Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.

Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132-requiring upregulation of neddylation to restore proteasomal function and proteasomal stress-led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature-delayed closure of the ischiopubic rami-correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.

On-site treatment of avalanche victims: Scoping review and 2023 recommendations of the international commission for mountain emergency medicine (ICAR MedCom).

INTRODUCTION: The International Commission for Mountain Emergency Medicine (ICAR MedCom) developed updated recommendations for the management of avalanche victims. METHODS: ICAR MedCom created Population Intervention Comparator Outcome (PICO) questions and conducted a scoping review of the literature. We evaluated and graded the evidence using the American College of Chest Physicians system. RESULTS: We included 120 studies including original data in the qualitative synthesis. There were 45 retrospective studies (38%), 44 case reports or case series (37%), and 18 prospective studies on volunteers (15%). The main cause of death from avalanche burial was asphyxia (range of all studies 65-100%). Trauma was the second most common cause of death (5-29%). Hypothermia accounted for few deaths (0-4%). CONCLUSIONS AND RECOMMENDATIONS: For a victim with a burial time ≤ 60 minutes without signs of life, presume asphyxia and provide rescue breaths as soon as possible, regardless of airway patency. For a victim with a burial time > 60 minutes, no signs of life but a patent airway or airway with unknown patency, presume that a primary hypothermic CA has occurred and initiate cardiopulmonary resuscitation (CPR) unless temperature can be measured to rule out hypothermic cardiac arrest. For a victim buried > 60 minutes without signs of life and with an obstructed airway, if core temperature cannot be measured, rescuers can presume asphyxia-induced CA, and should not initiate CPR. If core temperature can be measured, for a victim without signs of life, with a patent airway, and with a core temperature < 30 °C attempt resuscitation, regardless of burial duration.

Novel quantification of the regional strain distribution in the anterior cruciate ligament in response to simulated loading using micro-CT imaging.

PURPOSE: A large percentage of anterior cruciate ligament (ACL) surgical reconstructions experience sub-optimal outcomes within 2 years. A potential factor contributing to poor outcomes is an incomplete understanding of micro-level, regional ACL biomechanics. This research aimed to demonstrate a minimally invasive method that uses micro-CT imaging to quantify regional ACL strains under clinically relevant joint loading. METHODS: A pattern of 0.8 mm diameter zirconium dioxide beads were arthroscopically inserted into four regions of the ACL of four cadaveric knee specimens (mean [SD] age = 59 [9] years). A custom micro-CT compatible joint motion simulator then applied clinically relevant joint loading conditions, while an image was acquired at each condition. From the resulting images, strains within each region were calculated using the centroid coordinates of each tissue-embedded bead. Strain repeatability was assessed using the mean intra-specimen standard deviation across repeated load applications. A one-way repeated measures ANOVA (α = 0.05) was used to determine regional strain variations. RESULTS: The mean intra-specimen standard deviation across repeated load application was ±0.003 strain for all specimens. No statistically significant differences were found between tissue regions, although medium and large effect sizes (0.095-0.450) suggest that these differences may be clinically relevant. CONCLUSIONS: The method presented here demonstrates a minimally invasive measurement of regional ACL strain under clinically relevant joint loads using micro-CT imaging. The strain measurements demonstrated excellent reliability across the five repeated load applications and suggest a non-homogenous distribution of strain through the ACL.