Oligomeric assembly regulating mitochondrial HtrA2 function as examined by methyl-TROSY NMR.

Human High temperature requirement A2 (HtrA2) is a mitochondrial protease chaperone that plays an important role in cellular proteostasis and in regulating cell-signaling events, with aberrant HtrA2 function leading to neurodegeneration and parkinsonian phenotypes. Structural studies of the enzyme have established a trimeric architecture, comprising three identical protomers in which the active sites of each protease domain are sequestered to form a catalytically inactive complex. The mechanism by which enzyme function is regulated is not well understood. Using methyl transverse relaxation optimized spectroscopy (TROSY)-based solution NMR in concert with biochemical assays, a functional HtrA2 oligomerization/binding cycle has been established. In the absence of substrates, HtrA2 exchanges between a heretofore unobserved hexameric conformation and the canonical trimeric structure, with the hexamer showing much weaker affinity toward substrates. Both structures are substrate inaccessible, explaining their low basal activity in the absence of the binding of activator peptide. The binding of the activator peptide to each of the protomers of the trimer occurs with positive cooperativity and induces intrasubunit domain reorientations to expose the catalytic center, leading to increased proteolytic activity. Our data paint a picture of HtrA2 as a finely tuned, stress-protective enzyme whose activity can be modulated both by oligomerization and domain reorientation, with basal levels of catalysis kept low to avoid proteolysis of nontarget proteins.

Ultrathin and Flexible Bioelectronic Arrays for Functional Measurement of iPSC-Cardiomyocytes under Cardiotropic Drug Administration and Controlled Microenvironments.

Emerging heart-on-a-chip technology is a promising tool to establish in vitro cardiac models for therapeutic testing and disease modeling. However, due to the technical complexity of integrating cell culture chambers, biosensors, and bioreactors into a single entity, a microphysiological system capable of reproducing controlled microenvironmental cues to regulate cell phenotypes, promote iPS-cardiomyocyte maturity, and simultaneously measure the dynamic changes of cardiomyocyte function in situ is not available. This paper reports an ultrathin and flexible bioelectronic array platform in 24-well format for higher-throughput contractility measurement under candidate drug administration or defined microenvironmental conditions. In the array, carbon black (CB)-PDMS flexible strain sensors were embedded for detecting iPSC-CM contractility signals. Carbon fiber electrodes and pneumatic air channels were integrated to provide electrical and mechanical stimulation to improve iPSC-CM maturation. Performed experiments validate that the bioelectronic array accurately reveals the effects of cardiotropic drugs and identifies mechanical/electrical stimulation strategies for promoting iPSC-CM maturation.

Multisystem inflammatory syndrome in children: an Umbrella review.

We conducted an Umbrella review of eligible studies to evaluate what patient features have been investigated in the multisystem inflammatory syndrome in children (MIS-C) population, in order to guide future investigations. We comprehensively searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from December 1, 2019 to the May 6, 2022. The time period was limited to cover the coronavirus disease-2019 (COVID-19) pandemic period. The protocol was registered in the PROSPERO registry (CRD42022340228). Eligible studies included (1) a study population of pediatric patients ≤21 years of age diagnosed with MIS-C; (2) an original Systematic review or Mata-analysis; (3) published 2020 afterward; and (4) was published in English. A total of 41 studies met inclusion criteria and underwent qualitative analysis. 28 studies reported outcome data of MIS-C. 22 studies selected clinical features of MIS-C, and 6 studies chose demographic data as a main topic. The mortality rate for children with MIS-C was 1.9% (interquartile range (IQR) 0.48), the ICU admission rate was 72.6% (IQR 8.3), and the extracorporeal membrane oxygenation rate was 4.7% (IQR 2.0). A meta-analysis of eligible studies found that cerebral natriuretic peptide in children with MIS-C was higher than that in children with COVID-19, and that the use of intravenous immunoglobulin (IVIG) in combination with glucocorticoids to treat MIS-C compared to IVIG alone was associated with lower treatment failure. In the future, for patients with MIS-C, studies focused on safety of surgery requiring general anesthesia, risk factors, treatment, and long-term outcomes are warranted.

Argon inhalation attenuates systemic inflammation and rescues lung architecture during experimental neonatal sepsis.

PURPOSE: Neonatal sepsis is a systemic inflammatory infection common in premature infants and a leading cause of mortality. Argon is an emerging interest in the field of noble gas therapy. Neonates with severe sepsis are frequently mechanically ventilated creating an opportunity for inhalation therapy. We aimed to investigate argon inhalation as a novel experimental therapy in neonatal sepsis. METHODS: Sepsis was established in C57BL/6 neonatal mice by a lipopolysaccharide intraperitoneal injection on postnatal day 9. Septic pup mice were exposed to room air as well as non-septic controls. In the argon group, septic pup mice were exposed to argon (70% Ar, 30% O2) for 6 h in a temperature-controlled environment. RESULTS: At 6 h, survival was significantly enhanced when septic mice received argon compared to septic controls. Serum profiles of cytokine release were significantly attenuated as well as lung architecture restored. CONCLUSIONS: Our findings suggest that argon inhalation as a novel treatment for neonatal sepsis, reducing mortality and counteracting the acute systemic inflammatory response in the blood and preserving the architecture of the lung. This research can contribute to a paradigm shift in the treatment and outcome of neonates with sepsis.

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery.

Even with modern therapy, patients with heart failure only have a 50% five-year survival rate. To improve the development of new therapeutic strategies, preclinical models of disease are needed to properly emulate the human condition. Determining the most appropriate model represents the first key step for reliable and translatable experimental research. Rodent models of heart failure provide a strategic compromise between human in vivo similarity and the ability to perform a larger number of experiments and explore many therapeutic candidates. We herein review the currently available rodent models of heart failure, summarizing their physiopathological basis, the timeline of the development of ventricular failure, and their specific clinical features. In order to facilitate the future planning of investigations in the field of heart failure, a detailed overview of the advantages and possible drawbacks of each model is provided.

Local Anesthetic Cardiac Toxicity Is Mediated by Cardiomyocyte Calcium Dynamics.

BACKGROUND: Long-lasting local anesthetic use for perioperative pain control is limited by possible cardiotoxicity (e.g., arrhythmias and contractile depression), potentially leading to cardiac arrest. Off-target cardiac sodium channel blockade is considered the canonical mechanism behind cardiotoxicity; however, it does not fully explain the observed toxicity variability between anesthetics. The authors hypothesize that more cardiotoxic anesthetics (e.g., bupivacaine) differentially perturb other important cardiomyocyte functions (e.g., calcium dynamics), which may be exploited to mitigate drug toxicity. METHODS: The authors investigated the effects of clinically relevant concentrations of racemic bupivacaine, levobupivacaine, or ropivacaine on human stem cell-derived cardiomyocyte tissue function. Contractility, rhythm, electromechanical coupling, field potential profile, and intracellular calcium dynamics were quantified using multielectrode arrays and optical imaging. Calcium flux differences between bupivacaine and ropivacaine were probed with pharmacologic calcium supplementation or blockade. In vitro findings were correlated in vivo using an anesthetic cardiotoxicity rat model (females; n = 5 per group). RESULTS: Bupivacaine more severely dysregulated calcium dynamics than ropivacaine in vitro (e.g., contraction calcium amplitude to 52 ± 11% and calcium-mediated repolarization duration to 122 ± 7% of ropivacaine effects, model estimate ± standard error). Calcium supplementation improved tissue contractility and restored normal beating rhythm (to 101 ± 6%, and 101 ± 26% of control, respectively) for bupivacaine-treated tissues, but not ropivacaine (e.g., contractility at 80 ± 6% of control). Similarly, calcium pretreatment mitigated anesthetic-induced arrhythmias and cardiac depression in rats, improving animal survival for bupivacaine by 8.3 ± 2.4 min, but exacerbating ropivacaine adverse effects (reduced survival by 13.8 ± 3.4 min and time to first arrhythmia by 12.0 ± 2.9 min). Calcium channel blocker nifedipine coadministration with bupivacaine, but not ropivacaine, exacerbated cardiotoxicity, supporting the role of calcium flux in differentiating toxicity. CONCLUSIONS: Our data illustrate differences in calcium dynamics between anesthetics and how calcium may mitigate bupivacaine cardiotoxicity. Moreover, our findings suggest that bupivacaine cardiotoxicity risk may be higher than for ropivacaine in a calcium deficiency context.

Dexmedetomidine vs. total intravenous anaesthesia in paediatric emergence delirium: A network meta-analysis.

BACKGROUND: Emergence delirium is a common complication in paediatric anaesthesia associated with significant morbidity. Total intravenous anaesthesia (TIVA) and intra-operative dexmedetomidine as an adjuvant to sevoflurane anaesthesia can both reduce the incidence of emergence delirium compared with sevoflurane alone, but no studies have directly compared their relative efficacy. OBJECTIVE: The study objective was to compare the effects of TIVA and dexmedetomidine on the incidence of paediatric emergence delirium. STUDY DESIGN: The current study is a systematic review and network meta-analysis (NMA) of randomised controlled trials. DATA SOURCES: We conducted a systematic search of 12 databases including Medline (Ovid) and Web of Science (Clarivate Analytics) from their respective inception to December 2020. ELIGIBILITY: Inclusion criteria were randomised controlled trials of paediatric patients undergoing general anaesthesia using sevoflurane, sevoflurane with dexmedetomidine or TIVA. Data were extracted by two reviewers according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and analysed using NMA methodology. Risk ratios and 95% credible intervals (CrI) were calculated for all outcomes [emergence delirium, postoperative nausea and vomiting (PONV), and time to emergence and extubation]. The protocol was registered with PROSPERO (CRD42018091237). RESULTS: The systematic review returned 66 eligible studies comprising 5257 patients with crude median emergence delirium incidences of 12.8, 9.1 and 40% in the dexmedetomidine with sevoflurane, TIVA and sevoflurane alone groups, respectively. NMA indicated that compared with TIVA, sevoflurane with adjuvant dexmedetomidine decreased the incidence of emergence delirium without statistical difference (risk ratio 0.88, 95% CrI 0.61 to 1.20, low quality of evidence), but resulted in a higher incidence of PONV (risk ratio: 2.3, 95% CrI 1.1 to 5.6, low quality of evidence). CONCLUSION: Clinical judgement, considering the patient's risk factors for the development of clinically significant outcomes such as emergence delirium and PONV, should be used when choosing between TIVA and sevoflurane with adjuvant dexmedetomidine. These findings are limited by the low quality of evidence (conditional recommendation).

Unique challenges in pediatric anesthesia created by COVID-19.

Coronavirus disease 2019 (COVID-19) has affected anesthetic care worldwide, including the provision of anesthesia for pediatric patients. Hospitals have balanced the risks associated with the potential surges of resource-intensive COVID-19 patients against the probable morbidity of delaying elective surgical procedures. These decisions are complicated by the unclear influence that COVID-19 has on the perioperative risk for disease-positive pediatric patients. We conducted a comprehensive literature search on MEDLINE for publications involving pediatric patients with COVID-19 who underwent general anesthesia. A total of eight publications met inclusion criteria, and together described 20 patients. Nine patients had documented preoperative COVID-19 symptoms and one perioperative death was reported. Overall, further studies are needed to increase patient numbers and properly assess the perioperative risk. As we continue to provide care without clear guiding data, we present a discussion of modified anesthetic techniques for pediatric patients with suspected or confirmed COVID-19.

Multisystem inflammatory syndrome in children during the coronavirus disease pandemic of 2019: a review of clinical features and acute phase management.

The current coronavirus disease of 2019 (COVID-19) pandemic has presented unique health challenges in the pediatric population. Compared to adults, the most significant change in viral disease manifestation is encompassed by the multisystem inflammatory syndrome in children (MIS-C). MIS-C is a new inflammatory syndrome which develops 2-4 weeks after COVID-19 exposure, with evidence suggesting it is a post-infectious immune reaction. We describe its epidemiology, pathophysiology, diagnosis (which varies based on definition used) and treatment options based on published recommendations. A systematic literature search we conducted through MEDLINE yielded 518 abstracts and identified five studies that reported more than 100 cases of MIS-C and their mortality. Most cases developed multiorgan dysfunction, including cardiovascular, dermatologic, neurological, renal, and respiratory issues, and required intensive care unit (ICU) admission. Many patients admitted to the ICU needed inotrope support and invasive mechanical ventilation, and the most severe cases required extracorporeal membrane oxygenation support. Most clinicians treated MIS-C with intravenous immunoglobulin, systemic steroids, and biological therapies. Overall mortality was low (2-3%) in all studies. Further research is needed to: understand if early intervention can prevent its progression; optimize its treatment; and improve outcomes of this new syndrome for the patients who develop MIS-C.

Heart Rate Reduction Improves Right Ventricular Function and Fibrosis in Pulmonary Hypertension.

The potential benefit of heart rate reduction (HRR), independent of ß-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416 + hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding (PAB). Ivabradine (IVA) (10 mg/kg/d) was administered from 2 weeks after PH induction or PAB. Exercise tolerance, echocardiography, and pressure-volume hemodynamics were obtained at a terminal experiment 3 weeks later. RV myocardial samples were analyzed for putative mechanisms of HRR effects through fibrosis, profibrotic molecular signaling, and Ca++ handling. The effects of IVA versus carvedilol on human induced pluripotent stem cell-derived cardiomyocytes beat rate and relaxation properties were evaluated in vitro. Despite unabated severely elevated RV systolic pressures, IVA improved RV systolic and diastolic function, profibrotic signaling, and RV fibrosis in PH/PAB rats. RV systolic-elastance (control, 121 ± 116; MCT, 49 ± 36 vs. MCT+IVA, 120 ± 54; PAB, 70 ± 20 vs. PAB+IVA, 168 ± 76; SUHX, 86 ± 56 vs. SUHX +IVA, 218 ± 111; all P < 0.05), the time constant of RV relaxation, echo indices of RV function, and fibrosis (fibrosis: control, 4.6 ± 1%; MCT, 13.4 ± 6.5 vs. MCT+IVA, 6.7 ± 2.6%; PAB, 11.4 ± 4.5 vs. PAB+IVA, 6.4 ± 5.1%; SUHX, 10 ± 4.6 vs. SUHX+IVA, 3.9 ± 2.2%; all P < 0.001) were improved by IVA versus controls. IVA had a dose-response effect on induced pluripotent stem cell-derived cardiomyocytes beat rate by delaying Ca++ loss from the cytoplasm. In experimental PH or RV pressure loading, HRR improves RV fibrosis, function, and exercise endurance independent of ß-blockade. The balance between adverse tachycardia and bradycardia requires further study, but judicious HRR may provide a promising strategy to improve RV function in clinical PH.

DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.

PURPOSE: Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD). METHODS: Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). RESULTS: Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2-4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD). CONCLUSION: The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.

Renal tissue Po2 sensing during acute hemodilution is dependent on the diluent.

Sensing changes in blood oxygen content ([Formula: see text]) is an important physiological role of the kidney; however, the mechanism(s) by which the kidneys sense and respond to changes in [Formula: see text] are incompletely understood. Accurate measurements of kidney tissue oxygen tension ([Formula: see text]) may increase our understanding of renal oxygen-sensing mechanisms and could inform decisions regarding the optimal fluid for intravascular volume resuscitation to maintain renal perfusion. In some clinical settings, starch solution may be nephrotoxic, possibly due to inadequacy of tissue oxygen delivery. We hypothesized that hemodilution with starch colloid solutions would reduce [Formula: see text] to a more severe degree than other diluents. Anesthetized Sprague-Dawley rats (n = 77) were randomized to undergo hemodilution with either colloid (6% hydroxyethyl starch or 5% albumin), crystalloid (0.9% saline), or a sham procedure (control) (n = 13-18 rats/group). Data were analyzed by ANOVA with significance assigned at P < 0.05. After hemodilution, mean arterial pressure (MAP) decreased marginally in all groups, while hemoglobin (Hb) and [Formula: see text] decreased in proportion to the degree of hemodilution. Cardiac output was maintained in all groups after hemodilution. [Formula: see text] decreased in proportion to the reduction in Hb in all treatment groups. At comparably reduced Hb, and maintained arterial oxygen values, hemodilution with starch resulted in larger decreases in [Formula: see text] relative to animals hemodiluted with albumin or saline (P < 0.008). Renal medullary erythropoietin (EPO) mRNA levels increased more prominently, relative to other hypoxia-regulated molecules (GLUT-1, GAPDH, and VEGF). Our data demonstrate that the kidney acts as a biosensor of reduced [Formula: see text] following hemodilution and that [Formula: see text] may provide a quantitative signal for renal cellular responsiveness to acute anemia. Evidence of a more severe reduction in [Formula: see text] following hemodilution with starch colloid solution suggests that tissue hypoxia may contribute to starch induced renal toxicity.

Effect of moist heat reprocessing of N95 respirators on SARS-CoV-2 inactivation and respirator function.

BACKGROUND: Unprecedented demand for N95 respirators during the coronavirus disease 2019 (COVID-19) pandemic has led to a global shortage of these masks. We validated a rapidly applicable, low-cost decontamination protocol in compliance with regulatory standards to enable the safe reuse of N95 respirators. METHODS: We inoculated 4 common models of N95 respirators with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and evaluated viral inactivation after disinfection for 60 minutes at 70°C and 0% relative humidity. Similarly, we evaluated thermal disinfection at 0% to 70% relative humidity for masks inoculated with Escherichia coli. We assessed masks subjected to multiple cycles of thermal disinfection for structural integrity using scanning electron microscopy and for protective functions using standards of the United States National Institute for Occupational Safety and Health for particle filtration efficiency, breathing resistance and respirator fit. RESULTS: A single heat treatment rendered SARS-CoV-2 undetectable in all mask samples. Compared with untreated inoculated control masks, E. coli cultures at 24 hours were virtually undetectable from masks treated at 70°C and 50% relative humidity (optical density at 600 nm wavelength, 0.02 ± 0.02 v. 2.77 ± 0.09, p < 0.001), but contamination persisted for masks treated at lower relative humidity. After 10 disinfection cycles, masks maintained fibre diameters similar to untreated masks and continued to meet standards for fit, filtration efficiency and breathing resistance. INTERPRETATION: Thermal disinfection successfully decontaminated N95 respirators without impairing structural integrity or function. This process could be used in hospitals and long-term care facilities with commonly available equipment to mitigate the depletion of N95 masks.

Ultrasound-guided maxillary nerve block: an anatomical study using the suprazygomatic approach.

PURPOSE: Although a maxillary nerve (MN) block reportedly provides satisfactory analgesia for midface surgery and chronic maxillofacial pain syndromes, a safe and reliable MN block technique has not been reported. The goal of this anatomical study was to quantify the various angles and depth of the block needle, as well as to evaluate the impact of volume on the extent of injectate spread that might influence anesthetic coverage and block-related complications. METHODS: Following an ultrasound-guided suprazygomatic MN block with dye injection, a dissection was performed in the pterygopalatine fossa (PPF) of four lightly embalmed cadaveric specimens. Half of the specimens were injected with 5 mL of dye, and the other half with 1 mL of dye. The needle depth was measured from the ultrasound images and using rubber markers. Following injection, dissection was performed to map the area of dye spread. RESULTS: The median [interquartile range (IQR)] distance from the skin to the PPF was 37 [36-43] mm and 47 [40-50] mm by ultrasound and rubber marker methods, respectively. The median [IQR] needle orientation was 14 [11-32] degrees inferiorly and 15 [10-17] degrees posteriorly. The PPF was consistently dyed in the 5 mL group, but sporadically dyed in the 1 mL group. In the 5 mL group, spread outside of the PPF was seen. CONCLUSIONS: We showed that 5 mL of injectate far exceeds the capacity of the PPF, leading to drug spread outside of the PPF. Moreover, we found that 1 mL of injectate largely covered the nerve, suggesting a more efficacious and safer block procedure. This finding will need confirmation in future clinical studies.

Efficacy and safety of decontamination for N95 respirator reuse: a systematic literature search and narrative synthesis.

PURPOSE: Under times of supply chain stress, the availability of some medical equipment and supplies may become limited. The current pandemic involving severe acute respiratory syndrome coronavirus 2 has highlighted limitations to the ordinary provision of personal protective equipment (PPE). For perioperative healthcare workers, N95 masks provide a stark example of PPE in short supply necessitating the creation of scientifically valid protocols for their decontamination and reuse. METHODS: We performed a systematic literature search of MEDLINE, Embase, Cochrane CENTRAL databases, and ClinicalTrials.gov to identify peer-reviewed articles related to N95 mask decontamination and subsequent testing for the integrity of mask filtration and facial seal. To expand this search, we additionally surveyed the official statements from key health agencies, organizations, and societies for relevant citations. RESULTS: Our initial database search resulted in five articles that met inclusion criteria, with 26 articles added from the expanded search. Our search did not reveal any relevant randomized clinical trials or cohort studies. We found that moist mask heating (65-80°C at 50-85% relative humidity for 20-30 min) and vaporous hydrogen peroxide treatment were supported by the literature to provide consistent viral decontamination without compromising mask seal and filtration efficiency. Other investigated decontamination methods lacked comprehensive scientific evidence for all three of these key criteria. CONCLUSIONS: N95 mask reprocessing using either moist heat or vaporous hydrogen peroxide is recommended to ensure healthcare worker safety.

RéSUMé: OBJECTIF: Lorsque les chaînes d'approvisionnement sont mises sous pression, la disponibilité de certains équipements et fournitures médicaux pourrait devenir restreinte. La pandémie actuelle du syndrome respiratoire aigu sévère du coronavirus 2 a mis en lumière les limites de l'approvisionnement usuel des équipements de protection individuelle (EPI). Pour les travailleurs de la santé périopératoires, les masques N95 sont un exemple frappant d'EPI pouvant rapidement venir à manquer et nécessitant l'élaboration de protocoles scientifiquement rigoureux pour leur décontamination et leur réutilisation. MéTHODE: Nous avons réalisé une recherche de littérature systématique dans les bases de données MEDLINE, Embase, Cochrane CENTRAL et sur ClinicalTrials.gov afin d'identifier les articles révisés par les pairs portant sur la décontamination des masques N95 et les tests subséquents pour vérifier l'intégrité de la filtration du masque et son étanchéité sur le visage. Afin d'étendre notre recherche, nous avons également passé en revue les énoncés officiels émanant des agences de santé, ainsi que des organismes et sociétés médicales majeurs pour en extraire les citations pertinentes. RéSULTATS: Notre recherche initiale des bases de données nous a permis d'extraire cinq articles respectant nos critères d'inclusion, et 26 articles ont été ajoutés à la suite de notre recherche étendue. Notre recherche n'a pas découvert d'études cliniques randomisées ou d'études de cohorte pertinentes. Nous avons observé que la décontamination du masque par chaleur humide (65­80°C à une humidité relative de 50­85 % pendant 20-30 min) et le traitement par vapeur de peroxyde d'hydrogène constituaient les deux mesures endossées par la littérature. En effet, ces modalités offrent une décontamination virale constante sans pour autant compromettre l'étanchéité du masque ou son efficacité de filtration. Les autres méthodes de décontamination étudiées ne possédaient pas de données probantes scientifiques exhaustives quant à ces trois critères clés. CONCLUSION: Le retraitement des masques N95 à l'aide de chaleur humide ou de vapeur de peroxyde d'oxygène est recommandé pour assurer la sécurité des travailleurs de la santé.

Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness.

Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the ß subunit of G protein heterotrimer (Gαßγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling.

The incidence, significance, and management of accidental intra-arterial injection: a narrative review.

This narrative review discusses the incidence, risk factors, mechanisms of injury, complications, and treatment regimens for accidental intra-arterial injection of medications. Despite awareness of the issue and the establishment of safety recommendations by national agencies, accidental iatrogenic intra-arterial injection of medications continues to occur. Most of these injuries are caused by accidental injection into an established arterial cannula or the inadvertent and unrecognized cannulation of an artery instead of a vein. Although many medications have been injected into arteries without significant consequence, a number of drugs are consistently associated with severe morbidity, including the need for amputation, making early incident recognition and treatment vital. Accidental intra-arterial injection of medications has also been increasingly reported in those who use illicit drugs, as these intravenous injection attempts can be misdirected into an artery. These reports have improved understanding of these injuries and possible treatment modalities. While the characteristics of injuries from illicit injections are diverse and the optimal treatment modalities are still uncertain, a regimen that includes anticoagulation and intra-arterial injection of thrombolytics and prostaglandins may improve outcomes. Steroids, vasodilators, and sympathetic blocks do not appear to influence amputation rates. Owing to the small and sporadic number of cases, no definitive clinical trial evidence exists, but the treatment modalities found to be useful in the illicit intra-arterial injection group may benefit treatment of similar iatrogenic injuries.

RéSUMé: Ce compte rendu narratif traite de l'incidence, des facteurs de risque, des mécanismes de lésion, des complications et des régimes thérapeutiques lors de l'injection intra-artérielle accidentelle de médicaments. Malgré la reconnaissance de ce problème et la mise en place de recommandations de sécurité par les organismes nationaux, les injections intra-artérielles iatrogéniques accidentelles de médicaments surviennent encore. La plupart de ces lésions sont provoquées par l'injection accidentelle dans une canule artérielle déjà en place ou la canulation par inadvertance et non reconnue d'une artère au lieu d'une veine. Bien que de nombreux médicaments aient été injectés dans des artères sans conséquence importante, plusieurs médicaments sont régulièrement associés à une morbidité grave, notamment au recours à l'amputation, ce qui rend essentiels tant l'identification que le traitement rapides de l'incident. L'injection intra-artérielle accidentelle de médicaments est également rapportée de manière plus fréquente chez les personnes utilisant des drogues illicites, étant donné que ces tentatives d'injection intraveineuse peuvent accidentellement se retrouver en intra-artériel. Ces comptes rendus ont amélioré la compréhension de ces lésions et les modalités de traitement possibles. Alors que les caractéristiques des lésions provoquées par des injections illicites varient beaucoup et que les modalités optimales de traitement demeurent incertaines, un régime thérapeutique incluant une anticoagulation et l'injection intra-artérielle d'agents thrombolytiques et de prostaglandines pourrait améliorer les pronostics. Les stéroïdes, les vasodilatateurs et les blocs sympathiques ne semblent pas avoir d'impact sur les taux d'amputation. En raison du petit nombre de cas et de leur aspect sporadique, aucune donnée probante définitive tirée d'une étude clinique n'existe, mais les modalités de traitement qui se sont avérées utiles dans le groupe d'injection intra-artérielle illicite pourraient également être bénéfiques pour traiter des lésions iatrogéniques semblables.

An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. We sought to determine if anti-desmosome antibodies are present in subjects with ARVC. Methods and results: We evaluated ARVC subjects and controls for antibodies to cardiac desmosomal cadherin proteins. Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC. We identified anti-DSG2 antibodies in 12/12 and 25/25 definite ARVC cohorts and 7/8 borderline subjects. Antibody was absent in 11/12, faint in 1/12, and absent in 20/20 of two control cohorts. Anti-DSG2 antibodies were present in 10/10 Boxer dogs with ARVC, and absent in 18/18 without. In humans, the level of anti-DSG2 antibodies correlated with the burden of premature ventricular contractions (r = 0.70), and antibodies caused gap junction dysfunction, a common feature of ARVC, in vitro. Anti-DSG2 antibodies were present in ARVC subjects regardless of whether an underlying mutation was identified, or which mutation was present. A disease-specific DSG2 epitope was identified. Conclusion: Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.