Higher Onset of Periprosthetic Joint Infections in Patients With Teeth Compared to Those Without Teeth.

INTRODUCTION: Bacteria can enter the bloodstream through simple actions such as brushing teeth, flossing, and even chewing food, increasing the chance of hematogenous seeding of prosthetic joints. Antibiotics before dental work in patients with orthopedic hardware is a topic of debate because of concerns for antibiotic resistance. Patients with dentures theoretically avoid this risk due to the lack of teeth and their maintenance. Most periprosthetic joint infections (PJIs) that occur in the first six months after surgery are due to wound infection, whereas late PJIs are more commonly caused by hematogenous seeding. MATERIALS AND METHODS: Charts from patients who received primary total joint arthroplasty were interrogated for the condition of their teeth at the time of operation. If the patient had a PJI, the time from surgery and the organism responsible were noted. Multivariate linear regressions were performed for statistical analysis to compare rates of dental status, infection, comorbidities, and demographics. RESULTS: From the 1,500 charts reviewed, patients with teeth and edentulous had similar rates of comorbidities. PJI patients had higher rates of chronic kidney disease than patients who did not have the infection. The overall rate of infections in patients with teeth was 2.14%, close to the national average. The rate of infection in patients without teeth was 0.78%. Patients with teeth have a higher rate of infection one month or longer from surgery than edentulous patients. CONCLUSIONS: There was an increased infection rate in patients with teeth at six months and greater since the primary total joint arthroplasty. The organisms responsible for many of the PJIs are commonly found in the mouth of humans. Having teeth is a potential risk factor for late PJI.

Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS).

OBJECTIVE: To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS). METHODS: All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE-SWAS and EE-SWAS. Brain-specific gene co-expression analysis was performed for D/EE-SWAS genes. RESULTS: We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE-SWAS and 13/47 (28%) with EE-SWAS. A genetic etiology was identified in 31/91 (34%). D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE-SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS. INTERPRETATION: DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE-SWAS and EE-SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024.

Does the Addition of PROMIS Pain Instruments Improve the Sensitivity of PROMIS Upper Extremity Scores Following Arthroscopic Rotator Cuff Repair?

INTRODUCTION: Though Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity (P-UE) has been validated in upper extremity orthopedics, it's ability to capture a patient's functional recovery after arthroscopic rotator cuff repair (aRCR), as measured by its responsiveness, is minimal in the early postoperative period. The primary purpose of this study is to determine if addition of PROMIS Pain Intensity (P-Intensity) or Pain Interference (P-Interference) scores to PROMIS UE improves the responsiveness throughout the one-year postoperative period after aRCR. METHODS: This prospective, longitudinal study included 100 patients who underwent aRCR. Patients completed P-UE, P-Interference, P-Intensity, American Shoulder and Elbow Surgeons (ASES), and Western Ontario Rotator Cuff Index (WORC) scores preoperatively and at 2-weeks, 6-weeks, 3 months, 6-months and 12-months after surgery. Responsiveness at each time-point relative to preoperative baseline and one-way analysis of variance with post-hoc analysis was conducted for each PROM. Responsiveness of the outcome score was determined using the effect size (ES), graded as small (0.2), medium (0.5), or large (0.8). The Pearson correlation coefficient (r) was determined between these instruments at each time-point. RESULTS: In isolation, P-UE, P-Interference, and P-Intensity showed a medium-large ability to detect change (positive and negative) throughout the one-year postoperative period. The addition of PROMIS pain scores to P-UE improved the responsiveness of the instrument (from medium to a large effect size) starting at 3 months and continued throughout the 12 month follow-up period. Though the addition of pain scores increases the response burden for PROMIS, this was still lower when compared to the response burden for the legacy outcome scores (p<0.05). CONCLUSION: The addition of PROMIS pain instruments improves the responsiveness of the P-UE function score in patients undergoing aRCR.

Hybridizing mechanistic modeling and deep learning for personalized survival prediction after immune checkpoint inhibitor immunotherapy.

We present a study where predictive mechanistic modeling is combined with deep learning methods to predict individual patient survival probabilities under immune checkpoint inhibitor (ICI) immunotherapy. This hybrid approach enables prediction based on both measures that are calculable from mechanistic models of key mechanisms underlying ICI therapy that may not be directly measurable in the clinic and easily measurable quantities or patient characteristics that are not always readily incorporated into predictive mechanistic models. A deep learning time-to-event predictive model trained on a hybrid mechanistic + clinical data set from 93 patients achieved higher per-patient predictive accuracy based on event-time concordance, Brier score, and negative binomial log-likelihood-based criteria than when trained on only mechanistic model-derived values or only clinical data. Feature importance analysis revealed that both clinical and model-derived parameters play prominent roles in increasing prediction accuracy, further supporting the advantage of our hybrid approach.

Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties.

Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in Astn2 cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.

The diversity of clinical Mycobacterium abscessus isolates in morphology, glycopeptidolipids and infection rates in a macrophage model.

Introduction. Mycobacterium abscessus (MABS) is a pathogenic bacterium that can cause severe lung infections, particularly in individuals with cystic fibrosis. MABS colonies can exhibit either a smooth (S) or rough (R) morphotype, influenced by the presence or absence of glycopeptidolipids (GPLs) on their surface, respectively. Despite the clinical significance of these morphotypes, the relationship between GPL levels, morphotype and the pathogenesis of MABS infections remains poorly understood.Gap statement. The mechanisms and implications of GPL production and morphotypes in clinical MABS infections are unclear. There is a gap in understanding their correlation with infectivity and pathogenicity, particularly in patients with underlying lung disease.Aim. This study aimed to investigate the correlation between MABS morphology, GPL and infectivity by analysing strains from cystic fibrosis patients' sputum samples.Methodology. MABS was isolated from patient sputum samples and categorized by morphotype, GPL profile and replication rate in macrophages. A high-content ex vivo infection model using THP-1 cells assessed the infectivity of both clinical and laboratory strains.Results. Our findings revealed that around 50 % of isolates displayed mixed morphologies. GPL analysis confirmed a consistent relationship between GPL content and morphotype that was only found in smooth isolates. Across morphotype groups, no differences were observed in vitro, yet clinical R strains were observed to replicate at higher levels in the THP-1 infection model. Moreover, the proportion of infected macrophages was notably higher among clinical R strains compared to their S counterparts at 72 h post-infection. Clinical variants also infected THP-1 cells at significantly higher rates compared to laboratory strains, highlighting the limited translatability of lab strain infection data to clinical contexts.Conclusion. Our study confirmed the general correlation between morphotype and GPL levels in smooth strains yet unveiled more variability within morphotype groups than previously recognized, particularly during intracellular infection. As the R morphotype is the highest clinical concern, these findings contribute to the expanding knowledge base surrounding MABS infections, offering insights that can steer diagnostic methodologies and treatment approaches.

Marginated Neutrophils in the Lungs Effectively Compete for Nanoparticles Targeted to the Endothelium, Serving as a Part of the Reticuloendothelial System.

Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has yet to achieve this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs' numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens. We show that marginated neutrophils' uptake of many of these "endothelial-targeted" nanocarriers is on par with endothelial uptake. This generalizes across diverse nanomaterials and targeting moieties and was even found with physicochemical lung tropism (i.e., without targeting moieties). Further, we observed this in ex vivo human lungs and in vivo healthy mice, with an increase in marginated neutrophil uptake of nanoparticles caused by local or distant inflammation. These findings have implications for nanomedicine development for lung diseases. These data also suggest that marginated neutrophils, especially in the lungs, should be considered a major part of the reticuloendothelial system (RES), with a special role in clearing nanoparticles that adhere to the lumenal surfaces of blood vessels.

Neurodynamical Computing at the Information Boundaries of Intelligent Systems.

Artificial intelligence has not achieved defining features of biological intelligence despite models boasting more parameters than neurons in the human brain. In this perspective article, we synthesize historical approaches to understanding intelligent systems and argue that methodological and epistemic biases in these fields can be resolved by shifting away from cognitivist brain-as-computer theories and recognizing that brains exist within large, interdependent living systems. Integrating the dynamical systems view of cognition with the massive distributed feedback of perceptual control theory highlights a theoretical gap in our understanding of nonreductive neural mechanisms. Cell assemblies-properly conceived as reentrant dynamical flows and not merely as identified groups of neurons-may fill that gap by providing a minimal supraneuronal level of organization that establishes a neurodynamical base layer for computation. By considering information streams from physical embodiment and situational embedding, we discuss this computational base layer in terms of conserved oscillatory and structural properties of cortical-hippocampal networks. Our synthesis of embodied cognition, based in dynamical systems and perceptual control, aims to bypass the neurosymbolic stalemates that have arisen in artificial intelligence, cognitive science, and computational neuroscience.

The Effects of Slow Breathing during Inter-Set Recovery on Power Performance in the Barbell Back Squat.

Slow breathing (SB) reduces sympathetic nervous system activity, the heart rate (HR), and blood pressure (BP) and increases parasympathetic nervous system activity, HR variability, and oxygen saturation which may lead to quicker recovery between bouts of exercise. Therefore, the purpose of this study was to examine whether a SB technique using the 4-7-8 method between sets of barbell back squats (SQs) would attenuate drops in power and bar velocity. In a randomized, crossover design, 18 healthy resistance-trained college-aged males (age: 20.7 ± 1.4 years, body height: 178.6 ± 6.4 cm, body mass: 82.2 ± 15.0 kg, 4.5 ± 2.4 years of experience) performed 5 sets of 3 repetitions of SQs with normal breathing (CON) or SB during the 3-min recovery between sets. Peak and average power and bar velocity were assessed using a linear positioning transducer. HR recovery (RHR), systolic BP recovery (RBP), the rating of perceived exertion (RPE) and the rating of perceived recovery score (RS) were assessed after each set. There were no significant differences between conditions for peak and average power and bar velocity, RBP, RPE, and RS (p > 0.211). SB led to a greater RHR after set 2 (SB: 51.0 ± 14.9 bpm vs. CON: 44.5 ± 11.5 bpm, p = 0.025) and 3 (SB: 48.3 ± 13.5 bpm vs. CON: 37.7 ± 11.7 bpm, p = 0.006) compared to the CON condition. SB was well tolerated, did not hinder nor improve training performance and improved RHR after the middle sets of SQs. Further investigations are warranted to examine the effects of other SB techniques and to determine SB's effects on different training stimuli as well as its effects over an entire workout and post-workout recovery metrics.

Collective Intelligence-Based Participatory COVID-19 Surveillance in Accra, Ghana: Pilot Mixed Methods Study.

BACKGROUND: Infectious disease surveillance is difficult in many low- and middle-income countries. Information market (IM)-based participatory surveillance is a crowdsourcing method that encourages individuals to actively report health symptoms and observed trends by trading web-based virtual "stocks" with payoffs tied to a future event. OBJECTIVE: This study aims to assess the feasibility and acceptability of a tailored IM surveillance system to monitor population-level COVID-19 outcomes in Accra, Ghana. METHODS: We designed and evaluated a prediction markets IM system from October to December 2021 using a mixed methods study approach. Health care workers and community volunteers aged ≥18 years living in Accra participated in the pilot trading. Participants received 10,000 virtual credits to trade on 12 questions on COVID-19-related outcomes. Payoffs were tied to the cost estimation of new and cumulative cases in the region (Greater Accra) and nationwide (Ghana) at specified future time points. Questions included the number of new COVID-19 cases, the number of people likely to get the COVID-19 vaccination, and the total number of COVID-19 cases in Ghana by the end of the year. Phone credits were awarded based on the tally of virtual credits left and the participant's percentile ranking. Data collected included age, occupation, and trading frequency. In-depth interviews explored the reasons and factors associated with participants' user journey experience, barriers to system use, and willingness to use IM systems in the future. Trading frequency was assessed using trend analysis, and ordinary least squares regression analysis was conducted to determine the factors associated with trading at least once. RESULTS: Of the 105 eligible participants invited, 21 (84%) traded at least once on the platform. Questions estimating the national-level number of COVID-19 cases received 13 to 19 trades, and obtaining COVID-19-related information mainly from television and radio was associated with less likelihood of trading (marginal effect: -0.184). Individuals aged <30 years traded 7.5 times more and earned GH ¢134.1 (US $11.7) more in rewards than those aged >30 years (marginal effect: 0.0135). Implementing the IM surveillance was feasible; all 21 participants who traded found using IM for COVID-19 surveillance acceptable. Active trading by friends with communal discussion and a strong onboarding process facilitated participation. The lack of bidirectional communication on social media and technical difficulties were key barriers. CONCLUSIONS: Using an IM system for disease surveillance is feasible and acceptable in Ghana. This approach shows promise as a cost-effective source of information on disease trends in low- and middle-income countries where surveillance is underdeveloped, but further studies are needed to optimize its use.

Evidence-based food serving size labelling: Survey and laboratory analyses of consumer cooking spray usage.

Nutrition label serving sizes are determined primarily based on typical consumption when such data are available. However, such data are not available for certain foods such as spray cooking oil (cooking spray). Our study assessed cooking spray use by the United States (US) adults compared to the 0.25-s serving size used on US-sold cooking spray labels. Adults (n = 1041, aged 33 ± 16.7 years) completed a 13-question survey on cooking spray use and perceptions. In the survey, participants reported using cooking spray for 1.9 ± 0.9 s per use, and 42.3%-43.1% of participants reported being more likely to purchase products if they were labelled calorie- or fat-free. Next, 30 adults (aged 29.7 ± 11.0 years) completed a laboratory-based study which assessed cooking spray durations for seven cookware items. Spray times ranged from 1.0 ± 0.5 (smallest pan) to 2.5 ± 1.3 s (largest baking sheet), with 100% of sprays (210/210) exceeding the 0.25-s US serving size. Our results suggest that cooking spray serving size should be increased to 1 s to better reflect actual consumption, and this would have the added benefit of aligning better with cooking spray serving sizes in other developed countries (0.5-1.0 s). A 1-s serving size would also preclude cooking spray advertised as calorie- or fat-free, allowing consumers to make more informed choices on the dietary implications of using cooking spray.

Quadriceps Tendon Size Does not Affect Postoperative Strength Recovery Following Quadriceps Tendon Anterior Cruciate Ligament Reconstruction.

OBJECTIVE: The influence of quadriceps tendon (QT) size on postoperative quadriceps strength following QT anterior cruciate ligament reconstruction (ACLR) is unclear. Therefore, this study aimed to determine the relationship between QT morphology and postoperative quadriceps strength recovery following primary ACLR using a QT autograft. METHODS: Patients who underwent primary ACLR using QT autograft from 2014 to 2022 followed by a postoperative isometric strength measurement between 5 and 8 months were retrospectively reviewed. Using preoperative magnetic resonance imaging (MRI) findings, the anterior-posterior (A-P) thickness, medial-lateral (M-L) width, and cross-sectional area (CSA) of the QT were measured. Postoperative residual CSA of QT was estimated based on graft harvest diameter. The quadriceps index (QI) was also calculated, which was determined by dividing the maximum isometric quadriceps torque on the involved side by the maximum quadriceps torque on the uninvolved side. Associations between QI and QT morphology were assessed. Furthermore, multivariable logistic regression analysis with the addition of sex as a covariate was performed with the addition of each individual measure of QT morphology to determine the association with a QI ≥80%. RESULTS: A total of 84 patients (mean age 21.9 ± 7.3 years; 46 female) were included. Residual CSA showed a statistically significant positive correlation with QI (r = 0.221, p = 0.043). There were no statistically significant correlations between QI and CSA, A-P thickness, or M-L width. Multivariable logistic analysis adjusting for sex demonstrated that each individual measure of QT morphology was not statistically significantly associated with a QI ≥80%. CONCLUSION: A statistically significant correlation between measures of preoperative QT size and postoperative quadriceps strength were not detected in patients undergoing primary QT autograft ACLR. A smaller residual QT CSA based on QT harvest diameter was weakly associated with decreased quadriceps strength 5 - 8 months postoperatively, but this association was not independent of sex. Future studies examining the impact of QT morphology on quadriceps strength at longer follow up intervals are needed. LEVEL OF EVIDENCE: IV.

Species distribution models predict genetic isolation of Hetaerina vulnerata Hagen in Selys, 1853 (Odonata, Calopterygidae).

Understanding how past and current environmental conditions shape the demographic and genetic distributions of organisms facilitates our predictions of how future environmental patterns may affect populations. The Canyon Rubyspot damselfly (Odonata: Zygoptera: Hetaerina vulnerata) is an insect with a range distribution from Colombia to the arid southwestern United States, where it inhabits shaded mountain streams in the arid southwestern United States. Past spatial fragmentation of habitat and limited dispersal capacity of H. vulnerata may cause population isolation and genetic differentiation, and projected climate change may exacerbate isolation by further restricting the species' distribution. We constructed species distribution models (SDMs) based on occurrences of H. vulnerata and environmental variables characterizing the species' niche. We inferred seven current potential population clusters isolated by unsuitable habitat. Paleoclimate models indicated habitat contiguity in past conditions; projected models indicated some habitat fragmentation in future scenarios. Seventy-eight H. vulnerata individuals from six of the current clusters were sequenced via ddRADseq and processed with Stacks. Principal components and phylogeographic analyses resolved three subpopulations; Structure resolved four subpopulations. F ST values were low (<0.05) for nearby populations and >0.15 for populations separated by expanses of unsuitable habitat. Isolation by distance was an existing but weak factor in determining genomic structure; isolation by environment and the intervening landscape explained a significant proportion of genetic distance. Hetaerina vulnerata populations were shown to be isolated by a lack of tree canopy coverage, an important habitat predictor for oviposition and territoriality. Thus, H. vulnerata populations are likely separated and are genetically isolated. Integrating SDMs with landscape genetics allowed us to identify populations separated by distance and unsuitable habitat, explaining population genetic patterns and probable fates for populations under future climate scenarios.

Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.

Therapeutic small interfering RNA (siRNA) requires sugar and backbone modifications to inhibit nuclease degradation. However, metabolic stabilization by phosphorothioate (PS), the only backbone chemistry used clinically, may be insufficient for targeting extrahepatic tissues. To improve oligonucleotide stabilization, we report the discovery, synthesis and characterization of extended nucleic acid (exNA) consisting of a methylene insertion between the 5'-C and 5'-OH of a nucleoside. exNA incorporation is compatible with common oligonucleotide synthetic protocols and the PS backbone, provides stabilization against 3' and 5' exonucleases and is tolerated at multiple oligonucleotide positions. A combined exNA-PS backbone enhances resistance to 3' exonuclease by ~32-fold over the conventional PS backbone and by >1,000-fold over the natural phosphodiester backbone, improving tissue exposure, tissue accumulation and efficacy in mice, both systemically and in the brain. The improved efficacy and durability imparted by exNA may enable therapeutic interventions in extrahepatic tissues, both with siRNA and with other oligonucleotides such as CRISPR guide RNA, antisense oligonucleotides, mRNA and tRNA.

Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer.

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. CONCLUSIONS: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions.

One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networks in vivo relevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.

An assessment of nationwide trends in emergency department (ED) resuscitative endovascular balloon occlusion of the aorta (REBOA) use - A trauma quality improvement program registry analysis.

BACKGROUND: Use of resuscitative endovascular balloon occlusion of the aorta (REBOA) for temporary hemorrhage control in severe non-compressible torso trauma remains controversial, with limited data on patient selection and outcomes. This study aims to analyze the nationwide trends of its use in the emergency department (EDs). METHODS: A retrospective analysis of the American College of Surgeons Trauma Quality Improvement Program (ACS-TQIP) from 2017 to 2022 was performed, focusing on REBOA placements in EDs. RESULTS: The analysis included 3398 REBOA procedures. Majority patients were male (76 â€‹%) with a median age of 40 years (27-58) and injury severity score of 20 (20-41). The most common mechanism was collision (64 â€‹%), with emergency surgeries most frequently performed for pelvic trauma (14 â€‹%). Level 1 trauma centers performed 82 â€‹% of these procedures, with consistent low annual utilization (<200 facilities). Survival rates were 85 â€‹% at 1-h post-placement, decreasing significantly to 42 â€‹% by discharge. CONCLUSIONS: REBOA usage in remains limited but steady, primarily occurring at level 1 trauma center EDs. While short-term survival rates are favorable, they drop significantly by the time of discharge.

Percutaneous Cryoneurolysis for Pain Control After Rib Fractures in Older Adults.

This case series evaluates changes in numeric pain scores, opioid use, and other measures before, during, and 30 days after computed tomography­guided percutaneous cryoneurolysis in patients with rib injury.

Methods for Monitoring NCOA4-Mediated Ferritinophagy.

Ferritinophagy is a selective form of autophagy in which ferritin, the primary intracellular iron storage protein complex, is targeted by NCOA4 (Nuclear receptor coactivator 4) to the lysosome for degradation. NCOA4-mediated ferritinophagy plays a crucial role in cellular iron metabolism, influencing iron homeostasis, heme synthesis, mitochondrial respiratory function, and ferroptosis, an iron-dependent form of cell death. Targeting ferritinophagy has emerged as a potential anticancer therapeutic strategy. In this context, we provide a flowchart of the procedures and accompanying protocols for monitoring ferritinophagic flux.

Waves of Colonization and Gene Flow in a Great Speciator.

Secondary contact between previously allopatric lineages offers a test of reproductive isolating mechanisms that may have accrued in isolation. Such instances of contact can produce stable hybrid zones-where reproductive isolation can further develop via reinforcement or phenotypic displacement-or result in the lineages merging. Ongoing secondary contact is most visible in continental systems, where steady input from parental taxa can occur readily. In oceanic island systems, however, secondary contact between closely related species of birds is relatively rare. When observed on sufficiently small islands, relative to population size, secondary contact likely represents a recent phenomenon. Here, we examine the dynamics of a group of birds whose apparent widespread hybridization influenced Ernst Mayr's foundational work on allopatric speciation: the whistlers of Fiji (Aves: Pachycephala). We demonstrate two clear instances of secondary contact within the Fijian archipelago, one resulting in a hybrid zone on a larger island, and the other resulting in a wholly admixed population on a smaller, adjacent island. We leveraged low genome-wide divergence in the hybrid zone to pinpoint a single genomic region associated with observed phenotypic differences. We use genomic data to present a new hypothesis that emphasizes rapid plumage evolution and post-divergence gene flow.