Argumentation-based explanations of multimorbidity treatment plans

We present an argumentation model to explain the optimal treatment plans recommended by a Satisfiability Modulo Theories solver for multimorbid patients. The resulting framework can be queried to obtain supporting reasons for nodes on a path following a model of argumentation schemes. The modelling approach is generic and can be used for justifying similar sequences.Postprin

Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease

Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4- year- old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh- like lesions on brain imaging. She died shortly after. Her 8- year- old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G- >- A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162807/2/jimd12232.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162807/1/jimd12232_am.pd

Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics

Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AIMS Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. METHODS With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants. CONCLUSION This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics

Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data

There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Controversies in the management of hyperammonemia

International audienc

Maladies neurométaboliques traitables associées aux troubles du spectre de la schizophrénie

National audienceLes troubles du spectre de la schizophrénie représentent 1 % de la population générale. La prévalence des pathologies organiques dans cette sous-population est mal connue mais probablement sous-estimée. Nous nous intéressons à 7 maladies neurométaboliques traitables pouvant être associées à des troubles schizophréniques associés à des troubles neurologiques sub-cliniques, voire absents. L’existence de patients se présentant avec uniquement des signes psychiatriques représente un défi pour les psychiatres et tous les praticiens qui sont amenés à voir ces patients. Nous proposons une revue synthétique de la littérature et des tableaux pratiques pour connaître les éléments cliniques d’appel essentiels pour les troubles du métabolisme de l’homocystéine, les troubles du cycle de l’urée, la maladie de Wilson, le Niemann-Pick de type C, les porphyries aiguës et la xanthomatose cérébro-tendineuse qui bénéficient tous d’un traitement d’autant plus efficace que le diagnostic est précoce. L’analyse de la littérature nous amène à proposer une liste de signes psychiatriques atypiques comme l’existence d’hallucinations visuelles prépondérantes par rapport aux hallucinations auditives, des signes de confusion, de catatonie ou de déficit cognitif progressif… nous insistons également sur l’importance de considérer la résistance au traitement antipsychotique comme un signe majeur devant servir de suspicion d’organicité

The need for a non-invasive technology for endometriosis detection and care

Funding: Partially supported by Austrian FWF Fellowship M 3338-N (AH).Endometriosis is a complex, poorly understood, female health condition that can markedly reduce a woman’s quality of life. The gold-standard diagnostic method for endometriosis is invasive laparoscopic surgery, which is costly, not timely, and comes with risks to the patient. We argue that the need for a non-invasive diagnosis procedure, higher quality of patient care and reduced diagnosis delay, can be fulfilled by advances and research to devise innovative computational solutions. To leverage computational and algorithmic techniques, enhanced data recording and sharing are vital. We discuss the potential benefits of using personalised computational healthcare on both the clinician and patient side, reducing the lengthy average diagnosis time (currently around 8 years).Publisher PD

Virus or bacteria: Is It the only cause of sepsis-induced rhabdomyolysis?

International audienc