Humoral complementomics - exploration of noninvasive complement biomarkers as predictors of renal cancer progression.

Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a Humoral Complementomics approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC). In two prospective ccRCC cohorts, plasma C2, C5, Factor D and properdin were elevated compared to healthy controls, reflecting an inflammatory phenotype that correlated with plasma calprotectin levels but did not associate with CRP or with patient prognosis. Conversely, autoantibodies against the complement C3 and the reduced form of FH (a tumor neo-epitope reported in lung cancer) correlated with a favorable outcome. Our findings pointed to a specific group of patients with elevated plasma C4d and C1s-C1INH complexes, indicating the initiation of the classical pathway, along with elevated Ba and Bb, indicating alternative pathway activation. Boostrapped Lasso regularized Cox regression revealed that the most predictive complement biomarkers were elevated plasma C4d and Bb levels at the time of surgery, which correlated with poor prognosis. In conclusion, we propose Humoral Complementomics as an unbiased approach to study the global state of the complement system in any pathological plasma sample and disease context. Its implementation for ccRCC revealed that elevated C4d and Bb in plasma are promising prognostic biomarkers, correlating with shorter progression-free survival.

[Pernicious anemia with false normal vitamin B12 levels caused by intrinsic factor antibodies interference: a case report]. / Maladie de Biermer avec dosage de vitamine B12 faussement normal par interférence avec les anticorps anti-facteur intrinsèque : à propos d'un cas.

We present a case of a 48-year-old woman with a fortuitous discovery of macrocytic anemia and thrombocytopenia. Serum folate and vitamin B12 levels were normal. However, due to the presence of indirect signs of cobalamin deficiency, such as elevated homocysteine and methylmalonic acid, and signs of dyserythropoiesis on the bone marrow aspirate, pernicious anemia was suspected. Vitamin B12 dosage was repeated finding fluctuating but always normal results. Anti-intrinsic factor antibodies were present at a very high level, explaining the fluctuations and the interference found on the assay using competitive binding chemiluminescence (CBLA). Serum vitamin B12 dosage by electrochemiluminescence, a method described as not interfering with intrinsic factor antibodies, showed a collapsed vitamin B12 level. Measurement of vitamin B12 with CBLA after adsorption of immunoglobulins in the sample using protein G SepharoseTM, confirmed the interference of the cobalamin assay with autoantibodies. This case illustrates the difficulties regarding the analysis and standardization of the vitamin B12 assay for the diagnosis of pernicious anemia.

Ultrasensitive Troponin I and Incident Cardiovascular Disease.

BACKGROUND: To examine the association of ultrasensitive cTnI (cardiac troponin I) with incident cardiovascular disease events (CVDs) in the primary prevention setting. METHODS: cTnI was analyzed in the baseline plasma (2008-2012) of CVD-free volunteers from the Paris Prospective Study III using a novel ultrasensitive immunoassay (Simoa Troponin-I 2.0 Kit, Quanterix, Lexington) with a limit of detection of 0.013 pg/mL. Incident CVD hospitalizations (coronary heart disease, stroke, cardiac arrhythmias, deep venous thrombosis or pulmonary embolism, heart failure, or arterial aneurysm) were validated by critical review of the hospital records. Hazard ratios were estimated per log-transformed SD increase of cTnI in Cox models using age as the time scale. RESULTS: The study population includes 9503 participants (40% women) aged 59.6 (6.3) years. cTnI was detected in 99.6% of the participants (median value=0.63 pg/mL, interquartile range, 0.39-1.09). After a median follow-up of 8.34 years (interquartile range, 8.0-10.07), 516 participants suffered 612 events. In fully adjusted analysis, higher cTnI (per 1 SD increase of log cTnI) was significantly associated with CVD events combined (hazard ratio, 1.18 [1.08-1.30]). Among all single risk factors, cTnI had the highest discrimination capacity for incident CVD events (C index=0.6349). Adding log cTnI to the SCORE 2 (Systematic Coronary Risk Evaluation) risk improved moderately discriminatory capacity (C index 0.698 versus 0.685; bootstrapped C index difference: 0.0135 [95% CI, 0.0131-0.0138]), and reclassification of the participants (categorical net reclassification index, 0.0628 [95% CI, 0.023-0.102]). Findings were consistent using the US pooled cohort risk equation. CONCLUSIONS: Ultrasensitive cTnI is an independent marker of CVD events in the primary prevention setting.

Imbalance between alpha-1-antitrypsin and interleukin 6 is associated with in-hospital mortality and thrombosis during COVID-19.

Thrombosis is a hallmark of severe COVID-19. Alpha-1-antitrypsin (AAT), an inflammation-inducible serpin with anti-inflammatory, tissue protective and anticoagulant properties may be involved in severe COVID-19 pathophysiology including thrombosis onset. In this study, we examined AAT ability to predict occurrence of thrombosis and in-hospital mortality during COVID-19. To do so, we performed a monocentric cross-sectional study of 137 hospitalized patients with COVID-19 of whom 56 (41%) were critically ill and 33 (22.4%) suffered from thrombosis during hospitalization. We measured AAT and IL-6 plasma levels in all patients and phenotyped AAT in a subset of patients with or without thrombosis paired for age, sex and COVID-19 severity. We observed that AAT levels at admission were higher in both non-survivors and thrombosis patients than in survivors and non-thrombosis patients. AAT: IL-6 ratio was lower in non-survivors and thrombosis patients. In a logistic regression multivariable analysis model adjusted on age, BMI and D-dimer levels, a higher AAT: IL-6 was a protective factor of both in-hospital mortality (Odds ratio, OR: 0.07 95%CI [0.02-0.25], p < 0.001) and thrombosis (OR 0.36 95%CI [0.14-0.82], p = 0.02). AAT phenotyping did not show a higher proportion of AAT abnormal variants in thrombosis patients.Our findings suggest an insufficient production of AAT regarding inflammation intensity during severe COVID-19. AAT appeared as a powerful predictive marker of severity, mortality and thrombosis mirroring the imbalance between harmful inflammation and protective counter-balancing mechanism in COVID-19. Restoring the balance between AAT and inflammation could offer therapeutic opportunities in severe COVID-19.

Bioprosthetic Total Artificial Heart in Autoregulated Mode Is Biologically Hemocompatible: Insights for Multimers of von Willebrand Factor.

BACKGROUND: Carmat bioprosthetic total artificial heart (Aeson; A-TAH) is a pulsatile and autoregulated device. The aim of this study is to evaluate level of hemolysis potential acquired von Willebrand syndrome after A-TAH implantation. METHODS: We examined the presence of hemolysis and acquired von Willebrand syndrome in adult patients receiving A-TAH support (n=10) during their whole clinical follow-up in comparison with control subjects and adult patients receiving Heartmate II or Heartmate III support. We also performed a fluid structure interaction model coupled with computational fluid dynamics simulation to evaluate the A-TAH resulting shear stress and its distribution in the blood volume. RESULTS: The cumulative duration of A-TAH support was 2087 days. A-TAH implantation did not affect plasma free hemoglobin over time, and there was no association between plasma free hemoglobin and cardiac output or beat rate. For VWF (von Willebrand factor) evaluation, A-TAH implantation did not modify multimers profile of VWF in contrast to Heartmate II and Heartmate III. Furthermore, fluid structure interaction coupled with computational fluid dynamics showed a gradually increase of blood damage according to increase of cardiac output (P<0.01), however, the blood volume fraction that endured significant shear stresses was always inferior to 0.03% of the volume for both ventricles in all regimens tested. An inverse association between cardiac output, beat rate, and high-molecular weight multimers ratio was found. CONCLUSIONS: We demonstrated that A-TAH does not cause hemolysis or AWVS. However, relationship between HMWM and cardiac output depending flow confirms relevance of VWF as a biological sensor of blood flow, even in normal range.

Clinical diagnosis, outcomes and treatment of thiamine deficiency in a tertiary hospital.

BACKGROUND: Acute thiamine deficiency can occur in patients with or without history of alcohol abuse and can lead to life-threatening complications. Clinical diagnosis is challenging, often resulting in delayed recognition and treatment. Patients may present with heterogenous symptoms, more diverse than the historical neurological description. Cerebral MRI can contribute to the diagnosis in patients with neurological signs but it is not always feasible in emergency settings. Prompt parenteral supplementation is required to obtain the improvement of symptoms and avoid chronic complications. AIMS: To describe the clinical presentation of reported cases of thiamine deficiency, assess prescription and results of cerebral imaging, review treatments that had been prescribed in accordance or not with available guidelines, and study the short-term outcome of these patients. METHODS: This is a monocentric retrospective analysis of all reported cases of thiamine deficiency in a French tertiary hospital between January 1st 2008 and December 31st 2018. RESULTS: Fifty-six cases were identified during the study period. Forty-five (80%) patients had a history of alcohol abuse. Most patients were diagnosed based on neurological symptoms but non-specific and digestive symptoms were frequent. Thirty-four percent of patients fulfilled clinical criteria for malnutrition. A brain MRI was performed in 54% of patients and was abnormal in 63% of these cases. Eighty-five percent of patients were treated by parenteral thiamine administration and the supplementation was continued orally in 55% of them. The majority of patients initially received 1000 mg daily of IV thiamine but the dose and duration of thiamine supplementation were variable. At the time of discharge, partial or complete improvement of symptoms was noted in 59% of patients. CONCLUSION: This study highlights the clinical and radiological heterogeneity of thiamine deficiency. These observations should encourage starting thiamine supplementation early in patients with risk factors or suggestive symptoms even in non-alcoholic patients, and underline the importance of early nutritional support.

No SARS-CoV-2 reinfection among staff health-care workers: Prospective hospital-wide screening during the first and second waves in Paris.

OBJECTIVES: Risk of reinfection with SARS-CoV-2 among health-care workers (HCWs) is unknown. We assessed the incidence rate of SARS-CoV-2 reinfection in the real-life setting of a longitudinal observational cohort of HCWs from the Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, France, during the first and second waves of COVID-19 epidemic. METHODS: From March to December 2020, HCWs were subjected to molecular and serology testing of SARS-CoV-2. Reinfection was defined as a positive test result during the first wave, either by serology or PCR, followed by a positive PCR during the second wave. Evolution of COVID-19 status of HWCs was assessed by a Sankey diagram. RESULTS: A total of 7765 tests (4579 PCR and 3186 serology) were carried out and 4168 HCWs had at least one test result during the follow-up period with a positivity rate of 15.9%. No case of reinfection during the second wave could be observed among 102 positive HCWs of the first wave, nor among 175 HCWs found positive by PCR during the second wave who were negative during the first wave. CONCLUSIONS: SARS-CoV-2 reinfection was not observed among HCWs, suggesting a protective immunity against reinfection that lasts at least 8 months post infection.

Eicosapentaenoic acid membrane incorporation stimulates ABCA1-mediated cholesterol efflux from human THP-1 macrophages.

A high intake in polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) (C20:5 n-3), is cardioprotective. Dietary PUFAs incorporate into membrane phospholipids, which may modify the function of membrane proteins. We investigated the consequences of the membrane incorporation of several PUFAs on the key antiatherogenic ABCA1-mediated cholesterol efflux pathway. Human THP-1 macrophages were incubated with EPA, arachidonic acid (AA) (C20:4 n-6) or docosahexaenoic acid (DHA) (C22:6 n-3) for a long time to mimic a chronic exposure. EPA 70 µM, but not AA 50 µM or DHA 15 µM, increased ABCA1-mediated cholesterol efflux to apolipoprotein (apo) AI by 28% without altering aqueous diffusion. No variation in ABCA1 expression or localization was observed after EPA treatment. EPA incorporation did not affect the phenotype of THP-1 macrophages. The membrane phospholipids composition of EPA cells displayed higher levels of both EPA and its elongation product docosapentaenoic acid, which was associated with drastic lower levels of AA. Treatment by EPA increased the ATPase activity of the transporter, likely through a PKA-dependent mechanism. Eicosanoids were not involved in the stimulated ABCA1-mediated cholesterol efflux from EPA-enriched macrophages. In addition, EPA supplementation increased the apo AI binding capacity from macrophages by 38%. Moreover, the increased apo AI binding in EPA-enriched macrophages can be competed. In conclusion, EPA membrane incorporation increased ABCA1 functionality in cholesterol-normal human THP-1 macrophages, likely through a combination of different mechanisms. This beneficial in vitro effect may partly contribute to the cardioprotective effect of a diet enriched with EPA highlighted by several recent clinical trials.

Poor Masticatory Capacity and Blood Biomarkers of Elevated Cardiovascular Disease Risk in the Community: The Paris Prospective Study III.

[Figure: see text].

Sera Neutralizing Activities Against Severe Acute Respiratory Syndrome Coronavirus 2 and Multiple Variants 6 Months After Hospitalization for Coronavirus Disease 2019.

BACKGROUND: Humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs within the first weeks after coronavirus disease 2019 (COVID-19). Those antibodies exert a neutralizing activity against SARS-CoV-2, whose evolution over time after COVID-19 as well as efficiency against novel variants are poorly characterized. METHODS: In this prospective study, sera of 107 patients hospitalized with COVID-19 were collected at 3 and 6 months postinfection. We performed quantitative neutralization experiments on top of high-throughput serological assays evaluating anti-spike (S) and anti-nucleocapsid (NP) immunoglobulin G (IgG). RESULTS: Levels of seroneutralization and IgG rates against the ancestral strain decreased significantly over time. After 6 months, 2.8% of the patients had a negative serological status for both anti-S and anti-NP IgG. However, all sera had a persistent and effective neutralizing effect against SARS-CoV-2. IgG levels correlated with seroneutralization, and this correlation was stronger for anti-S than for anti-NP antibodies. The level of seroneutralization quantified at 6 months correlated with markers of initial severity, notably admission to intensive care units and the need for mechanical invasive ventilation. In addition, sera collected at 6 months were tested against multiple SARS-CoV-2 variants and showed efficient neutralizing effects against the D614G, B.1.1.7, and P.1 variants but significantly weaker activity against the B.1.351 variant. CONCLUSIONS: Decrease in IgG rates and serological assays becoming negative did not imply loss of neutralizing capacity. Our results indicate a sustained humoral response against the ancestral strain and the D614G, B.1.1.7, and P.1 variants for at least 6 months in patients previously hospitalized for COVID-19. A weaker protection was, however, observed for the B.1.351 variant.

Clarifying the relationship between pulmonary langerhans cell histiocytosis and Alpha 1 antitrypsin deficiency.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare, smoking related, progressive diffuse cystic lung disease that occurs primarily in smokers. The aim of this study was to determine if there was an increase in alpha-1 antitrypsin deficient alleles or phenotypes in a large series of PLCH patients and whether serum alpha-1 antitrypsin levels correlated with markers of disease severity. Fifty PLCH patients, 24 with a diffuse cystic lung pattern and 26 with a typical nodulo-cystic pattern on imaging were included. The mean alpha-1 antitrypsin levels were in normal range for both the population with diffuse cystic lung pattern population (1.39 g/L ± 0.37) and the nodulo-cystic pattern group (1.41 g/L ± 0.21). Deficiency alleles PiZ and PiS were 1% and 2% respectively in the entire study population of 50 patients, demonstrating no increased incidence of alpha-1 antitrypsin deficiency in PLCH. Alpha-1 antitrypsin levels showed no correlation with lung function parameters or extent of cystic lesions on lung computed tomography.

A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies.

Leber's hereditary optic neuropathy (LHON) is the most common disorder due to mitochondrial DNA mutations and complex I deficiency. It is characterized by an acute vision loss, generally in young adults, with a higher penetrance in males. How complex I dysfunction induces the peculiar LHON clinical presentation remains an unanswered question. To gain an insight into this question, we carried out a non-targeted metabolomic investigation using the plasma of 18 LHON patients, during the chronic phase of the disease, comparing them to 18 healthy controls. A total of 500 metabolites were screened of which 156 were accurately detected. A supervised Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) highlighted a robust model for disease prediction with a Q2 (cum) of 55.5%, with a reliable performance during the permutation test (cross-validation analysis of variance, P-value = 5.02284e-05) and a good prediction of a test set (P = 0.05). This model highlighted 10 metabolites with variable importance in the projection (VIP) > 0.8. Univariate analyses revealed nine discriminating metabolites, six of which were the same as those found in the Orthogonal Projections to Latent Structures Discriminant Analysis model. In total, the 13 discriminating metabolites identified underlining dietary metabolites (nicotinamide, taurine, choline, 1-methylhistidine and hippurate), mitochondrial energetic substrates (acetoacetate, glutamate and fumarate) and purine metabolism (inosine). The decreased concentration of taurine and nicotinamide (vitamin B3) suggest interesting therapeutic targets, given their neuroprotective roles that have already been demonstrated for retinal ganglion cells. Our results show a reliable predictive metabolomic signature in the plasma of LHON patients and highlighted taurine and nicotinamide deficiencies.

Predictive Factor for COVID-19 Worsening: Insights for High-Sensitivity Troponin and D-Dimer and Correlation With Right Ventricular Afterload.

Background: Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. Objectives: To explore clinical and biological parameters of COVID-19 patients with hospitalization criteria that could predict referral to intensive care unit (ICU). Methods: Analyzing the clinical and biological profiles of COVID-19 patients at admission. Results: Among 99 consecutive patients that fulfilled criteria for hospitalization, 48 were hospitalized in the medicine department, 21 were first admitted to the medicine ward department and referred later to ICU, and 30 were directly admitted to ICU from the emergency department. At admission, patients requiring ICU were more likely to have lymphopenia, decreased SpO2, a D-dimer level above 1,000 ng/mL, and a higher high-sensitivity cardiac troponin (Hs-cTnI) level. A receiver operating characteristic curve analysis identified Hs-cTnI above 9.75 pg/mL as the best predictive criteria for ICU referral [area under the curve (AUC), 86.4; 95% CI, 76.6-96.2]. This cutoff for Hs-cTnI was confirmed in univariate [odds ratio (OR), 22.8; 95% CI, 6.0-116.2] and multivariate analysis after adjustment for D-dimer level (adjusted OR, 20.85; 95% CI, 4.76-128.4). Transthoracic echocardiography parameters subsequently measured in 72 patients showed an increased right ventricular (RV) afterload correlated with Hs-cTnI (r = 0.42, p = 0.010) and D-dimer (r = 0.18, p = 0.047). Conclusion: Hs-cTnI appears to be the best relevant predictive factor for referring COVID-19 patients to ICU. This result associated with the correlation of D-dimer with RV dilatation probably reflects a myocardial injury due to an increased RV wall tension. This reinforces the hypothesis of a COVID-19-associated microvascular thrombosis inducing a higher RV afterload.

Unexpected diagnosis of COVID-19-associated disorders by SARS-CoV-2-specific serology.

Facing the ongoing pandemic caused by SARS-CoV-2, there is an urgent need for serological assays identifying individuals with on-going infection as well as past coronavirus infectious disease 2019 (COVID-19). We herein evaluated the analytical performances of the CE IVD-labeled Abbott SARS-CoV-2 IgG assay (Des Plaines, IL, USA) carried out with the automated Abbott Architect™ i2000 platform at Hôpital Européen Georges Pompidou, Paris, France, using serum sample panels obtained from health-workers with COVID-19 history confirmed by positive nucleic acid amplification-based diagnosis and from patients randomly selected for whom serum samples were collected before the COVID-19 epidemic. The Abbott SARS-CoV-2 IgG assay showed sensitivity of 94 % and specificity of 100 %, demonstrating high analytical performances allowing convenient management of suspected on-going and past-infections. In addition, the SARS-CoV-2 IgG positivity rates were compared in COVID-19 positive and COVID-19 free areas from our hospital. Thus, the frequency of SARS-CoV-2-specific IgG was around 10-fold higher in COVID-19 areas than COVID-19 free areas (75 % versus 8%; P < 0.001). Interestingly, several inpatients hospitalized in COVID-19 free areas suffering from a wide range of unexplained clinical features including cardiac, vascular, renal, metabolic and infectious disorders, were unexpectedly found seropositive for SARS-CoV-2 IgG by systematic routine serology, suggesting possible causal involvement of SARS-CoV-2 infection. Taken together, these observations highlight the potential interest of SARS-CoV-2-specific serology in the context of COVID-19 epidemic, especially to assess past SARS-CoV-2 infection as well as possible unexpected COVID-19-associated disorders.

Contrasting effects of membrane enrichment with polyunsaturated fatty acids on phospholipid composition and cholesterol efflux from cholesterol-loaded J774 mouse or primary human macrophages.

A high consumption of polyunsaturated fatty acids (PUFAs), particularly n-3 PUFAs, is atheroprotective. PUFAs incorporation into membrane phospholipids alters the functionality of membrane proteins. We studied the consequences of the in vitro supplementation of several PUFAs on the FA profiles and on ABCA1-dependent cholesterol efflux capacities from cholesterol-loaded macrophages. Arachidonic acid (AA, C20:4 n-6) and, to a lesser extent, eicosapentaenoic acid (EPA, C20:5 n-3), dose-dependently impaired cholesterol efflux from cholesterol-loaded J774 mouse macrophages without alterations in ABCA1 expression, whereas docosahexaenoic acid (DHA, C22:6 n-3) had no impact. AA cells exhibited higher proportions of arachidonic acid and adrenic acid (C22:4 n-6), its elongation product. EPA cells exhibited slightly higher proportions of EPA associated with much higher proportions of docosapentaenoic acid (C22:5 n-3), its elongation product and with lower proportions of AA. Conversely, both EPA and DHA and, to a lesser extent, AA decreased cholesterol efflux from cholesterol-loaded primary human macrophages (HMDM). The differences observed in FA profiles after PUFA supplementations were different from those observed for the J774 cells. In conclusion, we are the first to report that AA and EPA, but not DHA, have deleterious effects on the cardioprotective ABCA1 cholesterol efflux pathway from J774 foam cells. Moreover, the membrane incorporation of PUFAs does not have the same impact on cholesterol efflux from murine (J774) or human (HMDM) cholesterol-loaded macrophages. This finding emphasizes the key role of the cellular model in cholesterol efflux studies and may partly explain the heterogeneous literature data on the impact of PUFAs on cholesterol efflux.

What can millions of laboratory test results tell us about the temporal aspect of data quality? Study of data spanning 17 years in a clinical data warehouse.

OBJECTIVE: To identify common temporal evolution profiles in biological data and propose a semi-automated method to these patterns in a clinical data warehouse (CDW). MATERIALS AND METHODS: We leveraged the CDW of the European Hospital Georges Pompidou and tracked the evolution of 192 biological parameters over a period of 17 years (for 445,000 + patients, and 131 million laboratory test results). RESULTS: We identified three common profiles of evolution: discretization, breakpoints, and trends. We developed computational and statistical methods to identify these profiles in the CDW. Overall, of the 192 observed biological parameters (87,814,136 values), 135 presented at least one evolution. We identified breakpoints in 30 distinct parameters, discretizations in 32, and trends in 79. DISCUSSION AND CONCLUSION: our method allowed the identification of several temporal events in the data. Considering the distribution over time of these events, we identified probable causes for the observed profiles: instruments or software upgrades and changes in computation formulas. We evaluated the potential impact for data reuse. Finally, we formulated recommendations to enable safe use and sharing of biological data collection to limit the impact of data evolution in retrospective and federated studies (e.g. the annotation of laboratory parameters presenting breakpoints or trends).

Extreme hypomagnesemia: characteristics of 119 consecutive inpatients.

Extreme hypomagnesemia (hypoMg) can be encountered in many situations, but little data currently exist. Our aim is to describe the epidemiological, clinical, etiological characteristics, and the biological abnormalities of consecutive inpatients with extreme hypomagnesemia. In our observational monocentric study, between 1st July 2000 and April 2015, all inpatients with extreme hypomagnesemia, defined by at least one plasma magnesium concentration (PMg) below 0.3 mmol/L, were included. Demographic, clinical, biological characteristics and the drugs prescribed before the qualifying PMg measurement were retrospectively collected. 41,069 patients had at least one PMg assessment. The prevalence of extreme hypomagnesemia is 0.3% (119 inpatients). The median age is 70 years, 52% are women. The patients were mainly hospitalized in intensive care (n = 37, 31.1%), oncology (n = 21, 17.6%), gastroenterology (n = 18, 15.1%) and internal medicine (n = 16, 13.4%) departments. One hundred patients (84%) had a medical history of gastrointestinal disease (39% with bowel resections, 24% with stoma), and 50 (42%) had a cancer history. The drugs most commonly prescribed (known to induce hypoMg) are proton pump inhibitors (PPI) (n = 77, 70%), immunosuppressive regimens (n = 25, 22.5%), platinum salt-based chemotherapies (n = 19, 17.1%), and diuretics (n = 22, 19.8%). The suspected causes of hypomagnesemia are often multiple, but drugs (46%, including PPI in 19%) and chronic gastrointestinal disorders (37%) are prominent. Associated electrolyte disturbances include hypocalcemia (77%) and mild hypokalemia (51%). The 1-month mortality from all causes is 16%. Extreme hypomagnesemia is rare in inpatients, and is frequently associated with severe hypocalcemia. Digestive disorders and drugs are the main contributory causes.