Functional Composite Spacer (Antibiotic Cement around a Hemiarthroplasty) for the Treatment of Shoulder Infections: Minimum 5-Year Outcomes.

BACKGROUND: Periprosthetic infections remain a challenging complication following shoulder arthroplasty and an ideal treatment protocol has yet to be established. Two-stage revision is a common approach. Historically, the first stage entails placement of an all-cement antibiotic spacer. While prior studies have reported on cement spacers as definitive management, persistent pain and inadequate function often lead many to later request a second stage procedure. The functional composite spacer consists of a humeral hemiarthroplasty implant with antibiotic cement coated around the stem alone to preserve the metallic humeral head-glenoid articulation. Functional composite spacers have demonstrated improvements in function and motion with high patient satisfaction at 25 months, but longer-term follow-up is needed to better understand the role it may play in the management of shoulder infections. The purpose of this study is to evaluate outcomes at a minimum of 5 years in patients who initially planned to undergo two-stage revision but elected to retain the functional spacer. METHODS: A retrospective review of a single institution's shoulder surgery repository from 2007 to 2018 identified 30 patients who underwent placement of a composite spacer. Overall, 5 patients underwent second stage reimplantation and 12 patients did not have 5-year follow-up (6 lost to follow-up and 6 deceased). A total 13 patients were included who maintained a functional composite spacer and had minimum 5-year follow-up. Patient-reported outcome measures (ASES, SST, SANE, VAS F and VAS P), satisfaction, range of motion, and radiographic estimation of glenoid wear were evaluated. RESULTS: Two of 13 patients (15%) required additional surgery: one secondary closure for early superficial wound dehiscence and one revision spacer for pain. There were no re-infections. At most recent follow-up patient satisfaction was high and significant improvements were noted for ASES (45.4; p<0.001), SST (5.3; p=0.003), SANE (47.3; p=0.002), VAS F (4.9; p=0.004), and VAS P (-4.4; p=0.007) as well as range of motion including abduction (39.2˚; p=0.005) and elevation (65.9˚; p=0.005). There was no significant change in humeral head medialization (p=0.11). CONCLUSIONS: Patients who do not undergo an early revision and retain a functional composite spacer maintain good function and range of motion with minimal pain at mid-term follow-up.

Reconstructing 120 years of climate change impacts on Joshua tree flowering.

Quantifying how global change impacts wild populations remains challenging, especially for species poorly represented by systematic datasets. Here, we infer climate change effects on masting by Joshua trees (Yucca brevifolia and Y. jaegeriana), keystone perennials of the Mojave Desert, from 15 years of crowdsourced observations. We annotated phenophase in 10,212 geo-referenced images of Joshua trees on the iNaturalist crowdsourcing platform, and used them to train machine learning models predicting flowering from annual weather records. Hindcasting to 1900 with a trained model successfully recovers flowering events in independent historical records and reveals a slightly rising frequency of conditions supporting flowering since the early 20th Century. This reflects increased variation in annual precipitation, which drives masting events in wet years-but also increasing temperatures and drought stress, which may have net negative impacts on recruitment. Our findings reaffirm the value of crowdsourcing for understanding climate change impacts on biodiversity.

Recent developments in understanding RIG-I's activation and oligomerization.

Insights into mechanisms driving either activation or inhibition of immune response are crucial in understanding the pathology of various diseases. The differentiation of viral from endogenous RNA in the cytoplasm by pattern-recognition receptors, such as retinoic acid-inducible gene I (RIG-I), is one of the essential paths for timely activation of an antiviral immune response through induction of type I interferons (IFN). In this mini-review, we describe the most recent developments centered around RIG-I's structure and mechanism of action. We summarize the paradigm-changing work over the past few years that helped us better understand RIG-I's monomeric and oligomerization states and their role in conveying immune response. We also discuss potential applications of the modulation of the RIG-I pathway in preventing autoimmune diseases or induction of immunity against viral infections. Overall, our review aims to summarize innovative research published in the past few years to help clarify questions that have long persisted around RIG-I.

Versatility of the Peroneus Brevis Muscle Flap for Distal Leg, Ankle, and Foot Defects: A Comprehensive Review.

Soft tissue defects of the distal third of the leg are challenging and management with simple split thickness skin graft or conservative measures is often difficult. The peroneus brevis muscle flap is well described in the literature to cover such defects. The aim of our study was to review the different applications and potential complications of the peroneus brevis muscle flap. A comprehensive review of all existing evidence on the use of peroneus brevis muscle flaps for coverage of defects in the distal third of the leg in adult populations was performed. Two hundred forty-eight records were identified in the literature search, among which 15 met the PICOS (Patient, Intervention, Comparison, Outcome and Study design) criteria. All selected studies were retrospective. Overall, 222 patients who received peroneus brevis muscle flaps were analyzed. Indications for reconstruction were post-traumatic defects, infected wounds, and chronic wounds. The overall complication rate was 21% (46/222) with the most commonly reported complication being skin graft loss. We observed 2 cases of partial flap loss, 17 cases of skin graft loss, 2 cases of post-operative hematoma, 2 cases of recurrent infection, 12 cases of partial flap necrosis, 3 cases of skin graft necrosis, and 8 cases of delayed wound healing. Overall, 16 patients (7%) required revision surgery. No cases of donor site morbidity were described. The current review shows that the peroneus brevis muscle flap is a versatile and reliable option for the coverage of small to medium sized defects of the distal leg, ankle, and foot with low complication rates and donor site morbidity.

Measurement of transcranial Doppler insonation angles from three-dimensional reconstructions of CT angiography scans.

Blood velocities measured by Transcranial Doppler (TCD) are dependent on the angle between the incident ultrasound beam and the direction of blood flow (known as the Doppler angle). However, when TCD examinations are performed without imaging the Doppler angle for each vessel segment is not known. We have measured Doppler angles in the basal cerebral arteries examined with TCD using three-dimensional (3D) vessel models generated from computed tomography angiography (CTA) scans. This approach produces angle statistics that are not accessible during non-imaging TCD studies. We created 3D models of the basal cerebral arteries for 24 vasospasm patients. Standard acoustic windows were mapped to the specific anatomy of each patient. Virtual ultrasound transmit beams were generated that originated from the acoustic window and intersected the centerline of each arterial segment. Doppler angle measurements were calculated and compiled for each vessel segment. Doppler angles were smallest for the middle cerebral artery M1 segment (median 24.6°) and ophthalmic artery (median 25.0°), and largest for the anterior cerebral artery A2 segment (median 76.4°) and posterior cerebral artery P2 segment (median 75.8°). The ophthalmic artery had the highest proportion of Doppler angles that were less than 60° (99%) while the anterior cerebral artery A2 segment had the lowest proportion of Doppler angles that were less than 60° (10%). These angle measurements indicate the expected deviation between measured and true velocities in the cerebral arteries, highlighting specific segments that may be prone to underestimation of velocity.

Trends in Performance of Thrombectomy for Acute Ischemic Stroke Patients in Teaching and Non-teaching Hospitals.

OBJECTIVES: The value of thrombectomy in patients with acute ischemic stroke cannot be understated. As such, whether these patients get access to this treatment can significantly impact their disease outcomes. We analyzed the trends in thrombectomy adoption between teaching and non-teaching hospitals in the United States, and their impact on overall patient care. MATERIALS AND METHODS: We conducted a retrospective analysis of hospital admissions in the Nationwide Inpatient Sample with a diagnosis of acute ischemic stroke between 2012 and 2020. We compared the annual total number and proportion of patients undergoing thrombectomy between teaching and non-teaching hospitals, and their corresponding outcomes. RESULTS: 3,823,490 and 1,875,705 patients were admitted to teaching and non-teaching hospitals during the study duration, respectively. The proportion of patients who underwent thrombectomy increased from 1.60% to 7.02% (p-value for trend p<0.001) in teaching hospitals and from 0.32% to 2.20% (p-value trend p<0.001) in non-teaching hospitals. The absolute increase in the number of acute ischemic stroke patients undergoing thrombectomy was highest in teaching hospitals particularly those with large bed size, an increase from 3635 patients in 2012 to 24,730 patients in 2020. Higher rates of intravenous thrombolysis and patient transfer prior to thrombectomy were seen in teaching hospitals compared with non-teaching hospitals. CONCLUSIONS: The study highlights disparities between teaching and non-teaching hospitals, with teaching hospitals showing a disproportionately higher rate of thrombectomy adoption in acute ischemic stroke patients. Further studies are needed to understand the barriers to the adoption of thrombectomy in non-teaching hospitals.

Triangulation of Hard X-Ray Sources in an X-Class Solar Flare with ASO-S/HXI and Solar Orbiter/STIX.

HXI on ASO-S and STIX onboard Solar Orbiter are the first simultaneously operating solar hard X-ray imaging spectrometers. ASO-S's low Earth orbit and Solar Orbiter's periodic displacement from the Sun-Earth line enables multi-viewpoint solar hard X-ray spectroscopic imaging analysis for the first time. Here, we demonstrate the potential of this new capability by reporting the first results of 3D triangulation of hard X-ray sources in the SOL2023-12-31T21:55 X5 flare. HXI and STIX observed the flare near the east limb with an observer separation angle of 18°. We triangulated the brightest regions within each source, which enabled us to characterise the large-scale hard X-ray geometry of the flare. The footpoints were found to be in the chromosphere within uncertainty, as expected, while the thermal looptop source was centred at an altitude of 15.1 ± 1 Mm. Given the footpoint separation, this implies a more elongated magnetic-loop structure than predicted by a semi-circular model. These results show the strong diagnostic power of joint HXI and STIX observations for understanding the 3D geometry of solar flares. We conclude by discussing the next steps required to fully exploit their potential.

Diverse Proteomimetic Frameworks via Rational Design of π-Stacking Peptide Tectons.

Peptide-based frameworks aim to integrate protein architecture into solid-state materials using simpler building blocks. Despite the growing number of peptide frameworks, there are few strategies to rationally engineer essential properties like pore size and shape. Designing peptide assemblies is generally hindered by the difficulty of predicting complex networks of weak intermolecular interactions. Peptides conjugated to polyaromatic groups are a unique case where assembly appears to be strongly driven by π-π interactions, suggesting that rationally adjusting the geometry of the π-stackers could create novel structures. Here, we report peptide elongation as a simple mechanism to predictably tune the angle between the π-stacking groups to produce a remarkable diversity of pore shapes and sizes, including some that are mesoporous. Notably, rapid jumps in pore size and shape can occur with just a single amino acid insertion. The geometry of the π-stacking residues also significantly influences framework structure, representing an additional dimension for tuning. Lastly, sequence identity can also indirectly modulate the π-π interactions. By correlating each of these factors with detailed crystallographic data, we find that, despite the complexity of peptide structure, the shape and polarity of the tectons are straightforward predictors of framework structure. These guidelines are expected to accelerate the development of advanced porous materials with protein-like capabilities.

Tristetraprolin mediates immune evasion of mycobacterial infection in macrophages.

Immune evasion of Mycobacterium tuberculosis (Mtb) facilitates intracellular bacterial growth. The mechanisms of immune evasion, however, are still not fully understood. In this study, we reveal that tristetraprolin (TTP), one of the best characterized RNA-binding proteins controlling the stability of targeted mRNAs, mediates innate immune evasion of mycobacteria. We found that TTP knockout mice displayed reduced bacterial burden in the early stage after Mtb aerosol challenge. Macrophages deficient in TTP also showed an inhibition in intracellular mycobacterial growth. Live mycobacteria induced TTP protein expression in macrophages, which was blocked by the mTOR inhibitor rapamycin. Rapamycin and AZD8055 specifically blocked 4EBP1 phosphorylation in infected macrophages and suppressed intracellular BCG growth. Rapamycin promoted TTP protein degradation through the ubiquitination pathway, whereas the proteasome inhibitor MG-132 blocked rapamycin function and thus stabilized TTP protein. TTP induction suppressed the expression of iNOS/TNF-α/IL-12/IL-23, and weakened protective immune responses in macrophages, whereas rapamycin enhanced the bactericidal effects through TTP inhibition. Moreover, blocking TTP binding increased the expression of TNF-α and iNOS and suppressed intracellular mycobacterial growth. Overall, our study reveals a novel role for RNA-binding protein TTP in Mtb immune evasion mechanisms and provides a potential target for host-directed therapy against tuberculosis (TB).

Consequences of gene editing of PRLR on thermotolerance, growth, and male reproduction in cattle.

Global warming is a major challenge to the sustainable and humane production of food because of the increased risk of livestock to heat stress. Here, the example of the prolactin receptor (PRLR) gene is used to demonstrate how gene editing can increase the resistance of cattle to heat stress by the introduction of mutations conferring thermotolerance. Several cattle populations in South and Central America possess natural mutations in PRLR that result in affected animals having short hair and being thermotolerant. CRISPR/Cas9 technology was used to introduce variants of PRLR in two thermosensitive breeds of cattle - Angus and Jersey. Gene-edited animals exhibited superior ability to regulate vaginal temperature (heifers) and rectal temperature (bulls) compared to animals that were not gene-edited. Moreover, gene-edited animals exhibited superior growth characteristics and had larger scrotal circumference. There was no evidence for deleterious effects of the mutation on carcass characteristics or male reproductive function. These results indicate the potential for reducing heat stress in relevant environments to enhance cattle productivity.

Mechanical Stretch Induces Senescence of Lung Epithelial Cells and Drives Fibroblast Activation by Paracrine Mechanisms.

Severe lung injury requiring mechanical ventilation may lead to secondary fibrosis. Senescence, a cell response characterized by cell cycle arrest and a shift towards a proinflammatory/profibrotic phenotype, is one of the involved mechanisms. Here, we explore the contribution of mechanical stretch as trigger of senescence of the respiratory epithelium and its link with fibrosis. Human lung epithelial cells and fibroblasts were exposed in vitro to mechanical stretch, and senescence assessed. In addition, fibroblasts were exposed to culture media preconditioned by senescent epithelial cells and their activation was studied. Transcriptomic profiles from stretched, senescent epithelial cells and activated fibroblasts were combined to identify potential activated pathways. Finally, the senolytic effects of digoxin were tested in these models. Mechanical stretch induced senescence in lung epithelial cells, but not in fibroblasts. This stretch-induced senescence has specific features compared to senescence induced by doxorubicin. Fibroblasts were activated after exposure to supernatants conditioned by epithelial senescent cells. Transcriptomic analyses revealed notch signaling as a potential responsible for the epithelial-mesenchymal crosstalk, as blockade of this pathway inhibits fibroblast activation. Treatment with digoxin reduced the percentage of senescent cells after stretch and ameliorated the fibroblast response to preconditioned media. These results suggest that lung fibrosis in response to mechanical stretch may be caused by the paracrine effects of senescent cells. This pathogenetic mechanism can be pharmacologically manipulated to improve lung repair.

Traditional Black Midwifery to Enhance Birth Justice.

In this commentary, we explore the significance of traditional Black midwifery practices across diaspora and global contexts, focusing on their potential for birth justice. By integrating cultural, health, and historical perspectives, we highlight the transformative power of traditional Black midwifery. Furthermore, we address the challenges that Black traditional and formally trained midwives face within contemporary health care systems. Barriers such as legal restrictions, limited recognition, and inadequate resources hinder the integration of Black midwifery into formal health care frameworks. Finally, strategies to promote collaboration, cultural, and respectful dialogue between traditional Black midwives and modern health care providers are proposed to overcome these challenges.

Event boundaries drive norepinephrine release and distinctive neural representations of space in the rodent hippocampus.

Episodic memories are temporally segmented around event boundaries that tend to coincide with moments of environmental change. During these times, the state of the brain should change rapidly, or reset, to ensure that the information encountered before and after an event boundary is encoded in different neuronal populations. Norepinephrine (NE) is thought to facilitate this network reorganization. However, it is unknown whether event boundaries drive NE release in the hippocampus and, if so, how NE release relates to changes in hippocampal firing patterns. The advent of the new GRABNE sensor now allows for the measurement of NE binding with sub-second resolution. Using this tool in mice, we tested whether NE is released into the dorsal hippocampus during event boundaries defined by unexpected transitions between spatial contexts and presentations of novel objections. We found that NE binding dynamics were well explained by the time elapsed after each of these environmental changes, and were not related to conditioned behaviors, exploratory bouts of movement, or reward. Familiarity with a spatial context accelerated the rate in which phasic NE binding decayed to baseline. Knowing when NE is elevated, we tested how hippocampal coding of space differs during these moments. Immediately after context transitions we observed relatively unique patterns of neural spiking which settled into a modal state at a similar rate in which NE returned to baseline. These results are consistent with a model wherein NE release drives hippocampal representations away from a steady-state attractor. We hypothesize that the distinctive neural codes observed after each event boundary may facilitate long-term memory and contribute to the neural basis for the primacy effect.

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology.

Personality is influenced by both genetic and environmental factors and is associated with other psychiatric traits such as anxiety and depression. The 'big five' personality traits, which include neuroticism, extraversion, agreeableness, conscientiousness and openness, are a widely accepted and influential framework for understanding and describing human personality. Of the big five personality traits, neuroticism has most often been the focus of genetic studies and is linked to various mental illnesses, including depression, anxiety and schizophrenia. Our knowledge of the genetic architecture of the other four personality traits is more limited. Here, utilizing the Million Veteran Program cohort, we conducted a genome-wide association study in individuals of European and African ancestry. Adding other published data, we performed genome-wide association study meta-analysis for each of the five personality traits with sample sizes ranging from 237,390 to 682,688. We identified 208, 14, 3, 2 and 7 independent genome-wide significant loci associated with neuroticism, extraversion, agreeableness, conscientiousness and openness, respectively. These findings represent 62 novel loci for neuroticism, as well as the first genome-wide significant loci discovered for agreeableness. Gene-based association testing revealed 254 genes showing significant association with at least one of the five personality traits. Transcriptome-wide and proteome-wide analysis identified altered expression of genes and proteins such as CRHR1, SLC12A5, MAPT and STX4. Pathway enrichment and drug perturbation analyses identified complex biology underlying human personality traits. We also studied the inter-relationship of personality traits with 1,437 other traits in a phenome-wide genetic correlation analysis, identifying new associations. Mendelian randomization showed positive bidirectional effects between neuroticism and depression and anxiety, while a negative bidirectional effect was observed for agreeableness and these psychiatric traits. This study improves our comprehensive understanding of the genetic architecture underlying personality traits and their relationship to other complex human traits.

Spin-Polarization Control of Photoelectrons Using Poincaré Fields.

Efficient helicity transfer from Poincaré fields to electrons of hydrogenic ions is revealed for the first time by four-dimensional relativistic simulations. The magnetic multipole class of Poincaré fields is chosen due to its fundamental role in light-matter spin coupling, and the calculation is demonstrated for Ne^{9+} ion irradiated by single and multimode x-ray pulses. Photoelectrons of both helicities emerge synchronously from the ion ensemble, and their directionality is controllable through the radiation mode numbers. The helicity density distributions display novel structures composed of jets, spirals, and rings, among others, that are unique to the combination of atomic and field parameters. Our approach to generate spin-polarized leptons using Poincaré fields may provide a new platform for helicity characterization based on advanced numerical capabilities.

Protecting migrant children's well-being in Ecuador's public schools.

Education plays a crucial role in the adaptation and broader societal inclusion of immigrant students and their families. The current study explored the inclusion of migrants in Ecuador's school system as a fundamental tenet of protecting their health and well-being. We conducted a thematic analysis of 13 policy documents, 12 national laws and international agreements, and 31 key informant interviews, applying a human rights lens. We find that, although the 2008 Ecuadorian Constitution and migration laws protect the right of migrants to health and education, key informants argue that these laws are poorly implemented. Furthermore, they agree that the health sector generally does not consider education as a relevant setting for health. In contrast, the public education sector and non-profit organizations at the national and local levels appear to recognize the importance of coordination across the health and education sectors, including school-based initiatives for migrant inclusion.

Smooth muscle-specific deletion of Ccn2 causes severe aorta malformation and atherosclerosis.

AIMS: Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in fibrotic diseases, with ongoing clinical trials evaluating anti-CCN2-based therapies. By uncovering CCN2 as abundantly expressed in non-diseased artery tissue, this study aimed to investigate the hypothesis that CCN2 plays a pivotal role in maintaining smooth muscle cell (SMC) phenotype and protection against atherosclerosis. METHODS AND RESULTS: Global- and SMC-specific Ccn2 knockout mouse models were employed to demonstrate that Ccn2 deficiency leads to SMC de-differentiation, medial thickening, and aorta elongation under normolipidemic conditions. Inducing hyperlipidemia in both models resulted in severe aorta malformation and a 17-fold increase in atherosclerosis formation. Lipid-rich lesions developed at sites of the vasculature typically protected from atherosclerosis-development by laminar blood flow, covering 90% of aortas, and extending to other vessels, including coronary arteries. Evaluation at earlier time points revealed medial lipid accumulation as a lesion-initiating event. Fluorescently labelled LDL injection followed by confocal microscopy showed increased LDL retention in the medial layer of Ccn2 knockout aortas, likely attributed to marked proteoglycan enrichment of the medial extracellular matrix. Analyses leveraging data from the Athero-Express study cohort indicated relevance of CCN2 in established human lesions, as CCN2 correlated with SMC marker transcripts across 654 transcriptomically profiled carotid plaques. These findings were substantiated through in situ hybridization showing CCN2 expression predominantly in the fibrous cap. CONCLUSIONS: This study identifies CCN2 as a major constituent of the normal artery wall, critical in regulating SMC differentiation and aorta integrity, and possessing a protective role against atherosclerosis development. These findings underscore the need for further investigation into the potential effects of anti-CCN2-based therapies on the vasculature.

Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson's Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.