Obesity is associated with muscle atrophy in rotator cuff tear.

Objective: The primary goal of this study is to evaluate the relationship between Body Mass Index (BMI) and muscle atrophy in individuals with rotator cuff tears. Methods: This study consists of patients with rotator cuff tears identified by MRI from two independent cohorts, the Rotator Cuff Outcomes Workgroup (ROW) and the Multicenter Orthopaedic Outcomes Network (MOON). Presence of atrophy (yes/no) and severity of atrophy (as an ordinal variable) were assessed on MRI by expert physicians. We used multivariable regression models to evaluate the relationship between BMI and muscle atrophy while adjusting for age and sex in each study, conducted sensitivity analyses for full-thickness tear and combined results using inverse variance-weighted meta-analysis. Results: A total of 539 patients (MOON=395, ROW=144) from the combined cohorts had MRI data available on muscle atrophy. Among these patients, 246 (46%) had atrophy of at least one of the muscles of the rotator cuff and 282 (52%) had full-thickness tears. In meta-analysis across both cohorts, each 5 kg/m2 increase in BMI was associated with a 21% (aOR=1.21, 95% CI=1.02, 1.43) increased odds of having muscle atrophy among individuals with any tear size, and 36% (aOR=1.36, 95% CI=1.01-1.81) increased odds among individuals with full-thickness tear. Conclusions: Higher BMI was associated with significantly higher odds of muscle atrophy in patiens with rotator cuff tears. More study is needed to unders1tand why and how this relationship exists, as well as whether interventions to reduce BMI may help improve outcomes for these patients. Level of Evidence: III.

Progressive degeneration in a new Drosophila model of spinocerebellar ataxia type 7.

Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder resulting from abnormal expansion of an uninterrupted polyglutamine (polyQ) repeat in its disease protein, ataxin-7 (ATXN7). ATXN7 is part of Spt-Ada-Gcn5 acetyltransferase (SAGA), an evolutionarily conserved transcriptional coactivation complex with critical roles in chromatin remodeling, cell signaling, neurodifferentiation, mitochondrial health and autophagy. SCA7 is dominantly inherited and characterized by genetic anticipation and high repeat-length instability. Patients with SCA7 experience progressive ataxia, atrophy, spasticity, and blindness. There is currently no cure for SCA7, and therapies are aimed at alleviating symptoms to increase quality of life. Here, we report novel Drosophila lines of SCA7 with polyQ repeats in wild-type and human disease patient range. We find that ATXN7 expression has age- and polyQ repeat length-dependent reduction in fruit fly survival and retinal instability, concomitant with increased ATXN7 protein aggregation. These new lines will provide important insight on disease progression that can be used in the future to identify therapeutic targets for SCA7 patients.

Seclidemstat blocks the transcriptional function of multiple FET-fusion oncoproteins.

Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in rare sarcomas. FET-rearranged sarcomas are often aggressive malignancies affecting patients of all ages. New therapies are needed. These translocations fuse the 5' portion of the FET gene with a 3' partner gene encoding a transcription factor (TF). The resulting fusion proteins are oncogenic TFs with a FET protein low complexity domain (LCD) and a DNA binding domain. FET fusion proteins have proven stubbornly difficult to target directly and promising strategies target critical co-regulators. One candidate is lysine specific demethylase 1 (LSD1). LSD1 is recruited by multiple FET fusions, including EWSR1::FLI1. LSD1 promotes EWSR1::FLI1 activity and treatment with the noncompetitive inhibitor SP-2509 blocks EWSR1::FLI1 transcriptional function. A similar molecule, seclidemstat (SP-2577), is currently in clinical trials for FET-rearranged sarcomas (NCT03600649). However, whether seclidemstat has pharmacological activity against FET fusions has not been demonstrated. Here, we evaluate the in vitro potency of seclidemstat against multiple FET-rearranged sarcoma cell lines, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, and myxoid liposarcoma. We also define the transcriptomic effects of seclidemstat treatment and evaluated the activity of seclidemstat against FET fusion transcriptional regulation. Seclidemstat showed potent activity in cell viability assays across FET-rearranged sarcomas and disrupted the transcriptional function of all tested fusions. Though epigenetic and targeted inhibitors are unlikely to be effective as a single agents in the clinic, these data suggest seclidemstat remains a promising new treatment strategy for patients with FET-rearranged sarcomas.

Insertion-Deletion Events Are Depleted in Protein Regions with Predicted Secondary Structure.

A fundamental goal in evolutionary biology and population genetics is to understand how selection shapes the fate of new mutations. Here, we test the null hypothesis that insertion-deletion (indel) events in protein-coding regions occur randomly with respect to secondary structures. We identified indels across 11,444 sequence alignments in mouse, rat, human, chimp, and dog genomes and then quantified their overlap with four different types of secondary structure-alpha helices, beta strands, protein bends, and protein turns-predicted by deep-learning methods of AlphaFold2. Indels overlapped secondary structures 54% as much as expected and were especially underrepresented over beta strands, which tend to form internal, stable regions of proteins. In contrast, indels were enriched by 155% over regions without any predicted secondary structures. These skews were stronger in the rodent lineages compared to the primate lineages, consistent with population genetic theory predicting that natural selection will be more efficient in species with larger effective population sizes. Nonsynonymous substitutions were also less common in regions of protein secondary structure, although not as strongly reduced as in indels. In a complementary analysis of thousands of human genomes, we showed that indels overlapping secondary structure segregated at significantly lower frequency than indels outside of secondary structure. Taken together, our study shows that indels are selected against if they overlap secondary structure, presumably because they disrupt the tertiary structure and function of a protein.

Nature-based solutions as buffers against coastal compound flooding: Exploring potential framework for process-based modeling of hazard mitigation.

As coastal regions face escalating risks from flooding in a changing climate, Nature-based Solutions (NbS) have garnered attention as promising adaptation measures to mitigate the destructive impacts of coastal flooding. However, the challenge of compound flooding, which involves the combined effects of multiple flood drivers, demands a deeper understanding of the efficacy of NbS against this complex phenomenon. This manuscript reviews the literature on process-based modeling of NbS for mitigating compound coastal flooding and identifies knowledge gaps to enhance future research efforts. We used an automated search strategy within the SCOPUS database, followed by a screening process that ultimately resulted in 141 publications assessing the functionality of NbS against coastal flooding. Our review identified a dearth of research (9 %) investigating the performance of NbS against compound flooding scenarios. We examined the challenges and complexities involved in modeling such scenarios, including hydrologic, hydrodynamic, and ecological feedback processes by exploring the studies that used a process-based modeling framework. Key research gaps were identified, such as navigating the complex environment, managing computational costs, and addressing the shortages of experts and data. We outlined potential modeling pathways to improve NbS characterization in the compound flooding framework. Additionally, uncertainties associated with numerical modeling and steps to bridge the research-to-operation gaps were briefly discussed, highlighting the bottlenecks in operational implementation.

Impact of a Lightly Branched Star Polyelectrolyte Architecture on Polyelectrolyte Complexes.

The effect of charge density in blocky and statistical linear polyelectrolytes on polyelectrolyte complex (PEC) properties has been studied with the finding that increased charge density in a polyelectrolyte tends to increase the salt resistance and modulus of a PEC across various polyelectrolyte pairs. Here, we demonstrate the ability to orthogonally alter PEC salt resistance while maintaining rheological properties and internal structure by going from linear to lightly branched architectures with similar total degrees of polymerization. Using a model system built around glycidyl methacrylate (GMA) and thiol-epoxy "click" functionalization, we create a library of homologous linear, 4-armed, 6-armed, and 8-armed star polyelectrolytes. The PECs formed from these model polyelectrolyte pairs are then characterized via optical microscopy, rheology, and small-angle X-ray scattering to evaluate their salt resistance, mechanical properties, and internal structure. We argue that our results are due to the difference between linear charge density or charge per unit length along backbone segments for each polyelectrolyte and spatial charge density, the number of charges per unit volume of the polyelectrolyte prior to complexation. Our findings suggest that linear charge density is the dominant factor in determining intermolecular interactions of the complex, leading to identical rheological and structural behavior, whereas the spatial charge density primarily influences the stability of the complexes. These distinct mechanisms for altering various sought-after PEC properties offer greater potential applications in precision design of polyelectrolyte complex materials.

High variability among surgeons in evaluation, treatment, and rehabilitation of medial ulnar collateral ligament injuries.

Hypothesis and/or Background: The incidence of elbow medial ulnar collateral ligament (MUCL) injuries has been increasing, leading to advances in surgical treatments. However, it is not clear that there is consensus among surgeons regarding diagnostic imaging, the indications for acute surgery and postoperative rehabilitation. The purpose of this study is evaluate surgeon variability in the presurgical, surgical, and postsurgical treatment of MUCL injuries regarding the imaging modalities used for diagnosis, indications for acute surgical treatment, and postoperative treatment recommendations for rehabilitation and return to play (RTP). Our hypothesis is that indications for acute surgical treatment will be highly variable based on MUCL tear patterns and that agreement on the time to RTP will be consistent for throwing athletes and inconsistent for nonthrowing athletes. Methods: A survey developed by 6 orthopedic surgeons with expertise in throwing athlete elbow injuries was distributed to 31 orthopedic surgeons who routinely treat MUCL injuries. The survey evaluated diagnostic and treatment topics related to MUCL injuries, and responses reaching 75% agreement were considered as high-level agreement. Results: Twenty-four surgeons responded to the survey, resulting in a 77% response rate. There is 75% or better agreement among surveyed surgeons regarding acute surgical treatment for distal full thickness tears, ulnar nerve transposition in symptomatic patients or with ulnar nerve subluxation, postoperative splinting for 1-2 weeks with initiation of rehabilitation within 2 weeks, the use of bracing after surgery and the initiation of a throwing program at 3 months after MUCL repair with internal brace by surgeons performing 20 or more MUCL surgeries per year. There were a considerable number of survey topics without high-level agreement, particularly regarding the indications for acute surgical treatment, the time to return to throwing and time RTP in both throwing and nonthrowing athletes. Discussion and/or Conclusion: The study reveals that there is agreement for the indication of acute surgical treatment of distal MUCL tears, duration of bracing after surgery, and the time to initiate physical therapy after surgery. There is not clear agreement on indications for surgical treatment for every MUCL tear pattern, RTP time for throwing, hitting and participation in nonthrowing sports.

PKMYT1 is a Marker of Treatment Response and a Therapeutic Target for CDK4/6 Inhibitor-Resistance in ER+ Breast Cancer.

Endocrine therapies (ET) with CDK4/6 inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of 22 ER+ breast cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.

Influence of Four Veterinary Antibiotics on Constructed Treatment Wetland Nitrogen Transformation.

The use of wetlands as a treatment approach for nitrogen in runoff is a common practice in agroecosystems. However, nitrate is not the sole constituent present in agricultural runoff and other biologically active contaminants have the potential to affect nitrate removal efficiency. In this study, the impacts of the combined effects of four common veterinary antibiotics (chlortetracycline, sulfamethazine, lincomycin, monensin) on nitrate-N treatment efficiency in saturated sediments and wetlands were evaluated in a coupled microcosm/mesocosm scale experiment. Veterinary antibiotics were hypothesized to significantly impact nitrogen speciation (e.g., nitrate and ammonium) and nitrogen uptake and transformation processes (e.g., plant uptake and denitrification) within the wetland ecosystems. To test this hypothesis, the coupled study had three objectives: 1. assess veterinary antibiotic impact on nitrogen cycle processes in wetland sediments using microcosm incubations, 2. measure nitrate-N reduction in water of floating treatment wetland systems over time following the introduction of veterinary antibiotic residues, and 3. identify the fate of veterinary antibiotics in floating treatment wetlands using mesocosms. Microcosms containing added mixtures of the veterinary antibiotics had little to no effect at lower concentrations but stimulated denitrification potential rates at higher concentrations. Based on observed changes in the nitrogen loss in the microcosm experiments, floating treatment wetland mesocosms were enriched with 1000 µg L-1 of the antibiotic mixture. Rates of nitrate-N loss observed in mesocosms with the veterinary antibiotic enrichment were consistent with the microcosm experiments in that denitrification was not inhibited, even at the high dosage. In the mesocosm experiments, average nitrate-N removal rates were not found to be impacted by the veterinary antibiotics. Further, veterinary antibiotics were primarily found in the roots of the floating treatment wetland biomass, accumulating approximately 190 mg m-2 of the antibiotic mixture. These findings provide new insight into the impact that veterinary antibiotic mixtures may have on nutrient management strategies for large-scale agricultural operations and the potential for veterinary antibiotic removal in these wetlands.

Isolated, Proximal Tibiofibular Injuries in Athletic Patients: A Critical Analysis Review.

While infrequently reported, isolated injuries to the proximal tibiofibular (TF) joint primarily occur in young, athletic patients participating in sporting activities requiring explosive, high-impact movements, increasing the risk for potential twisting injuries, especially across a hyperflexed knee. The proximal TF joint is stabilized by bony, muscular and ligamentous structures, including both the anterior and posterior proximal TF complexes, with the anterior complex providing more robust stability. Proximal TF injuries frequently involve anterior and lateral displacement of the proximal fibula relative to its native articulation with the tibia. Proper diagnosis is dependent on careful and meticulous history and physical examination, as missed injuries are common, leading to the potential for continued pain, weakness and disability, especially in athletic patients. While spontaneous joint reduction has been reported, injuries may require formal closed reduction, with irreducible and chronic injuries requiring open reduction and stabilization, with recent investigations reporting satisfactory outcomes following anatomic reconstruction of the proximal TF ligament.

Relationship between Kinesiophobia and Dynamic Postural Stability after Anterior Cruciate Ligament Reconstruction: A Prospective Cohort Study.

INTRODUCTION: Anterior cruciate ligament (ACL) injuries in young, active patients generally require ACL reconstruction (ACLR) to restore mechanical and postural stability. The fear of movement or reinjury (kinesiophobia) has become increasingly recognized in the post-ACLR population; however, the association between restoration of postural stability and kinesiophobia remains largely unknown. The purpose of this study was to investigate changes in mean Tampa Scale of Kinesiophobia-11 (TSK-11), dynamic motion analysis (DMA) scores, and time on the testing platform, as well as any correlation between TSK-11 and mean overall and individual translational and rotational DMA scores during the first 12 months following ACLR. DESIGN: Cohort study. METHODS: Patients undergoing ACLR were prospectively enrolled and dynamic postural stability and kinesiophobia based on the TSK-11 were collected within 2 days prior to surgery and at 6 and 12 months following ACLR. Dynamic postural stability was quantified by calculating a DMA score, with score calculated in three translational (anterior/posterior [AP], up/down [UD], medial/lateral [ML]) and three rotational (left/right [LR], flexion/extension, and internal/external rotation) independent planes of motions. Correlations between DMA and TSK-11 scores at each time point were analyzed. RESULTS: A total of 25 patients meeting inclusion criteria were analyzed. Mean overall DMA and TSK-11 scores increased with each successive testing interval. At 6-month follow-up, a weakly positive association between TSK-11 and DMA scores was appreciated based on overall DMA, AP, UD, ML, and LR. At 12 months, a moderately positive correlation was appreciated between TSK-11 and the translational, but not rotational, planes of motion. CONCLUSIONS: Following ACLR, lower level of kinesiophobia were found to be moderately associated with improved dynamic stability, especially in the translation planes of motion.

(Phenoxyimine)nickel-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross-Coupling: Evidence for a Recovering Radical Chain Mechanism.

Phenoxyimine (FI)-nickel(II)(2-tolyl)(DMAP) compounds were synthesized and evaluated as precatalysts for the C(sp2)-C(sp3) Suzuki-Miyaura cross coupling of (hetero)arylboronic acids with alkyl bromides. With 5 mol % of the optimal (MeOMeFI)Ni(Aryl)(DMAP) precatalyst, the scope of the cross-coupling reaction was established and included a variety of (hetero)arylboronic acids and alkyl bromides (>50 examples, 33-97% yield). A ß-hydride elimination-reductive elimination sequence from reaction with potassium isopropoxide base, yielding a potassium (FI)nickel(0)ate, was identified as a catalyst activation pathway that is responsible for halogen atom abstraction from the alkyl bromide. A combination of NMR and EPR spectroscopies identified (FI)nickel(II)-aryl complexes as the resting state during catalysis with no evidence for long-lived organic radical or odd-electron nickel intermediates. These data establish that the radical chain is short-lived and undergoes facile termination and also support a "recovering radical chain" process whereby the (FI)nickel(II)-aryl compound continually (re)initiates the radical chain. Kinetic studies established that the rate of C(sp2)-C(sp3) product formation was proportional to the concentration of the (FI)nickel(II)-aryl resting state that captures the alkyl radical for chain propagation. The proposed mechanism involves two key and concurrently operating catalytic cycles; the first involving a nickel(I/II/III) radical propagation cycle consisting of radical capture at (FI)nickel(II)-aryl, C(sp2)-C(sp3) reductive elimination, bromine atom abstraction from C(sp3)-Br, and transmetalation; and the second involving an off-cycle catalyst recovery process by slow (FI)nickel(II)-aryl → (FI)nickel(0)ate conversion for nickel(I) regeneration.

Most Anterior Cruciate Ligament Injuries in Professional Athletes Occur Without Contact to the Injured Knee: A Systematic Review of Video Analysis Studies.

PURPOSE: To systematically review studies using video analyses to evaluate anterior cruciate ligament (ACL) injury mechanisms in athletes during sport to better understand risk factors and the potential for injury prevention. METHODS: A literature search was conducted in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines statement using SCOPUS, PubMed, Medline, and the Cochrane Central Register for Controlled Trials from database inception through June 2023. Inclusion criteria included studies reporting on ACL injury mechanisms occurring in athletes based on video analysis. Athlete demographics, injury mechanisms, position of the lower extremity, and activity at the time of injury were recorded. RESULTS: A total of 13 studies, consisting of 542 athletes, met inclusion criteria. Most athletes competed at the professional level (91%, n = 495/542), with 79% (n = 422/536) of athletes being male. The most common sports were soccer (33%, n = 178/542) and American football (26%, n = 140/542). The most common injury mechanism was noncontact in 42.9% (n = 230/536) of athletes, followed by indirect contact (32.6%, n = 175/536) and direct contact (22.4%, n = 120/536). The most common position of injury was with a planted foot (91.7%, n = 110/120), full or near-full knee extension (84.4%, n = 49/58), and axial loading (81.3%, n = 87/107). Injuries commonly involved a deceleration/shift in momentum (50.4%, n = 123/244) or pivoting maneuver (36.1%, n = 77/213). At the time of injury, the knee commonly fell into valgus (76.8%, n = 225/293) with associated internal (53.5%, n = 46/86) or external tibiofemoral rotation (57.7%, n = 101/175). CONCLUSIONS: Most ACL injuries, when evaluated by video analysis, involve professional athletes participating in soccer and American football. The most common injury mechanism occurred without contact with the knee in extension during a deceleration or momentum shift, with resultant valgus and rotational force across the knee. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.

Effects of Charge Sequence Pattern and Lysine-to-Arginine Substitution on the Structural Stability of Bioinspired Polyampholytes.

A comprehensive study focusing on the combined influence of the charge sequence pattern and the type of positively charged amino acids on the formation of secondary structures in sequence-specific polyampholytes is presented. The sequences of interest consisting exclusively of ionizable amino acids (lysine, K; arginine, R; and glutamic acid, E) are (EKEK)5, (EKKE)5, (ERER)5, (ERRE)5, and (EKER)5. The stability of the secondary structure was examined at three pH values in the presence of urea and NaCl. The results presented here underscore the combined prominent effects of the charge sequence pattern and the type of positively charged monomers on secondary structure formation. Additionally, (ERRE)5 readily aggregated across a wide range of pH. In contrast, sequences with the same charge pattern, (EKKE)5, as well as the sequences with the equivalent amino acid content, (ERER)5, exhibited no aggregate formation under equivalent pH and concentration conditions.

Six Square Miles of Urban America: Association Between Firearm Discharge, Injury, and Fatality.

BACKGROUND: Despite the increase in firearm injury observed across the country, significant gaps remain relevant to our understanding of how firearm exposure translates to injury. Using acoustic gunshot detection and a collaborative hospital and law enforcement firearm injury database, we sought to identify the relationship between firearm discharge and injury over time. STUDY DESIGN: From 2018-2021, instances of firearm discharge captured via acoustic detection in six-square miles of Louisville, KY was merged with data from the collaborative firearm injury database. Key outcomes included the total number of rounds fired, injury and fatality rates per round, and the percentage of rounds discharged from automatic weapons and high-capacity magazines. RESULTS: Over the study period, 54,397 rounds of ammunition were discharged resulting in 914 injuries, 435 hospital admissions, 2,442 hospital days, 155 emergent operations, and 180 fatalities. For each round of ammunition fired, the risk of injury and fatality was 1.7% and 0.3% respectively. The total number of rounds fired per month nearly tripled (614 vs. 1,623, p < 0.001) leading to increased injury (15 vs. 37, p < 0.001) and fatality (3 vs. 7, p < 0.001). The percentage of rounds fired from automatic weapons (0 vs. 6.8%, p < 0.001) and high-capacity magazines (7.6 vs. 28.9%, p < 0.001) increased over time. CONCLUSIONS: The increased burden of firearm injury is related to an overall increase in firearm exposure as measured by the total number of rounds discharged. High-capacity magazines and automatic weaponry are being used with increasing frequency in urban American.

Ligand Field Sensitive Spin Acceleration in the Iron-Catalyzed [2 + 2] Cycloaddition of Unactivated Alkenes and Dienes.

Redox-active pyridine(diimine) (PDI) iron catalysts promote the reversible [2 + 2] cycloaddition of alkenes and dienes to cyclobutane derivatives that have applications ranging from fuels to chemically recyclable polymers. Metallacycles were identified as key intermediates, and spin crossover from the singlet to the triplet surface was calculated to facilitate the reductive coupling step responsible for the formation of the four-membered ring. In this work, a series of sterically and electronically differentiated PDI ligands was studied for the [2 + 2] cycloaddition of ethylene and butadiene to vinylcyclobutane. Kinetic studies revealed that the fastest and slowest turnover were observed with equally electron-deficient supporting ligands that either feature phenyl-substituted imine carbon atoms (MeBPDI) or a pyrazine core (MePZDI). While the oxidative cyclization was comparatively slow for both catalysts, the rate of reductive coupling─determined by stoichiometric 13C2H4 labeling studies─correlated with the turnover frequencies. Two-state density functional theory studies and the distinct electronic structures of related (iPrBPDI) and (iPrPZDI) iron methyl complexes revealed significantly different ligand field strengths due to either diminished ligand σ-donation (MeBPDI) or promoted metal π-backbonding (MePZDI). Spin acceleration, leading to fast reductive coupling and catalytic turnover, was promoted in the case of the weaker ligand field and depends on both the nature and position of the electron-withdrawing group. This study provides strong evidence for the role of two-state reactivity in C(sp3)-C(sp3) bond formation and insights on how ligand design either promotes or inhibits spin acceleration in earth-abundant metal catalysis.

Trabectedin Enhances Oncolytic Virotherapy by Reducing Barriers to Virus Spread and Cytotoxic Immunity in Preclinical Pediatric Bone Sarcoma.

We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular anti-viral response which increases viral transcript spread throughout the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing immunosuppressive macrophages and stimulating granzyme expression in infiltrating T and NK cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

Monkey Prefrontal Cortex Learns to Minimize Sequence Prediction Error.

In this study, we develop a novel recurrent neural network (RNN) model of pre-frontal cortex that predicts sensory inputs, actions, and outcomes at the next time step. Synaptic weights in the model are adjusted to minimize sequence prediction error, adapting a deep learning rule similar to those of large language models. The model, called Sequence Prediction Error Learning (SPEL), is a simple RNN that predicts world state at the next time step, but that differs from standard RNNs by using its own prediction errors from the previous state predictions as inputs to the hidden units of the network. We show that the time course of sequence prediction errors generated by the model closely matched the activity time courses of populations of neurons in macaque prefrontal cortex. Hidden units in the model responded to combinations of task variables and exhibited sensitivity to changing stimulus probability in ways that closely resembled monkey prefrontal neurons. Moreover, the model generated prolonged response times to infrequent, unexpected events as did monkeys. The results suggest that prefrontal cortex may generate internal models of the temporal structure of the world even during tasks that do not explicitly depend on temporal expectation, using a sequence prediction error minimization learning rule to do so. As such, the SPEL model provides a unified, general-purpose theoretical framework for modeling the lateral prefrontal cortex.

Contemporary Management and Outcomes of Veterans Hospitalized With Alcohol Withdrawal: A Multicenter Retrospective Cohort Study.

OBJECTIVES: Few studies describe contemporary alcohol withdrawal management in hospitalized settings or review current practices considering the guidelines by the American Society of Addiction Medicine (ASAM). METHODS: We conducted a retrospective cohort study of patients hospitalized with alcohol withdrawal on medical or surgical wards in 19 Veteran Health Administration (VHA) hospitals between October 1, 2018, and September 30, 2019. Demographic and comorbidity data were obtained from the Veteran Health Administration Corporate Data Warehouse. Inpatient management and hospital outcomes were obtained by chart review. Factors associated with treatment duration and complicated withdrawal were examined. RESULTS: Of the 594 patients included in this study, 51% were managed with symptom-triggered therapy alone, 26% with fixed dose plus symptom-triggered therapy, 10% with front loading regimens plus symptom-triggered therapy, and 3% with fixed dose alone. The most common medication given was lorazepam (87%) followed by chlordiazepoxide (33%), diazepam (14%), and phenobarbital (6%). Symptom-triggered therapy alone (relative risk [RR], 0.68; 95% confidence interval [CI], 0.57-0.80) and front loading with symptom-triggered therapy (RR, 0.75; 95% CI, 0.62-0.92) were associated with reduced treatment duration. Lorazepam (RR, 1.20; 95% CI, 1.02-1.41) and phenobarbital (RR, 1.28; 95% CI, 1.06-1.54) were associated with increased treatment duration. Lorazepam (adjusted odds ratio, 4.30; 95% CI, 1.05-17.63) and phenobarbital (adjusted odds ratio, 6.51; 95% CI, 2.08-20.40) were also associated with complicated withdrawal. CONCLUSIONS: Overall, our results support guidelines by the ASAM to manage patients with long-acting benzodiazepines using symptom-triggered therapy. Health care systems that are using shorter acting benzodiazepines and fixed-dose regimens should consider updating alcohol withdrawal management pathways to follow ASAM recommendations.

Degenerative Meniscus Tears Treated Nonoperatively With Platelet-Rich Plasma Yield Variable Clinical and Imaging Outcomes: A Systematic Review.

Purpose: To perform a systematic review on clinical and radiologic outcomes for meniscus tears treated nonoperatively with platelet-rich plasma (PRP). Methods: A literature search was performed according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using keywords and Boolean operators in SCOPUS, PubMed, Medline, and the Cochrane Central Register for Controlled Trials in April 2023. Inclusion criteria were limited to Level I to IV human studies reporting on outcomes of meniscus tears treated nonoperatively with PRP. Results: A total of 6 studies, consisting of 184 patients, were identified. There was 1 Level I study and 5 Level IV studies. Mean patient age was 47.8 ± 7.9 years, with 62% (n = 114/184) being female. The medial meniscus was treated in 95.7% (n = 157/164) of patients. Mean follow-up ranged from 75.9 days to 31.9 months. Meniscus tears were generally described as chronic, degenerative, or intrasubstance. In 4 studies, magnetic resonance imaging revealed variable improvement in meniscus grade with complete healing in 0% to 44% of patients and partial healing in 0% to 40% of patients. Four of 5 studies reported significant statistical improvement in pain from baseline to final follow-up. Studies reporting on clinical outcomes showed significant improvements Lysholm score (2 studies), Knee injury and Osteoarthritis Outcome Score total score (2 studies), and Tegner score (1 study). Successful return to sport occurred in 60% to 100% of patients. Two studies reported that most patients were either very satisfied or satisfied following treatment. Conclusions: The use of PRP injections for the treatment of meniscus tears led to variable results based on postoperative magnetic resonance evaluation and improvements in clinical outcomes, although the clinical significance remains unclear. The heterogeneity of PRP protocols, short-term follow-up, and lack of comparative studies limit findings. Level of Evidence: Level IV, systematic review of Level I to IV studies.