VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation.

Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1ß and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.

Intravenous administration of a branched-chain amino-acid-free solution in children and adults with acute decompensation of maple syrup urine disease: a prospective multicentre observational study.

BACKGROUND: Patients with maple syrup urine disease (MSUD) experiencing metabolic decompensations have traditionally been treated with branched-chain amino acid (BCAA)-free mixture via oral or nasogastric administration routes. In some patients, enteral administration is not possible, either because the patient presents with vomiting, coma, or refuses nasogastric administration, thus intravenous (IV) BCAA-free solution is an appropriate intervention for these challenging cases. AIMS: This study aimed to evaluate the effectiveness and safety of managing metabolic decompensations by administering an IV BCAA-free solution. METHODS: This is an observational prospective study of data from MSUD patients hospitalised for decompensation episodes between 2010 and 2016 at 6 centres for rare metabolic diseases in France. RESULTS: A total of 24 patients (16 males; 8 females) experiencing 126 MSUD metabolic decompensation episodes (39 in children; 87 in adults) were admitted to hospital. At presentation, mean leucine plasma concentration was ≥ 381 µmol/L in 113/126 (89.7%) episodes. Children were treated with continuous IV BCAA-free solution at doses of 0.8 to 2.0 g/kg/day, for 4.8 days and adults for 3.8 days at doses of 0.5 to 2.6 g/kg/day. In the efficacy set of 102 analysable episodes leucine concentrations were normalised (to below 381 µmol/L) in 82% (n = 18/22) of episodes in children and in 84% (n = 67/80) of episodes in adults. Mean time to leucine normalisation was 3.0 days. This was significantly (p < 0.001) shorter than the algorithmically predicted time to leucine normalisation with traditional BCAA-free mixture. Duration of hospitalisation was significantly longer for children than for adults (7.1 days in children vs 5.2 days in adults, p = 0.012). No treatment-related adverse events were reported in any patients on IV BCAA-free solution. CONCLUSION: The IV BCAA-free solution is safe and effective in normalising leucine concentrations during MSUD decompensation episodes in both children and adults, offering a practical treatment alternative for those patients who cannot receive BCAA-free mixture via oral or nasogastric routes.

Musculoskeletal Tuberculosis: New Insights on Diagnosis Strategy and Treatment.

BACKGROUND/ OBJECTIVE: Skeletal tuberculosis (TB) is rare. We aimed to report on diagnostic strategy and treatment of skeletal TB. METHODS: In this multidisciplinary single-center medical records review study, all adult patients admitted between January 2009 and December 2019 with microbiologically proven skeletal TB were included. Demographic, medical history, laboratory, imaging, pathologic findings, treatment, and follow-up data were extracted from medical records. RESULTS: Among 184 patients identified with TB, 21 (16 women, 42 years [27, 48 years]) had skeletal involvement. Skeletal TB included spondylitis (n = 11), lytic bone lesions (n = 7), sacroiliitis (n = 5), arthritis (n = 3), osteitis (n = 2), and diffuse muscle abscesses without bone lesion (n = 1). Lytic lesions involved both axial and peripheral skeleton at multiple sites in most cases. 18F-fluorodeoxyglucose positron emission tomography was performed in 13 patients and helped to detect multifocal asymptomatic lesions and to target biopsy. All patients were treated with anti-TB therapy for 7 to 18 months. Fifteen patients (71.4%) received steroids as an adjunct therapy. Eleven patients needed an orthopedic immobilization corset, and 3 patients underwent surgery. All patients clinically improved under treatment, but 2 relapsed over a median follow-up of 24 months (12-30 months). No patient died or suffered long-term disabilities. CONCLUSION: Our study emphasizes the diversity of skeletal involvement in TB. 18F-fluorodeoxyglucose positron emission tomography scanner at diagnosis is key to assess the extension of skeletal involvement and guide extraskeletal biopsy. Neurological complications might be prevented by adding corticosteroids to anti-TB therapy.

A 29-Year-Old Man With an Osteolytic Rib Lesion.

CASE PRESENTATION: A 29-year-old man with no significant medical history presented to the ED with a 4-week history of chest pain. The pain was insidious, located on the right side of the chest, increased by deep breathing, and incompletely alleviated by acetaminophen. The patient had never smoked tobacco. He denied any recent fevers, chills, dyspnea, cough, night sweats, hemoptysis, or history of trauma but had lost at least 8 kg in the past 6 months. The patient was from Morocco and had lived in France for 1 year.

Analysis of fomepizole safety based on a 16-year post-marketing experience in France.

Introduction: Fomepizole has been recommended as first-line antidote to treat ethylene glycol and methanol poisoning. Despite more than 30 years of utilization, the safety of fomepizole when used clinically has not been well documented. Based on the long-standing clinical experience with fomepizole in France, we investigated its safety profile in patients treated for suspected toxic alcohol poisoning.Methods: We designed a 16-year post-marketing study to evaluate the indications for fomepizole prescriptions and to investigate its safety. Data were retrospectively collected using a standardized questionnaire sent each month by post to each French hospital that ordered fomepizole during the month before. The response rate to our survey was 59%.Results: Five hundred and thirty-six patients [188 females/348 males; age, 46 years [34-55] (median [25th-75th percentiles])] were treated with fomepizole [cumulative dose, 18.6 mg/kg [15.5-26.3] (1,268 mg [900-2,100])]. Ethylene glycol/methanol poisoning was confirmed in 275 patients (51%) while a nontoxic exposure was diagnosed in 147 patients (27%). Toxic alcohol poisoning was misdiagnosed in the remaining 114 patients (21%), before the assessment of an alternative poisoning or non-poisoning diagnosis. Fifty adverse reactions were attributed to fomepizole in 36 patients (7%) including general reactions (N = 22), local reactions (N = 22) and laboratory test impairments (N = 6). All were considered mild and transient. None required stopping fomepizole. The most frequent adverse effects were injection site pain/burning (N = 13), nausea/vomiting (N = 8), vessel puncture site inflammation (N = 7), drowsiness/confusion (N = 5) and serum aminotransferase elevation (N = 3). None of the fatalities (N = 37, 7%) or persistent symptoms on discharge (N = 9; 2%) was related to fomepizole.Conclusion: Our longitudinal cohort study supports the safety of fomepizole administered to treat presumed EG and methanol poisoning.

Fomepizole to treat disulfiram-ethanol reaction: a case series.

Introduction: Disulfiram-ethanol reaction (DER) due to acetaldehyde accumulation occurs after drinking ethanol during disulfiram therapy. DER may result in life-threatening toxicity requiring urgent critical care. Fomepizole, an alcohol dehydrogenase inhibitor used to treat toxic alcohol poisoning, has been suggested for treating DER by preventing the metabolism of ethanol to acetaldehyde. However, its effectiveness and safety have been poorly assessed in this setting.Cases: Ten DER patients (median age, 40 years; 7 males/3 females) were included in the study. DER features consisted of consciousness impairment (median Glasgow coma score, 13; need for mechanical ventilation, 30%) with flushing (50%), vomiting (40%), electrocardiogram abnormalities (30%) and circulatory failure requiring norepinephrine (30%). Patients were successfully treated with a single intravenous infusion of fomepizole (median dose, 7.5 mg/kg). The three patients receiving norepinephrine did not improve until fomepizole was administered. The other seven patients improved promptly following fomepizole infusion without requirement for vasopressor support. All patients fully recovered. Local pain at the injection site was the only reported adverse reaction in one patient.Conclusion: Our case series supports the effectiveness and safety of fomepizole in rapidly reversing DER-induced vasodilatation and toxicity.

Safety of parenteral nutrition in newborns: Results from a nationwide prospective cohort study.

BACKGROUND & AIMS: Limited or delayed availability of parenteral nutrition (PN) solutions, as well as difficulties in ordering are often identified as reasons for non-compliance with international guidelines in newborns. This study aims at assessing the modality of use and safety of premixed standardized PN solutions in a nationwide prospective cohort of newborns treated in clinical practice. METHODS: Two premixed fixed formulations with respective osmolarity of 715 and 790 mOsm/L specifically designed for neonates were made available throughout the country for clinical use from birth onwards. Descriptive data and modality of use were prospectively collected in a case report form, whereas all related and unrelated adverse events were recorded on a separate adverse event form. RESULTS: A total of 14,167 infants were prospectively included and 16,640 parenteral nutrition periods were analyzed. Mean age was 33 weeks of gestation, and mean weight was 2086 g. The majority of infants (81%) started the parenteral nutrition the first day of life or the day after. The route of parenteral nutrition delivery was peripheral in 47% of the parenteral nutrition periods. During the whole study, a total of 72 adverse events occurring in 68 infants were reported. Of these adverse events, 59 (0.37% of the nutrition periods), among which 19 serious adverse events, were reported as related to the parenteral nutrition solutions. The events related to parenteral nutrition solutions were general disorders and administration site conditions (n = 42 including 9 cases of cutaneous necrosis), and nutrition and metabolism disorders (n = 17). There was no case of thrombophlebitis. Six of the 19 serious events related to the parenteral nutrition solutions (32%) were due to the misuse of the infusion bag. CONCLUSIONS: These data support the concept that ready-to-use parenteral nutrition formulations can safely provide parenteral nutrition from birth onwards. They further support that parenteral solutions with an osmolarity up to 800 mOsm/L are well-tolerated when infused on a peripheral vein. Considering the potential risk of errors and misuses, this study also highlights the need for nutrition practice care guidelines for neonates and for regular campaigns providing information and strategies for a safe use of parenteral nutrition solutions.

Efficacy and Safety of Two Methadone Titration Methods for the Treatment of Cancer-Related Pain: The EQUIMETH2 Trial (Methadone for Cancer-Related Pain).

CONTEXT: In the European Association for Palliative Care recommendations for cancer pain management, there was no consensus regarding the indications, titration, or monitoring of methadone. OBJECTIVES: This national, randomized, multicenter trial aimed to compare two methadone titration methods (stop-and-go vs. progressive) in patients with cancer-related pain who were inadequately relieved by or intolerant to Level 3 opioids. METHODS: The primary end point was the rate of success/failure at Day 4, defined as pain relief (reduction of at least two points on the visual scale and a pain score <5 for two consecutive days) and no overdose (Rudkin scale ≥3 and respiratory rate <8/minute). The patients were followed for two months after enrollment. RESULTS: The cancer-related pain characteristics of the 146 patients were as follows: 16% were nociceptive, 85% experienced breakthrough pain, and 84% had mixed types of pain. The reasons for switching to methadone were a lack of efficacy that was either isolated (56%) or associated with intolerance (38%). Adequate pain relief was obtained in 80% of the patients (median of three days in both groups [P = 0.12]) and lasted until D56. The rate of success/failure was approximately 40% at Day 4 in both groups, with overdoses in 13% of the patients throughout the study. The two methods were considered equally easy to perform by nearly 60% of the clinicians. CONCLUSION: Methadone is an effective and sustainable second-line alternative opioid for the treatment of cancer-related pain. The methods of titration are comparable in terms of efficacy, safety, and ease of use.