect against the risk of resistance emergence. A comparison of HTA opinions was possible across HTA for only 8 antibiotics. The G-BA granted a reserve status for 4 drugs and NICE a reserve with restricted use for 5 antibiotics. Three of these antibiotics were positioned similarly by the English, German, and French HTA bodies. This qualitative analysis of HTA opinions between different European HTA bodies shows a consistent reimbursement decision of antibiotics against MDR bacteria and tuberculosis besides the differences in the applied assessment methods. This work also shows how HTA bodies could recognize a clinical added value in a context of the emergence of antibiotic resistance.

Background Nivolumab obtained approval in advanced melanoma (AM) with weight‐adjusted dose (WAD) administration (3 mg/kg/2 weeks). In 2018, the dosage regimen was changed to flat dose (FD) administration (240 mg/2 weeks or 480 mg/4 weeks) based on a modeling study, without clinical data. Methods AM patients have been prospectively included in the French national multicenter MelBase database since 2013. First‐line patients treated with nivolumab monotherapy were included in the WAD or FD groups of this study. The primary end point was the incidence of grade ≥3 immune‐related adverse events (irAEs). Secondary end points were incidence of any grade irAEs, and overall survival (OS) and progression‐free survival (PFS). Inverse probability of treatment weighting was used to balance groups on their baseline characteristics. Results Between 2015 and 2022, 348 patients were included: 160 in the WAD and 188 in the FD groups. In the FD group, 45% and 27% of patients weighed <75 kg and >85 kg, respectively. Grade ≥3 and any grade irAEs rates were 13.1% versus 11.7% (p = .8) and 63.1% versus 67.0% (p = .5) in the WAD and FD groups, respectively. After weighting, median PFS was 3.1 and 3.7 months (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.65–1.07), and median OS was 24.8 and 37.0 months (HR, 0.74; 95% CI, 0.54–1.01) in the WAD and FD groups, respectively. Conclusions There was no difference in the incidence of severe irAEs and in median PFS between AM patients treated by WAD or FD nivolumab. The median OS between patient groups did not reach statistical significance.

Ongoing innovation in diabetes technologies has led to the development of advanced tools such as automated insulin delivery (AID) systems that adjust insulin delivery in response to current and predicted glucose levels, residual insulin action, and other inputs (eg, meal and exercise announcements). However, infusion sets continue to be the “Achilles heel” of accurate and precise insulin delivery and continued device use. A recent study by Kalus et al (DERMIS Study) revealed higher vessel density and signals of inflammation by optical coherence tomography (OCT), in addition to increased inflammation, fat necrosis, fibrosis, and eosinophilic infiltration by histopathology. Although the study provided a comprehensive description of what was happening, the results raise important questions that require additional research. On February 29, 2024, the Leona M. and Harry B. Helmsley Charitable Trust sponsored a conference to begin addressing these issues. This article summarizes the DERMIS study findings and testing methodologies discussed at the conference and proposes the next steps for developing insulin infusion sets that reduce the variability in insulin delivery and extend wear.

BACKGROUND AND OBJECTIVES Diagnosing ventriculostomy-related infection (VRI), a common complication after external ventricular drainage (EVD), is challenging and often associated with delayed initiation of antibiotic therapy. We aimed to develop a stewardship score to help in the decision of antibiotic therapy initiation when VRI is suspected. METHODS This retrospective, single-center cohort study included patients admitted to the intensive care unit after EVD placement who were suspected of having healthcare-associated ventriculitis and/or meningitis between January 1, 2012, and August 31, 2022. A multiple logistic regression model was used to identify factors associated with the development of healthcare-associated meningitis or ventriculitis after EVD placement. RESULTS A total of 331 patients were included. Eighty-one (23%) patients developed VRI between January 1, 2012, and August 31, 2022, whereas 250 (77%) did not (from January 1, 2018, to August 31, 2022). VRI-associated factors were EVD count >1 (odds ratio [OR] 3.69, P < .001), EVD duration >8 days (OR 6.71, P < .001), immunosuppression (OR 3.45, P = .028), recent neurosurgery (OR 7.74, P < .001), cerebrospinal fluid leak (OR 6.08, P < .001), and prophylactic antimicrobials (OR 0.26, P < .001). The VEntriculostomy-Related Infection score (VERI) score categorized VRI risk into 4 levels, with an area under the curve of 0.84. CONCLUSION The VERI score is a robust, predictive tool for assessing the risk of VRI in patients with EVD, potentially guiding more judicious use of antibiotic therapy in the intensive care unit setting.

Retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and migraine headache (ROSAH) syndrome is an autosomal dominant disorder and to date is known to be caused by either the Thr237Met or Tyr254Cys variant in the protein kinase ALPK1. Here, we identify a family in which ROSAH syndrome is caused by a novel variant in which Ser277 is changed to Phe. All six patients examined display ocular inflammation and optic nerve elevation, four have retinal degeneration and four are registered blind. In contrast to wild-type ALPK1, which is activated specifically by bacterial ADP-heptose, ALPK1[Ser277Phe] is also activated by the human metabolites UDP-mannose and ADP-ribose and more strongly than the most frequent ROSAH-causing variant (ALPK1[Thr237Met]) but, unlike ALPK1[Thr237Met], ALPK1[Ser277Phe] is also activated by GDP-mannose. These observations can explain why ALPK1 variants causing ROSAH syndrome display constitutive activity in human cells. The side chains of Ser277 and Tyr254 interact in the crystal structure of ALPK1, but mutational analysis established that it is not the loss of this hydrogen bond between Ser277 and Tyr254 that alters the specificity of the ADP-heptose-binding pocket in the Ser277Phe and Tyr254Cys variants. The characterization of ALPK1 variants that cause ROSAH syndrome suggests ways in which drugs that selectively inhibit these disease-causing variants may be developed.

Proton pump inhibitor (PPI) use in children increases the risk of infections, prompting inquiry into the impact of prenatal PPIs exposure on serious infections in offspring. As a research gap in this area exists, this study aimed to address it by assessing the association between prenatal PPIs exposure and serious infections in infants during their first year of life. Using the French health insurance data warehouse (SNDS) (2013–2018), we conducted a retrospective cohort study on singleton, full-term liveborn non-immunocompromised infants, stratified by PPI use during the first three months of life (early-life use). Proton pump inhibitor dispensing in ambulatory care settings during pregnancy defined exposure. Outcomes concerned any serious infections in offspring aged between 3 and 12 months. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariable models to control for potential confounders. Of the 2,485,545 infants included, 497,060 (23.3%) were prenatally exposed to PPIs and 97,767 (4.6%) had PPI use during the first three months of life. Prenatal PPI exposure was associated with serious infections in offspring (aOR, 1.09 [95% CI, 1.07–1.10]) in infants without early-life PPIs use. No association was found for infants with early-life PPI use (aOR, 1.05 [95% CI, 1.00–1.11]). Gastrointestinal infections were the sole site with persistent significance. Prenatal PPI exposure is common and is not associated with a major risk of serious infections in infants during their first year. However, even after adjusting for several confounding factors, a weak association remains, especially in infants without early-life PPI use. While offering reassurance, adherence to clinical guidelines is still crucial.

Deep dissecting haematoma (DDH) occurs on the lower legs after extensive bleeding in the potential space between skin and subcutaneous fat and along the fascia. lt is a rare condition, little known in the literature and by healthcare professionals, and is serious, potentially fatal. They occur in the majority of cases following trauma, however minor, and are very often a complication of dermatoporosis.

Martorell hypertensive ischemic ulcer, also called necrotic angiodermatitis, is a particular form of ischemic leg ulcer associated with arterial hypertension that is often underdiagnosed. The underlying vascular lesions involve small-caliber vessels. These are arteriolosclerosis and arteriolar vasospasm responsible for the tissue ischemia and skin necrosis that characterize the ulcer. This pathology is very painful, often recurrent and difficult to treat. The diagnosis is essentially clinical. Early treatment should help control pain and prevent the rapid spread of skin necrosis. Complications are fortunately rare, but in a few cases, osteitis and extension of trophic disorders can lead to amputation. Current treatment is based on rapid skin grafting and correction of cardiovascular risk factors. Calciphylaxis is the main differential diagnosis and is more often observed in hemodialysis or transplant patients.

Some causes of necrosis are specific to the elderly population such as deep dissecting hematomas, skin tears or incontinence-associated dermatitis (ICD) lesions. Pressure sores are also common. Necrosis of arterial origin in the lower limbs is common but chronic obliterating arteriopathy is underestimated. Rarer causes of necrosis such as necrotic angiodermatitis, pyoderma gangrenosum, calciphylaxis, drug-induced necrosis and infectious necrosis also occur in old age. The risk if it involves amputation wounds of the lower limbs then poses an ethical problem which must be discussed with trained teams.

Background Recruitment of cancer patients into clinical trials (CTs) is a challenge. We aimed to explore how patient eligibility assessment is conducted in practice, what factors support or hinder this process, and to assess the potential usefulness of Clinical Trial Recruitment Support Systems (CTRSS) for patient‐to‐trial matching. Methods We conducted semi‐structured interviews in France with healthcare professionals involved in cancer CTs and experts on trial recruitment. We focused on the stages in‐between trial feasibility, and patient information and consent. Interviews were recorded, and the transcripts were analyzed thematically. We used the Systems Engineering Initiative for Patient Safety (SEIPS) 2.0 framework to organize our results. Results We interviewed 25 participants. We identified common steps for cancer patient eligibility assessment: prescreening under medical supervision, followed by the validation of patient‐trial matching based on manual chart review. This process built on rich interactions between clinicians, other professionals (clinical research assistants, data scientists, medical coding experts), and patients. Technological factors, mainly related to data infrastructure (both for patient data and trial data), and organizational factors (research culture, incentives, formal and informal research networks) mediated the performance of the recruitment process. Participants had mixed feelings towards CTRSSs; they welcomed automated pre‐screening but insisted on manual verification. Given the necessary collaborative nature of multisite trials, coordinated efforts to support a common data infrastructure could be helpful. Conclusions Material, organizational, and human factors affect cancer patient eligibility assessment for CTs. Patient‐to‐trial matching tools bear potential, but good understanding of the ecosystem, including stakeholders' motivations, is a prerequisite.

Cancer cells are known to express the Warburg effect—increased glycolysis and formation of lactic acid even in the presence of oxygen—as well as high glutamine uptake. In tumors, cancer cells are surrounded by collagen, immune cells, and neoangiogenesis. Whether collagen formation, neoangiogenesis, and inflammation in cancer are associated with the Warburg effect needs to be established. Metabolic modelling has proven to be a tool of choice to understand biological reality better and make in silico predictions. Elementary Flux Modes (EFMs) are essential for conducting an unbiased decomposition of a metabolic model into its minimal functional units. EFMs can be investigated using our tool, aspefm, an innovative approach based on logic programming where biological constraints can be incorporated. These constraints allow networks to be characterized regardless of their size. Using a metabolic model of the human cell containing collagen, neoangiogenesis, and inflammation markers, we derived a subset of EFMs of biological relevance to the Warburg effect. Within this model, EFMs analysis provided more adequate results than parsimonious flux balance analysis and flux sampling. Upon further inspection, the EFM with the best linear regression fit to cancer cell lines exometabolomics data was selected. The minimal pathway, presenting the Warburg effect, collagen synthesis, angiogenesis, and release of inflammation markers, showed that collagen production was possible directly de novo from glutamine uptake and without extracellular import of glycine and proline, collagen’s main constituents.

Background Data on patients aged 90 or older are rare. This study aims to describe clinical characteristics, treatment strategies, and clinical outcomes (rates of VTE recurrence, major bleeding, and mortality), during the first 3 months of anticoagulant treatment for VTE, depending on the treatment period. Methods We analyzed data from RIETE, an ongoing global observational registry of patients with objectively confirmed acute VTE, grouped in 5‐year intervals (2004–2008, 2009–2013, 2014–2018, and 2019–2023). Results Among 3477 patients aged 90 or older, clinical characteristics have changed over time (less heart failure, more dementia), with an increase in PE diagnoses from 57% in 2004–2008 to 69% in 2019–2023 ( p ‐trends <0.001), but of lower severity. For long‐term therapy, there was an increase in patients receiving DOACs ( p ‐trends <0.001), with a decrease in patients on VKAs ( p ‐trends <0.001). Mortality and fatal PE respectively showed a temporal trend: 19% and 4% in 2004–2008 to 15% ( p ‐trends 0.026) and 2% ( p ‐trends 0.002) in 2019–2023. In multivariable analyses, fatal PE declined from 2004 to 2023 (HR: 0.91; 95% CI: 0.87–0.96). Compared with VKAs, receiving LMWH during the first 3 months of anticoagulation was associated with a higher risk of major bleeding (HR: 1.91; 95% CI: 1.16–3.14) and death (HR: 2.20; 95% CI: 1.71–2.82). The effect seems to be the opposite for DOACs (HR: 0.50; 95% CI: 0.20–1.30 for major bleeding; HR: 0.86; 95% CI: 0.57–1.28 for all‐cause death). Conclusions Fatal PE declined from 2004 to 2023, despite an increase in the diagnosis of PE. Since the arrival of DOACs, there seems to be better management of the therapeutic and diagnostic aspects of VTE in this population, underlining the need for further research on patients aged 90 or older.

Cancer patients with haematological malignancies are at risk for chronic hepatitis E virus infection following chimeric antigen receptor (CAR) T‐cell therapy. Strong clinical suspicion is essential for the early diagnosis and prompt treatment of this difficult‐to‐treat type of viral hepatitis. Commentary on: Schwarz et al. Chronic hepatitis E in a patient after CAR‐T cell treatment for diffuse large B‐cell lymphoma and rapid progression towards decompensated liver cirrhosis. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19892.

The diaphragm is the chief muscle of inspiration and the most powerful of the respiratory muscles. The diaphragm also serves as a mechanical barrier separating the thorax from the abdomen and maintains the pressure gradient between both compartments (Nason et al. 2012). Under normal conditions, this thin dome-shaped muscular structure acts like a piston within a syringe, generating airflow within airways as its dome descends and enabling tidal breathing. The pressure generated across the dome between the thoracic and abdominal cavities is called the transdiaphragmatic pressure and is proportional to the tension developed within the muscle fibers. Therefore, in terms of physiological meaning, the diaphragm function can be estimated by its capacity to generate this transdiaphragmatic pressure. Diaphragm dysfunction can be associated with the presence of respiratory symptoms, in particular dyspnea, exercise intolerance, and sleep disturbances, and, in the more severe cases, may have a negative impact on survival. Uni- and bilateral diaphragm dysfunction diagnosis and management may be problematic for the clinician because of its relative rarity, its sometimes-subtle clinical manifestations, and difficulties in obtaining a physiologically confirmed diagnosis. As such, diaphragm dysfunction is probably underdiagnosed, but should not be neglected, as it may negatively impact the quality of life, can be a marker of disease severity, and, in some instances such as in the intensive care unit, can be a prognostic marker.