Interferon‐induced transmembrane protein 3 (IFITM3) is an antiviral protein that alters cell membranes to block fusion of viruses. Conflicting reports identified opposing effects of IFITM3 on ...SARS‐CoV‐2 infection of cells, and its impact on viral pathogenesis in vivo remains unclear. Here, we show that IFITM3 knockout (KO) mice infected with SARS‐CoV‐2 experience extreme weight loss and lethality compared to mild infection in wild‐type (WT) mice. KO mice have higher lung viral titers and increases in inflammatory cytokine levels, immune cell infiltration, and histopathology. Mechanistically, we observe disseminated viral antigen staining throughout the lung and pulmonary vasculature in KO mice, as well as increased heart infection, indicating that IFITM3 constrains dissemination of SARS‐CoV‐2. Global transcriptomic analysis of infected lungs shows upregulation of gene signatures associated with interferons, inflammation, and angiogenesis in KO versus WT animals, highlighting changes in lung gene expression programs that precede severe lung pathology and fatality. Our results establish IFITM3 KO mice as a new animal model for studying severe SARS‐CoV‐2 infection and overall demonstrate that IFITM3 is protective in SARS‐CoV‐2 infections in vivo.
Synopsis
IFITM3 limits severity of SARS‐CoV‐2 infections by restricting viral replication and spread, thereby reducing lung inflammation, immune cell infiltration, angiogenesis, and pathology. IFITM3 KO mice are a new model for studying severe SARS‐CoV‐2 infections.
IFITM3 limits morbidity and mortality following SARS‐CoV‐2 infection in two mouse models.
Enhanced viral replication in IFITM3 KO mice is accompanied by increased lung pathology and extrapulmonary virus dissemination.
IFITM3 KO mice upregulate inflammatory, angiogenic, and pro‐thrombotic gene programs following SARS‐CoV‐2 infection.
IFITM3 KO mice provide a tool for studying severe SARS‐CoV‐2 infections with likely relevance to human populations with IFITM3 deficiencies.
IFITM3 limits severity of SARS‐CoV‐2 infections by restricting viral replication and spread, thereby reducing lung inflammation, immune cell infiltration, angiogenesis, and pathology. IFITM3 KO mice are a new model for studying severe SARS‐CoV‐2 infections.
PARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic ...strategies are poorly characterized.
We collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease.
Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib.
Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value. See related commentary by Tsang and Gallinger, p. 5005.
•Stigma accounts for the relationship between body image and community integration.•Symptoms of posttraumatic stress disorder also account for this relationship.•Posttraumatic growth did not moderate ...or mediate this relationship.•Burn recovery should aim to reduce symptoms of distress and experienced stigma.
Due to medical advances, care for patients that experience burns has shifted from saving life to improving quality of life. Reintegrating into the community and maintain body image satisfaction may be difficult after a severe burn. Several studies have analyzed these two variables independently, but none have addressed a potential interrelationship.
To investigate the indirect or direct relationship of body image and community integration, potentially mediated or moderated by social stigma, symptoms of depression, symptoms of post-traumatic stress disorder (PTSD), or posttraumatic growth.
Data from the Burn Models Systems (BMS) Database between the years 2014 and 2020, patients who were at least 18 years of age and who had completed questionnaires that measured body image satisfaction, attitudes of community integration, perceived social stigma, and symptoms of depression, symptoms of PTSD, and posttraumatic growth were used to analyze potential mediators and moderators of the relationship between body image and community integration using multivariable linear regression models and structural equation modeling.
Social stigma, symptoms of depression, and symptoms of PTSD were determined to completely mediate the association of body image and community integration. Posttraumatic growth did not mediate this association. Social stigma, symptoms of depression, symptoms of PTSD, and posttraumatic growth did not moderate the relationship between body image and community integration.
The finding that symptoms of distress and social stigma account for the relationship between body image satisfaction and community integration support the potential for interventions that ameliorate distress to improve community integration and quality of life in people recovering from burn injuries.
Colorectal cancer (CRC) is a multifactorial disease resulting from both genetic predisposition and environmental factors including the gut microbiota (GM), but deciphering the influence of genetic ...variants, environmental variables, and interactions with the GM is exceedingly difficult. We previously observed significant differences in intestinal adenoma multiplicity between C57BL/6 J-Apc
(B6-Min/J) from The Jackson Laboratory (JAX), and original founder strain C57BL/6JD-Apc
(B6-Min/D) from the University of Wisconsin.
To resolve genetic and environmental interactions and determine their contributions we utilized two genetically inbred, independently isolated Apc
mouse colonies that have been separated for over 20 generations. Whole genome sequencing was used to identify genetic variants unique to the two substrains. To determine the influence of genetic variants and the impact of differences in the GM on phenotypic variability, we used complex microbiota targeted rederivation to generate two Apc mutant mouse colonies harboring complex GMs from two different sources (GMJAX originally from JAX or GMHSD originally from Envigo), creating four Apc
groups. Untargeted metabolomics were used to characterize shifts in the fecal metabolite profile based on genetic variation and differences in the GM.
WGS revealed several thousand high quality variants unique to the two substrains. No homozygous variants were present in coding regions, with the vast majority of variants residing in noncoding regions. Host genetic divergence between Min/J and Min/D and the complex GM additively determined differential adenoma susceptibility. Untargeted metabolomics revealed that both genetic lineage and the GM collectively determined the fecal metabolite profile, and that each differentially regulates bile acid (BA) metabolism. Metabolomics pathway analysis facilitated identification of a functionally relevant private noncoding variant associated with the bile acid transporter Fatty acid binding protein 6 (Fabp6). Expression studies demonstrated differential expression of Fabp6 between Min/J and Min/D, and the variant correlates with adenoma multiplicity in backcrossed mice.
We found that both genetic variation and differences in microbiota influences the quantitiative adenoma phenotype in Apc
mice. These findings demonstrate how the use of metabolomics datasets can aid as a functional genomic tool, and furthermore illustrate the power of a multi-omics approach to dissect complex disease susceptibility of noncoding variants.
Conversion of adenosine to inosine in RNA by ADAR enzymes, termed "RNA editing," is essential for healthy brain development. Editing is dysregulated in neuropsychiatric diseases, but has not yet been ...investigated at scale at the level of individual neurons. We quantified RNA editing sites in nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical female donor, and found 41,930 sites present in at least ten nuclei. Most sites were located within Alu repeats in introns or 3' UTRs, and approximately 80% were cataloged in public RNA editing databases. We identified 9285 putative novel editing sites, 29% of which were also detectable in unrelated donors. Intersection with results from bulk RNA-seq studies provided cell-type and spatial context for 1730 sites that are differentially edited in schizophrenic brain donors, and 910 such sites in autistic donors. Autism-related genes were also enriched with editing sites predicted to modify RNA structure. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons, and the highest editing rates were observed in the frontal cortex. We used generalized linear models to identify differentially edited sites and genes between cell types. Twenty nine genes were preferentially edited in excitatory neurons, and 43 genes were edited more heavily in inhibitory neurons, including
, its target genes, and genes in the autism-associated Prader-Willi locus (15q11). The abundance of SNORD115/116 genes from locus 15q11 was positively associated with editing activity across the transcriptome. We contend that insufficient editing of autism-related genes in inhibitory neurons may contribute to the specific perturbation of those cells in autism.
Bleeding after acute myocardial infarction (AMI) is associated with an increased morbidity and mortality. The frequency and consequences of bleeding events in patients with AMICS are not well ...described. The objective was to investigate incidence and outcome of bleeding complications among unselected patients with AMI complicated by cardiogenic shock (AMICS) and referred for immediate revascularization. Bleeding events were assessed by review of medical records in consecutive AMICS patients admitted between 2010 and 2017. Bleedings during admission were classified according to Bleeding Academic Research Consortium classification. Patients who did not survive to admission in the intensive care unit were excluded. Of the 1,716 patients admitted with AMICS, 1,532 patients (89%) survived to ICU admission. At 30 days, mortality was 48%. Severe bleedings classified as BARC 3/5 were seen in 87 non-coronary bypass grafting patients (6.1%). Co-morbidity did not differ among patients; however, patients who had a BARC 3/5 bleeding had significantly higher lactate and lower systolic blood pressure at admission, indicating a more severe state of shock. The use of mechanical assist devices was significantly associated with severe bleeding events. Univariable analysis showed that patients with a BARC 3/5 bleeding had a significantly higher 30-day mortality hazard compared with patients without severe bleedings. The association did not sustain after multivariable adjustment (hazard ratio 0.90, 95% confidence interval 0.64; 1.26, p = 0.52). In conclusion, severe bleeding events according to BARC classification in an all-comer population of patients with AMICS were not associated with higher mortality when adjusting for immediate management, hemodynamic, and metabolic state. This indicates that mortality in these patients is primarily related to other factors.
•In an unselected cohort of patients with AMICS, severe bleedings occurred in 6.1%.•Bleedings were more common in patients with left ventricular assist devices.•Severe bleedings were not associated with higher mortality after multivariable adjustment.•Despite heavy instrumentation, <1% of patients suffered a fatal, nonsurgery-related bleeding.
We sought to investigate the role of group III/IV muscle afferents in limiting endurance exercise performance, independently of their role in optimizing locomotor muscle O
delivery. While breathing ...100% O
to ensure a similar arterial O
content (Formula: see text) in both trials, eight male cyclists performed 5-km time trials under control conditions (H
) and with lumbar intrathecal fentanyl (H
) impairing neural feedback from the lower limbs. After each time trial, common femoral artery blood flow (FBF) was quantified (Doppler ultrasound) during constant-load cycling performed at the average power of the preceding time trial. The assessment of end-tidal gases, hemoglobin content and saturation, and FBF facilitated the calculation of leg O
delivery. Locomotor muscle activation during cycling was estimated from vastus lateralis EMG. With electrical femoral nerve stimulation, peripheral and central fatigue were quantified by pre- to postexercise decreases in quadriceps twitch torque (ΔQ
) and voluntary activation (ΔVA), respectively. FBF (~16 mL·min
·W
;
= 0.6), Formula: see text (~24 mL O
/dL;
= 0.9), and leg O
delivery (~0.38 mL O
·min
·W
;
= 0.9) were not different during H
and H
. Mean power output and time to completion were significantly improved by 9% (~310 W vs. ~288 W) and 3% (~479 s vs. ~463 s), respectively, during H
compared with H
. Quadriceps muscle activation was 9 ± 7% higher during H
compared with H
(
< 0.05). ΔQ
was significantly greater in H
compared with H
(54 ± 8% vs. 39 ± 9%), whereas ΔVA was not different (~5%;
= 0.3) in both trials. These findings reveal that group III/IV muscle afferent feedback limits whole body endurance exercise performance and peripheral fatigue by restricting neural activation of locomotor muscle.
Group III/IV muscle afferent feedback facilitates endurance performance by optimizing locomotor muscle O
delivery but also limits performance by restricting neural drive to locomotor muscle. To isolate the performance-limiting effect of these sensory neurons, we pharmacologically attenuated their central projection during a cycling time trial while controlling for locomotor muscle O
delivery. With no difference in leg O
delivery, afferent blockade attenuated the centrally mediated restriction in motoneuronal output and improved cycling performance.
The aim of this study was to investigate the association between academic adjustments and recovery from sport-related concussions (SRCs) in collegiate athletes.
A retrospective medical chart review ...was performed between the 2015-2016 and 2019-2020 sport seasons at 11 Long-term Impact of Military-relevant Brain Injury Consortium Military and Tactical Athlete Research Study (LIMBIC MATARS) sites. Days between injury and symptom resolution, and injury and return to sport (dependent variables) for collegiate athletes who did or did not receive academic adjustments (independent variable) were analyzed using Mann-Whitney
tests.
The number of days between date of injury and symptom-resolution between those who did (median = 9 interquartile range = 5,16) and did not have (73,12) academic adjustments were statistically different (
=-2.76,
< 0.01,
=-0.17). However, no differences were observed between days to return to sport among those who did (1410,22) and did not (138,20) receive assigned academic adjustments (
= -1.66,
= 0.10,
= -.10).
Recovery trajectories were similar between athletes diagnosed with a SRC who did or did not receive academic adjustments.. Our findings suggest academic adjustments supported recovery for those who needed academic adjustments. Clinicians and healthcare professionals should assist and support collegiate athletes after SRCs on an individual basis, including academic adjustments when appropriate based on patient presentation.
Purpose
Patients who are successfully resuscitated following out-of-hospital cardiac arrest (OHCA) are still at a high risk of neurological damage and death. Inflammation and brain injury are ...components of the post-cardiac arrest syndrome, and can be assessed by systemic interleukin 6 (IL-6) and neuron-specific enolase (NSE). Anti-inflammatory treatment with methylprednisolone may dampen inflammation, thereby improving outcome. This study aimed to determine if prehospital high-dose methylprednisolone could reduce IL-6 and NSE in comatose OHCA patients.
Methods
The STEROHCA trial was a randomized, blinded, placebo-controlled, phase II prehospital trial performed at two cardiac arrest centers in Denmark. Resuscitated comatose patients with suspected cardiac etiology were randomly assigned 1:1 to a single intravenous injection of 250 mg methylprednisolone or placebo. The co-primary outcome was reduction of IL-6 and NSE-blood levels measured daily for 72 h from admission. The main secondary outcome was survival at 180 days follow-up.
Results
We randomized 137 patients to methylprednisolone (
n
= 68) or placebo (
n
= 69). We found reduced IL-6 levels (
p
< 0.0001) in the intervention group, with median (interquartile range, IQR) levels at 24 h of 2.1 pg/ml (1.0; 7.1) and 30.7 pg/ml (14.2; 59) in the placebo group. We observed no difference between groups in NSE levels (
p
= 0.22), with levels at 48 h of 18.8 ug/L (14.4; 24.6) and 14.8 ug/L (11.2; 19.4) in the intervention and placebo group, respectively. In the intervention group, 51 (75%) patients survived and 44 (64%) in the placebo group.
Conclusion
Prehospital treatment with high-dose methylprednisolone to resuscitated comatose OHCA patients, resulted in reduced IL-6 levels after 24 h, but did not reduce NSE levels.
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