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Swiss Medical Weekly Jan 2021The authors present the case of a 58-year-old man with the unique combination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and, later on,...
The authors present the case of a 58-year-old man with the unique combination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and, later on, haemophagocytic lymphohistiocytosis admitted to the intensive care unit. During his ICU stay the patient developed a variety of complications including acute respiratory distress syndrome, pulmonary embolism, right heart failure and suspected HLH leading to multiorgan failure and death. Despite the proven diagnosis of haemophagocytic lymphohistiocytosis, the excessively high ferritin levels of the patient did not seem fully explained by this diagnosis. Therefore, the authors want to highlight different causes of hyperferritinaemia in critically ill patients and underline the importance of differential diagnoses when interpreting continuously rising ferritin levels.
Topics: Acute Kidney Injury; Alanine Transaminase; COVID-19; Creatinine; Disease Progression; Fatal Outcome; Heart Failure; Humans; Hyperferritinemia; Liver Failure; Lymphohistiocytosis, Hemophagocytic; Male; Middle Aged; Multiple Organ Failure; Pulmonary Embolism; Respiratory Distress Syndrome; SARS-CoV-2
PubMed: 33516166
DOI: 10.4414/smw.2021.20420 -
The Lancet. Respiratory Medicine Mar 2021To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We...
BACKGROUND
To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae.
METHODS
This multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged ≥18 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression.
FINDINGS
Between Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40·0 (30·0 to 53·0). 1397 (66·9%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87·5%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64·0%) of 2088 patients were given benzodiazepines for a median of 7·0 days (4·0 to 12·0) and 1481 (70·9%) were given propofol for a median of 7·0 days (4·0 to 11·0). Median Richmond Agitation-Sedation Scale score while on invasive mechanical ventilation was -4 (-5 to -3). 1704 (81·6%) of 2088 patients were comatose for a median of 10·0 days (6·0 to 15·0) and 1147 (54·9%) were delirious for a median of 3·0 days (2·0 to 6·0). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p≤0·04), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p<0·0001). During the 21-day study period, patients were alive without delirium or coma for a median of 5·0 days (0·0 to 14·0). At baseline, older age, higher SAPS II scores, male sex, smoking or alcohol abuse, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 were independently associated with fewer days alive and free of delirium and coma (all p<0·01). 601 (28·8%) of 2088 patients died within 28 days of admission, with most of those deaths occurring in the ICU.
INTERPRETATION
Acute brain dysfunction was highly prevalent and prolonged in critically ill patients with COVID-19. Benzodiazepine use and lack of family visitation were identified as modifiable risk factors for delirium, and thus these data present an opportunity to reduce acute brain dysfunction in patients with COVID-19.
FUNDING
None.
TRANSLATIONS
For the French and Spanish translations of the abstract see Supplementary Materials section.
Topics: Aged; COVID-19; Coma; Critical Illness; Delirium; Female; Humans; Hypnotics and Sedatives; Intensive Care Units; Male; Middle Aged; Prevalence; Respiration, Artificial; Retrospective Studies; Risk Factors; SARS-CoV-2
PubMed: 33428871
DOI: 10.1016/S2213-2600(20)30552-X -
Cells Dec 2020Genetic alterations in genes lead to peroxisome biogenesis disorder. In humans, they are associated with Zellweger spectrum disorders (ZSD). No validated treatment has...
Genetic alterations in genes lead to peroxisome biogenesis disorder. In humans, they are associated with Zellweger spectrum disorders (ZSD). No validated treatment has been shown to modify the dismal natural history of ZSD. Liver transplantation (LT) improved clinical and biochemical outcomes in mild ZSD patients. Hepatocyte transplantation (HT), developed to overcome LT limitations, was performed in a mild ZSD 4-year-old child with encouraging short-term results. Here, we evaluated low dose (12.5 million hepatocytes/kg) and high dose (50 million hepatocytes/kg) syngeneic male HT via intrasplenic infusion in the -G844D NMRI mouse model which recapitulates a mild ZSD phenotype. HT was feasible and safe in growth retarded ZSD mice. Clinical (weight and food intake) and biochemical parameters (very long-chain fatty acids, abnormal bile acids, etc.) were in accordance with ZSD phenotype but they were not robustly modified by HT. As expected, one third of the infused cells were detected in the liver 24 h post-HT. No liver nor spleen microchimerism was detected after 7, 14 and 30 days. Future optimizations are required to improve hepatocyte engraftment in -G844D NMRI mouse liver. The mouse model exhibited the robustness required for ZSD liver-targeted therapies evaluation.
Topics: Animals; Biomarkers; Disease Models, Animal; Hepatocytes; Humans; Liver; Male; Mice; Peroxisomes; Phenotype; Zellweger Syndrome
PubMed: 33396635
DOI: 10.3390/cells10010040 -
International Journal of Cardiology.... Feb 2021To investigate the effect of the corona virus disease 2019 (COVID-19) pandemic on the acute treatment of patients with ST-segment elevation (STEMI) and Non-ST-segment...
BACKGROUND
To investigate the effect of the corona virus disease 2019 (COVID-19) pandemic on the acute treatment of patients with ST-segment elevation (STEMI) and Non-ST-segment elevation acute coronary syndrome (NSTE-ACS).
METHODS
We retrospectively identified patients presenting to the emergency department (ED) with suspected ACS. We evaluated the number of percutaneous coronary interventions (PCIs) for STEMI, NSTE-ACS, and elective PCI cases. In STEMI patients, we assessed the time from chest pain onset (cpo) to ED presentation, post-infarction left ventricular ejection fraction (LVEF), and time from ED presentation to PCI. We directly compared cases from two time intervals: January/February 2020 versus March/April 2020 (defined as 2 months before and after the COVID-19 outbreak). In a secondary analysis, we directly compared cases from March/April 2020 with patients from the same time interval in 2019.
RESULTS
From January to April 2020, 765 patients presented with acute chest pain to the ED. A dramatic reduction of ED presentations after compared to before the COVID-19 outbreak (31% relative reduction) was observed. Overall, 398 PCIs were performed, 220/398 PCIs (55.3%) before versus 178/398 PCIs (44.7%) after the outbreak. While numbers for NSTE-ACS and elective interventions declined by 21% and 31%, respectively, the number of STEMI cases remained stable. Time from cpo to ED presentation, post-infarction LVEF, and median door-to-balloon time remained unchanged.
CONCLUSIONS
In contrast to previous reports, our findings do not confirm the dramatic drop in STEMI cases and interventions in northwestern Switzerland as observed in other regions and hospitals around the world.
PubMed: 33335974
DOI: 10.1016/j.ijcha.2020.100686 -
Frontiers in Cell and Developmental... 2020Cholesterol biosynthesis is a multi-step process involving several subcellular compartments, including peroxisomes. Cells adjust their sterol content by both...
Cholesterol biosynthesis is a multi-step process involving several subcellular compartments, including peroxisomes. Cells adjust their sterol content by both transcriptional and post-transcriptional feedback regulation, for which sterol regulatory element-binding proteins (SREBPs) are essential; such homeostasis is dysregulated in peroxisome-deficient knockout mice. Here, we compared the regulation of cholesterol biosynthesis in Chinese hamster ovary (CHO-K1) cells and in three isogenic peroxisome-deficient CHO cell lines harboring gene mutations. Peroxisome deficiency activated expression of cholesterogenic genes, however, cholesterol levels were unchanged. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) protein levels were increased in mutant cells, whereas HMGCR activity was significantly decreased, resulting in reduced cholesterol synthesis. U18666A, an inhibitor of lysosomal cholesterol export, induced cholesterol biosynthetic enzymes; yet, cholesterol synthesis was still reduced. Interestingly, peroxisome deficiency promoted ER-to-Golgi SREBP cleavage-activating protein (SCAP) trafficking even when cells were cholesterol-loaded. Restoration of functional peroxisomes normalized regulation of cholesterol synthesis and SCAP trafficking. These results highlight the importance of functional peroxisomes for maintaining cholesterol homeostasis and efficient cholesterol synthesis.
PubMed: 33240873
DOI: 10.3389/fcell.2020.560266 -
BMC Medical Genetics Nov 2020Peroxisome biogenesis disorders (PBDs) are a group of metabolic diseases caused by dysfunction of peroxisomes. Different forms of PBDs are described; the most severe one...
BACKGROUND
Peroxisome biogenesis disorders (PBDs) are a group of metabolic diseases caused by dysfunction of peroxisomes. Different forms of PBDs are described; the most severe one is the Zellweger syndrome (ZS). We report on an unusual presentation of Zellweger syndrome manifesting in a newborn with severe and fulminant sepsis, causing death during the neonatal period.
CASE PRESENTATION
A term male Caucasian neonate presented at birth with hypotonia and poor feeding associated with dysmorphic craniofacial features and skeletal abnormalities. Blood tests showed progressive leukopenia; ultrasounds revealed cerebral and renal abnormalities. He died on the fourth day of life because of an irreversible Gram-negative sepsis. Post-mortem tests on blood and urine samples showed biochemical alterations suggestive of ZS confirmed by genetic test.
CONCLUSIONS
ZS is an early and severe forms of PBDs. Peroxisomes are known to be involved in lipid metabolism, but recent studies suggest their fundamental role in modulating immune response and inflammation. In case of clinical suspicion of ZS it is important to focus the attention on the prevention and management of infections that can rapidly progress to death.
Topics: ATPases Associated with Diverse Cellular Activities; Fatal Outcome; Gene Expression; Gram-Negative Bacterial Infections; Humans; Immunity, Innate; Infant, Newborn; Male; Mutation; Peroxisomes; Sepsis; Zellweger Syndrome
PubMed: 33213396
DOI: 10.1186/s12881-020-01175-y -
Molecular Genetics and Metabolism... Dec 2020Defects in are associated with a severe neonatal-lethal form of Zellweger spectrum disorder. We report two moderately affected siblings whose clinical and biochemical...
Defects in are associated with a severe neonatal-lethal form of Zellweger spectrum disorder. We report two moderately affected siblings whose clinical and biochemical phenotypes expand the reported spectrum of -related disease. Genome sequencing of an adolescent male with progressive movement disorder, spasticity and neurodegeneration, and previous non-diagnostic plasma very-long chain fatty acid analysis, revealed a homozygous likely pathogenic missense variant in [c.991G > A; p.(Gly331Arg)]. A younger sibling with significant motor decline since the age of three years was also subsequently found to be homozygous for the familial variant. A comprehensive review of the scientific literature identified three additional families with non-lethal infantile- or childhood-onset -related disease, which together with this clinical report illustrate the potential for highly variable disease severity. Our findings demonstrate the diagnostic utility of genome-wide sequencing for identifying clinically and biochemically heterogeneous inherited metabolic disorders such as the peroxisome biogenesis disorders.
PubMed: 33101983
DOI: 10.1016/j.ymgmr.2020.100664 -
Journal of Korean Medical Science Oct 2020Peroxisomal D-bifunctional protein (DBP), encoded by the gene, catalyzes β-oxidation of very long chain fatty acids (VLCFAs). The deficiency of this peroxisomal enzyme...
Peroxisomal D-bifunctional protein (DBP), encoded by the gene, catalyzes β-oxidation of very long chain fatty acids (VLCFAs). The deficiency of this peroxisomal enzyme leads to the accumulation of VLCFAs, causing multisystemic manifestations including the brain, retina, adrenal gland, hearing, and skeletal system. Herein, we report the first Korean neonatal case of peroxisomal DBP deficiency and the clinical prognosis over 2 years. This patient showed craniofacial dysmorphism, club foot, and seizures with cyanosis one day after birth. Elevated VLCFAs levels were indicative of a peroxisomal disorder. Targeted exome sequencing was performed and two missense mutations p.Asp117Val and p.Phe279Ser in the gene were identified. The patient had type III DBP deficiency; therefore, docosahexaenoic acid and non-soluble vitamins were administered. However, progressive nystagmus, optic nerve atrophy, and bilateral hearing defects were observed and follow-up brain imaging revealed leukodystrophy and brain atrophy. Multiple anti-epileptic drugs were required to control the seizures. Over two years, the patient achieved normal growth with home ventilation and tube feeding. Hereby, the subject's parents had support during the second pregnancy from the proven molecular information. Moreover, targeted exome sequencing is an effective diagnostic approach, considering genetic heterogeneity of Zellweger spectrum disorders.
Topics: Brain; Female; Heterozygote; Humans; Infant, Newborn; Magnetic Resonance Imaging; Mutation, Missense; Pedigree; Peroxisomal Multifunctional Protein-2; Republic of Korea; Seizures; Zellweger Syndrome
PubMed: 33045774
DOI: 10.3346/jkms.2020.35.e357 -
PloS One 2020VLCFA levels correlate with the severity of the clinical course of ZS, DBP and mild ZSD. The best predictive value for estimating the projected disease severity and...
VLCFA levels correlate with the severity of the clinical course of ZS, DBP and mild ZSD. The best predictive value for estimating the projected disease severity and survival time is a concentration of C26:0.
Topics: Adolescent; Biomarkers; Child; Child, Preschool; Fatty Acids; Female; Humans; Infant; Infant, Newborn; Male; Peroxisomal Disorders; Prognosis; Retrospective Studies; Severity of Illness Index; Survival Analysis; Young Adult; Zellweger Syndrome
PubMed: 32946460
DOI: 10.1371/journal.pone.0238796