Quantifying the risk of spillover reduction programs for human health.

Reducing spillover of zoonotic pathogens is an appealing approach to preventing human disease and minimizing the risk of future epidemics and pandemics. Although the immediate human health benefit of reducing spillover is clear, over time, spillover reduction could lead to counterintuitive negative consequences for human health. Here, we use mathematical models and computer simulations to explore the conditions under which unanticipated consequences of spillover reduction can occur in systems where the severity of disease increases with age at infection. Our results demonstrate that, because the average age at infection increases as spillover is reduced, programs that reduce spillover can actually increase population-level disease burden if the clinical severity of infection increases sufficiently rapidly with age. If, however, immunity wanes over time and reinfection is possible, our results reveal that negative health impacts of spillover reduction become substantially less likely. When our model is parameterized using published data on Lassa virus in West Africa, it predicts that negative health outcomes are possible, but likely to be restricted to a small subset of populations where spillover is unusually intense. Together, our results suggest that adverse consequences of spillover reduction programs are unlikely but that the public health gains observed immediately after spillover reduction may fade over time as the age structure of immunity gradually re-equilibrates to a reduced force of infection.

Synthetic, self-oscillating vocal fold models for voice production researcha).

Sound for the human voice is produced by vocal fold flow-induced vibration and involves a complex coupling between flow dynamics, tissue motion, and acoustics. Over the past three decades, synthetic, self-oscillating vocal fold models have played an increasingly important role in the study of these complex physical interactions. In particular, two types of models have been established: "membranous" vocal fold models, such as a water-filled latex tube, and "elastic solid" models, such as ultrasoft silicone formed into a vocal fold-like shape and in some cases with multiple layers of differing stiffness to mimic the human vocal fold tissue structure. In this review, the designs, capabilities, and limitations of these two types of models are presented. Considerations unique to the implementation of elastic solid models, including fabrication processes and materials, are discussed. Applications in which these models have been used to study the underlying mechanical principles that govern phonation are surveyed, and experimental techniques and configurations are reviewed. Finally, recommendations for continued development of these models for even more lifelike response and clinical relevance are summarized.

Personal and professional development activity tracking in a pharmacy curriculum.

BACKGROUND AND PURPOSE: Personal and professional development (PPD) is an essential focus of pharmacy school curriculum in developing future pharmacists. This manuscript describes the creation, implementation, and data collection of a PPD Activity Tracker in a pharmacy curriculum. EDUCATIONAL ACTIVITY AND SETTING: Previously, in "Standards 2016" and currently in "Standards 2025", colleges of pharmacy are tasked with documenting how students achieve PPD throughout their academic careers. Therefore, the PPD course directors developed a PPD Activities Tracker to provide student pharmacists a central location to document curriculum and co-curricular activities as they matriculate through the pharmacy program. The tracker was created using an electronic survey platform. Eleven activity categories were established, and students noted whether the activity was directed toward personal and/or professional development. The purpose of the tracker was to create a repository for student documentation of their PPD-promoting experiences and to provide a mechanism for individual and cohort reporting for assessment and accreditation. FINDINGS: Student pharmacists from two class cohorts entered 3254 PPD activities into the tracker over a two-year period. All PPD categories were tracked with the highest attended activities, including personal development & self-care (19%) and self-reflection (19%); the next highest category was interprofessional education/collaboration (15%). Students noted that most PPD activities enhanced their personal and professional development (49%), while personal development only and professional development only were 31% and 19%, respectively. The students "highly recommended" (72%) most tracked PPD activities, while 26% of activities were "recommended." Individual student and class cohort data were also readily accessible. SUMMARY: The PPD tracker created a central, easily accessible, and organized storehouse for successfully collecting curricular and co-curricular PPD activities throughout the student pharmacist's career. The data from this tracker could easily be collected and sorted individually as a class cohort or for an individual student pharmacist.

CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer.

BACKGROUND: Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates. METHODS: The activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry. Effects of CDKI-73 on prostate cancer cells were determined by cell-based assays, molecular profiling and transcriptomic/epigenomic approaches. RESULTS: CDKI-73 inhibited proliferation and enhanced cell death in diverse in vitro and in vivo models of androgen receptor (AR)-driven and AR-independent models. Mechanistically, CDKI-73-mediated inhibition of RNA polymerase II serine 2 phosphorylation resulted in reduced expression of BCL-2 anti-apoptotic factors and transcriptional defects. Transcriptomic and epigenomic approaches revealed that CDKI-73 suppressed signaling pathways regulated by AR, MYC, and BRD4, key drivers of dysregulated transcription in prostate cancer, and reprogrammed cancer-associated super-enhancers. These latter findings prompted the evaluation of CDKI-73 with the BRD4 inhibitor AZD5153, a combination that was synergistic in patient-derived organoids and in vivo. CONCLUSION: Our work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.

Longitudinal Study of Cognitive Function in People with HIV and Toxoplasmic Encephalitis or Latent toxoplasma Infection.

BACKGROUND: Neurocognitive impairment (NCI) may occur during and persist even after recovery from HIV-related CNS co-infections such as toxoplasmic encephalitis (TE). The long-term cognitive effects of TE and latent toxoplomasmic infections (LTI) among persons with HIV (PWH) are unknown. We measured longitudinal effects on NC functioning in PWH with TE compared to LTI or no toxoplasmal infection. METHODS: PWH (n = 345) followed in two longitudinal cohort studies underwent comprehensive neurocognitive assessments and an anti-Toxoplamic IgG assay. Participants were classified into one of three groups: TE+ (n = 39), LTI+ (n = 34), LTI- (n = 272). The primary outcome was change in neurocognitive function between baseline and 7-year visit. RESULTS: The mean age was 48 ±â€Š11 years, mean educational level 13 ±â€Š3 years, and 13% were female. TE+ patients were less likely to have undetectable viral loads (≤50 copies/mL) and had lower absolute CD4 counts. The TE+ group had the highest prevalence of NCI globally and in domains of verbal, executive function, learning, recall, working memory, processing speed and motor at baseline and at 7-year follow-up. Changes in longitudinal NC function over 7 years were small and did not differ significantly among all groups, except that speed of information processing improved more in TE+ compared with LTI- participants. CONCLUSIONS: PWH with a history of TE had cognitive impairment over a broad range of severity at both baseline and last follow-up. Changes in cognition from baseline to last examination in all groups were minimal and did not differ significantly among the groups with the exception of speed of information processing.

An Approach to Successful Development of Clinician-Scientists in Neurology: The NINDS R25 Experience.

OBJECTIVE: Training clinician-scientists is a primary objective of many academic neurology departments, as these individuals are uniquely positioned to perform insightful clinical or laboratory-based research informed both by clinical knowledge and their own experiences caring for patients. Despite its importance, training clinician-scientists has perhaps never been so challenging. The National Institute of Neurologic Disorders and Stroke (NINDS) R25 program was designed in an attempt to support these individuals, decrease the time needed to obtain National Institutes of Health K awards, and to help educate a cohort of trainees preparing for a career in academic neurology. We endeavored to describe the structure and features of the program while examining its outcomes. METHODS: R25 outcome data from 2009 to 2024 were reviewed. Statistical comparisons were made using 2-sided Mann-Whitney U testing. RESULTS: A total of 67% of adult neurologists who received an R25 had a successful application for a National Institutes of Health K award compared with 45% of adult neurologists who had not received R25 support (p < 0.0001). Among child neurologists, 73% who applied went on to receive K funding after R25 support, compared with 45% who had not been part of the R25 program (p < 0.001). The average time between completion of residency and obtaining a K award for R25 participants was decreased by 26 months among those with an MD/PhD degree, and 32 months for those with an MD degree compared with non-R25 individuals. INTERPRETATION: The R25 program has been successful in achieving its training goals, but stands as only one component of support for aspiring clinician-scientists. Investments and commitments made by academic neurology departments are key to supporting this success. ANN NEUROL 2024.

Diagnostic Validation of the Updated Pediatric Sepsis Biomarker Risk II for Acute Kidney Injury Prediction Model in Pediatric Septic Shock.

OBJECTIVES: We previously derived the updated Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (PERSEVERE-II AKI) prediction model, which had robust diagnostic test characteristics for severe AKI on day 3 (D3 severe AKI) of septic shock. We now sought to validate this model in an independent cohort of children to the one in which the model was developed. DESIGN: A secondary analysis of a multicenter, prospective, observational study carried out from January 2019 to December 2022. SETTING: Ten PICUs in the United States. PATIENTS: Children with septic shock 1 week to 18 years old admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Seventy-nine of 363 patients (22%) had D3 severe AKI, defined as Kidney Disease Improving Global Outcomes stage 2 or higher. Patients were assigned a probability of D3 severe AKI using the PERSEVERE-II AKI model. The model predicted D3 severe AKI with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.85-0.93), sensitivity of 77% (95% CI, 66-86%), specificity of 88% (95% CI, 84-92%), positive predictive value of 65% (95% CI, 54-74%), and negative predictive value of 93% (95% CI, 89-96%). These data represent an increase in post-test probability of D3 severe AKI with a positive test from 22% to 65%, and a prevalence threshold of 28%. On multivariable regression, the PERSEVERE-II AKI prediction model demonstrated greater adjusted odds ratio (aOR) for D3 severe AKI (aOR, 11.2; 95% CI, 4.9-25.3) and lesser aOR for failure of D3 renal recovery from early AKI (aOR, 0.31; 95% CI, 0.13-0.69). CONCLUSIONS: The PERSEVERE-II AKI model demonstrates consistently robust performance for prediction of new or persistent D3 severe AKI in children with septic shock. A major limitation is that actual D3 severe AKI prevalence is below the prevalence threshold for the test, and thus future work should focus on evaluating use in enriched populations.

Revisiting the Posterior Approach for Cervical Radiculopathy Utilizing Endoscopic Techniques: A Favorable Short-Term Outcome and Cost Comparison With Anterior Cervical Discectomy and Fusion.

BACKGROUND: Cervical radiculopathy is a spine ailment frequently requiring surgical decompression via anterior cervical discectomy and fusion (ACDF) or posterior foraminotomy/discectomy. While endoscopic posterior foraminotomy/discectomy is gaining popularity, its financial impact remains understudied despite equivalent randomized long-term outcomes to ACDF. In a cohort of patients undergoing ACDF vs endoscopic posterior cervical foraminotomy/discectomy, we sought to compare the total cost of the surgical episode while confirming an equivalent safety profile and perioperative outcomes. METHODS: A single-center retrospective cohort study of patients with unilateral cervical radiculopathy undergoing ACDF or endoscopic cervical foraminotomy between 2018 and 2023 was undertaken. Primary outcomes included the total cost of care for the initial surgical episode (not charges or reimbursement). Perioperative variables and neurological recovery were recorded. Multivariable analysis tested age, body mass index, race, gender, insurance type, operative time, and length of stay. RESULTS: A total of 38 ACDF and 17 endoscopic foraminotomy/discectomy operations were performed. All patients underwent single-level surgery except for 2 two-level endoscopic decompressions. No differences were found in baseline characteristics and symptom length except for younger age (46.8 ± 9.4 vs 57.6 ± 10.3, P = 0.002) and more smokers (18.4% vs 11.8%, P = 0.043) in the ACDF group. Actual hospital costs for the episode of surgical care were markedly higher in the ACDF cohort (mean ±95% CI; $27,782 ± $2011 vs $10,103 ± $720, P < 0.001) driven by the ACDF approach (ß = $17,723, P < 0.001) on multivariable analysis. On sensitivity analysis, ACDF was never cost-efficient compared with endoscopic foraminotomy, and endoscopic failure rates of 64% were required for break-even cost. ACDF was associated with significantly longer operative time (167.7 ± 22.0 vs 142.7 ± 27.4 minutes, P < 0.001) and length of stay (1.1 ± 0.5 vs 0.1 ± 0.2 days, P < 0.001). No significant difference was found regarding 90-day neurological improvement, readmission, reoperation, or complications. CONCLUSION: Compared with patients treated with a single-level ACDF for unilateral cervical radiculopathy, endoscopic posterior cervical foraminotomy/discectomy can achieve a similar safety profile, pain relief, and neurological recovery at considerably less cost. These findings may help patients and surgeons revisit offering the posterior cervical foraminotomy/discectomy utilizing endoscopic techniques. CLINICAL RELEVANCE: Endoscopic posterior cervical foraminotomy/discectomy offers comparable safety, pain relief, and neurological recovery to traditional methods but at a significantly lower cost.

Untangling the pseudoknots of SARS-CoV-2: Insights into structural heterogeneity and plasticity.

Since the onset of the COVID-19 pandemic, one productive area of research has focused on the intricate two- and three-dimensional structures taken on by SARS-CoV-2's RNA genome. These structures control essential viral processes, making them tempting targets for therapeutic intervention. This review focuses on two such structured regions, the frameshift stimulation element (FSE), which controls the translation of viral protein, and the 3' untranslated region (3' UTR), which is thought to regulate genome replication. For the FSE, we discuss its canonical pseudoknot's threaded and unthreaded topologies, as well as the diversity of competing two-dimensional structures formed by local and long-distance base pairing. For the 3' UTR, we review the evidence both for and against the formation of its replication-enabling pseudoknot.

Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation.

OBJECTIVES: Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with MASH. Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcription and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation. METHODS: We examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre + Cc1fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts. RESULTS: LratCre + Cc1fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HSCs. This was inhibited by nicotinic acid treatment which blunted the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1. CONCLUSIONS: Loss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.

Open Versus Endoscopic Approach for Thoracic Disk Herniations: Equivalent Short-Term Outcomes With Significantly Different Costs.

BACKGROUND AND OBJECTIVES: Open thoracic diskectomy often requires significant bone resection and fusion, whereas an endoscopic thoracic diskectomy offers a less invasive alternative. Therefore, we sought to compare one-level open vs endoscopic thoracic diskectomy regarding (1) perioperative outcomes, (2) neurological recovery, and (3) total cost. METHODS: A single-center, retrospective, cohort study using prospectively collected data of patients undergoing one-level thoracic diskectomy was undertaken from 2018 to 2023. The primary exposure variable was open vs endoscopic. The primary outcome was perioperative outcomes and neurological recovery. Secondary outcomes were total cost of care. Multivariable regression analysis controlled for age, body mass index, sex, symptom onset, disk characteristics, operative time, and length of stay. RESULTS: Of 29 patients undergoing thoracic diskectomy, 17 were open and 12 were endoscopic. Preoperative demographics, symptoms, and radiographic findings were comparable between the cohorts. Perioperatively, open surgery had significantly higher mean length of stay (4.9 ± 1.5 vs 0.0 ± 0.0 days, P < .001), median (IQR) longer operative time (342.8 [68.4] vs 141.5 [36] minutes, P < .001), and more blood loss (350 [390] vs 6.5 [20] mL; P < .001). 16 (94%) open patients required fusion vs 0 endoscopic (P < .001). Postoperative opioid use (P = .119), readmission (P = .665), reoperation (P = .553), and rate of neurological improvement (P > .999) were similar between the 2 groups. Financially, open surgical median costs were 7x higher than endoscopic ($59 792 [$16 118] vs $8128 [$1848]; P < .001), driven by length of stay (ß = $2261/night, P < .001), open surgery (ß = $24 106, P < .001), and number of pedicle screws (ß = $1829/screw, P = .002) on multivariable analysis. On sensitivity analysis, open surgery was never cost-efficient against endoscopic surgery and excess endoscopic revision rates of 86% above open revision rates were required for break-even costs between the surgical approaches. CONCLUSION: Endoscopic thoracic diskectomy was associated with decreased length of stay, operative time, blood loss, and total cost compared with the open approach, with similar neurological outcomes. These findings may help patients and surgeons seek endoscopic approach as a less morbid and less costly alternative.

The impacts of positive selection on genomic variation in Drosophila serrata: Insights from a deep learning approach.

This study explores the impact of positive selection on the genetic composition of a Drosophila serrata population in eastern Australia through a comprehensive analysis of 110 whole genome sequences. Utilizing an advanced deep learning algorithm (partialS/HIC) and a range of inferred demographic histories, we identified that approximately 14% of the genome is directly affected by sweeps, with soft sweeps being more prevalent (10.6%) than hard sweeps (2.1%), and partial sweeps being uncommon (1.3%). The algorithm demonstrated robustness to demographic assumptions in classifying complete sweeps but faced challenges in distinguishing neutral regions from partial sweeps and linked regions under demographic misspecification. The findings reveal the indirect influence of sweeps on nearly two-thirds of the genome through linkage, with an over-representation of putatively deleterious variants suggesting that positive selection drags deleterious variants to higher frequency due to hitchhiking with beneficial loci. Gene ontology enrichment analysis further supported our confidence in the accuracy of sweep detection as several traits expected to be under positive selection due to evolutionary arms races (e.g. immunity) were detected in hard sweeps. This study provides valuable insights into the direct and indirect contributions of positive selection in shaping genomic variation in natural populations.

Discovery and Quantification of Long-Range RNA Base Pairs in Coronavirus Genomes with SEARCH-MaP and SEISMIC-RNA.

RNA molecules perform a diversity of essential functions for which their linear sequences must fold into higher-order structures. Techniques including crystallography and cryogenic electron microscopy have revealed 3D structures of ribosomal, transfer, and other well-structured RNAs; while chemical probing with sequencing facilitates secondary structure modeling of any RNAs of interest, even within cells. Ongoing efforts continue increasing the accuracy, resolution, and ability to distinguish coexisting alternative structures. However, no method can discover and quantify alternative structures with base pairs spanning arbitrarily long distances - an obstacle for studying viral, messenger, and long noncoding RNAs, which may form long-range base pairs. Here, we introduce the method of Structure Ensemble Ablation by Reverse Complement Hybridization with Mutational Profiling (SEARCH-MaP) and software for Structure Ensemble Inference by Sequencing, Mutation Identification, and Clustering of RNA (SEISMIC-RNA). We use SEARCH-MaP and SEISMIC-RNA to discover that the frameshift stimulating element of SARS coronavirus 2 base-pairs with another element 1 kilobase downstream in nearly half of RNA molecules, and that this structure competes with a pseudoknot that stimulates ribosomal frameshifting. Moreover, we identify long-range base pairs involving the frameshift stimulating element in other coronaviruses including SARS coronavirus 1 and transmissible gastroenteritis virus, and model the full genomic secondary structure of the latter. These findings suggest that long-range base pairs are common in coronaviruses and may regulate ribosomal frameshifting, which is essential for viral RNA synthesis. We anticipate that SEARCH-MaP will enable solving many RNA structure ensembles that have eluded characterization, thereby enhancing our general understanding of RNA structures and their functions. SEISMIC-RNA, software for analyzing mutational profiling data at any scale, could power future studies on RNA structure and is available on GitHub and the Python Package Index.

Distinct mitochondrial respiration profiles in pediatric patients with febrile illness versus sepsis.

OBJECTIVE: Mitochondrial dysfunction, linked to sepsis-related organ failure, is unknown in febrile illness. METHODS: Prospective study of children in an Emergency Department (ED) with febrile illness or without infection (ED controls); secondary analysis of ICU patients with sepsis or without infection (ICU controls). Mitochondrial oxygen consumption measured in peripheral blood mononuclear cells using respirometry, with primary outcome of spare respiratory capacity (SRC). Mitochondrial content measured as citrate synthase (CS: febrile illness and ED controls) and mitochondrial to nuclear DNA ratio (mtDNA:nDNA: all groups). RESULTS: SRC was lower in febrile illness (6.7 ± 3.0 pmol/sec/106 cells) and sepsis (5.7 ± 4.7) than ED/PICU controls (8.5 ± 3.7; both p < 0.05), but not different between febrile illness and sepsis (p = 0.26). Low SRC was driven by increased basal respiration in febrile illness and decreased maximal uncoupled respiration in sepsis. Differences were no longer significant after adjustment for patient demographics. Febrile illness demonstrated lower CS activity than ED controls (p = 0.07) and lower mtDNA:nDNA than both ED/PICU controls and sepsis (both p < 0.05). CONCLUSION: Mitochondrial SRC was reduced in both febrile illness and sepsis, but due to distinct mitochondrial profiles and impacted by demographics. Further work is needed to determine if mitochondrial profiles could differentiate febrile illness from early sepsis. IMPACT STATEMENT: Mitochondrial dysfunction has been linked to organ failure in sepsis, but whether mitochondrial alterations are evident in febrile illness without sepsis is unknown. In our study, while mitochondrial spare respiratory capacity (SRC), an index of cellular bioenergetic reserve under stress, was reduced in children with both febrile illness and sepsis compared to children without infections, low SRC was driven by increased basal respiration in febrile illness compared with decreased maximal uncoupled respiration in sepsis. Additional research is needed to understand if distinct mitochondrial profiles could be used to differentiate febrile illness from early sepsis in children.

The value of long-term ecological research for evolutionary insights.

Scientists must have an integrative understanding of ecology and evolution across spatial and temporal scales to predict how species will respond to global change. Although comprehensively investigating these processes in nature is challenging, the infrastructure and data from long-term ecological research networks can support cross-disciplinary investigations. We propose using these networks to advance our understanding of fundamental evolutionary processes and responses to global change. For ecologists, we outline how long-term ecological experiments can be expanded for evolutionary inquiry, and for evolutionary biologists, we illustrate how observed long-term ecological patterns may motivate new evolutionary questions. We advocate for collaborative, multi-site investigations and discuss barriers to conducting evolutionary work at network sites. Ultimately, these networks offer valuable information and opportunities to improve predictions of species' responses to global change.

Clinical Effectiveness of Anterior Cervical Discectomy and Fusion Using Tritanium C Anterior Cervical Cage vs. PEEK Cage.

Introduction: Anterior cervical discectomy and fusion (ACDF) has proven to be a clinically efficient and cost-effective method for treating patients with degenerative cervical spine conditions. New intervertebral implant products are being developed to improve fusion and stability while decreasing complications. This study assesses the effectiveness of Tritanium C (Tri-C) Anterior Cervical Cage (Stryker) in the treatment of degenerative disk disease (DDD) of the cervical spine compared with polyetheretherketone (PEEK) cages. Methods: A retrospective cohort analysis was conducted using data prospectively collected from two institutions. Patients who underwent ACDFs for DDD using either the Tri-C cage or PEEK cage were identified. The patients' demographics, comorbidities, operative variables, and baseline patient-reported outcomes (PROs) were collected. PROs included the Neck Disability Index (NDI) and numeric rating scale (NRS) for neck and arm pain. The primary outcomes included 3- and 12-month PROs as well as the rates of 90-day readmission, 90-day reoperation, and perioperative complication. The radiographic outcomes included rates of subsidence, cage movement, and successful fusion within 12 months. Multivariate linear regression models were run to identify variables predictive of 12-month PROs. Results: A total of 275 patients who underwent ACDF were included in this study and were divided into two groups: PEEK (n=213) and Tri-C (n=62). Both groups showed improvement in neck and arm pain and NDI postoperatively. When Tri-C and PEEK were compared, no significant differences were observed in the 3- or 12-month changes in neck or arm pain or NDI. Furthermore, there were no differences in the rates of 90-day readmission, 90-day reoperation, and perioperative complication. Regression analysis revealed that Tri-C vs. PEEK was not a significant predictor of any outcome. Conclusions: Our results indicate that the use of porous titanium Tri-C cage during ACDFs is an effective method for managing cervical DDD in terms of PROs, perioperative morbidity, and radiologic parameters. No significant difference was observed in any clinical outcome between patients undergoing ACDF using the Tri-C cage and those in whom the PEEK cage was used. Level of Evidence: III.

Reflex Xpert MTB/XDR Testing of Residual Rifampicin-Resistant Specimens: A Clinical Laboratory-Based Diagnostic Accuracy and Feasibility Study in South Africa.

Background: The World Health Organization-approved Xpert MTB/XDR test detects Mycobacterium tuberculosis and resistance to isoniazid, fluoroquinolones, ethionamide, and injectable drugs directly in specimens. This pragmatic, laboratory-based study assessed the diagnostic accuracy and feasibility of a reflex testing approach, where Xpert MTB/XDR was performed on residual specimens previously processed for Xpert MTB/RIF Ultra. Methods: Routine respiratory specimens, processed for Xpert MTB/RIF Ultra, were stored in sample reagent buffer at 2°C-8°C. If rifampicin resistant, the residual specimen was assessed for adequate volume (≥2 mL) and tested with Xpert MTB/XDR, with storage time recorded. A second specimen was used for routine and reference standard testing (culture and sequencing). Results: Specimens (99% sputum) from 763 participants submitted to 2 large routine laboratories were included. Xpert MTB/XDR yielded valid resistance detection results in 639 (84%), compared with 507 (66%) for routine testing (difference [95% CI], 18% [13%-22%]). The median turnaround time for results was 23 hours for Xpert MTB/XDR and 15 days for routine testing. While 748 specimens (98%) were ≥2 mL, only 102 (13%) were stored for ≤4 hours. By the reference standard, 284 of 394 (72%) were isoniazid resistant, and 57 of 380 (15%) were fluroquinolone resistant. The sensitivities of Xpert MTB/XDR were 94% (95% CI, 91%-97%) for isoniazid and 91% (81%-97%) for fluoroquinolone resistance detection. The specificities were 98% (94%-100%) and 100% (98%-100%), respectively. Conclusions: Xpert MTB/XDR performed favorably compared with the reference, and the reflex testing approach increased results availability over routine testing, while dramatically decreasing turnaround time from weeks to hours. Laboratory workflow precluded testing within the manufacturer-recommended 4-hour storage time, but longer storage did not appear detrimental.

Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes.

BACKGROUND: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches. METHODS: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme. RESULTS: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes. CONCLUSIONS: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

Management of Central Airway Obstruction: An American College of Chest Physicians Clinical Practice Guideline.

BACKGROUND: Central airway obstruction (CAO), seen in a variety of malignant and non-malignant airway disorders, is associated with a poor prognosis. The management of CAO is dependent on provider training and local resources, which may make the clinical approach and outcomes highly variable. We reviewed the current literature and provided evidence-based recommendations for the management of CAO. METHODS: A multidisciplinary expert panel developed key questions using the PICO (Patient, Intervention, Comparator, and Outcomes) format and conducted a systematic literature search using MEDLINE (PubMed) and the Cochrane Library. The panel screened references for inclusion and used vetted evaluation tools to assess the quality of included studies and extract data, and graded the level of evidence supporting each recommendation. A modified Delphi technique was used to reach consensus on recommendations. RESULTS: A total of 9,688 abstracts were reviewed, 150 full-text articles were assessed, and 31 studies were included in the analysis. One good practice statement and 10 graded recommendations were developed. The overall certainty of evidence was very low. CONCLUSIONS: Therapeutic bronchoscopy can improve the symptoms, quality of life, and survival of patients with malignant and non-malignant CAO. Multi-modality therapeutic options, including rigid bronchoscopy with general anesthesia, tumor/tissue debridement, ablation, dilation, and stent placement, should be utilized when appropriate. Therapeutic options and outcomes are dependent on the underlying etiology of CAO. A multidisciplinary approach and shared decision-making with the patient are strongly encouraged.

Neighborhood Resources Associated With Psychological Trajectories and Neural Reactivity to Reward After Trauma.

Importance: Research on resilience after trauma has often focused on individual-level factors (eg, ability to cope with adversity) and overlooked influential neighborhood-level factors that may help mitigate the development of posttraumatic stress disorder (PTSD). Objective: To investigate whether an interaction between residential greenspace and self-reported individual resources was associated with a resilient PTSD trajectory (ie, low/no symptoms) and to test if the association between greenspace and PTSD trajectory was mediated by neural reactivity to reward. Design, Setting, and Participants: As part of a longitudinal cohort study, trauma survivors were recruited from emergency departments across the US. Two weeks after trauma, a subset of participants underwent functional magnetic resonance imaging during a monetary reward task. Study data were analyzed from January to November 2023. Exposures: Residential greenspace within a 100-m buffer of each participant's home address was derived from satellite imagery and quantified using the Normalized Difference Vegetation Index and perceived individual resources measured by the Connor-Davidson Resilience Scale (CD-RISC). Main Outcome and Measures: PTSD symptom severity measured at 2 weeks, 8 weeks, 3 months, and 6 months after trauma. Neural responses to monetary reward in reward-related regions (ie, amygdala, nucleus accumbens, orbitofrontal cortex) was a secondary outcome. Covariates included both geocoded (eg, area deprivation index) and self-reported characteristics (eg, childhood maltreatment, income). Results: In 2597 trauma survivors (mean [SD] age, 36.5 [13.4] years; 1637 female [63%]; 1304 non-Hispanic Black [50.2%], 289 Hispanic [11.1%], 901 non-Hispanic White [34.7%], 93 non-Hispanic other race [3.6%], and 10 missing/unreported [0.4%]), 6 PTSD trajectories (resilient, nonremitting high, nonremitting moderate, slow recovery, rapid recovery, delayed) were identified through latent-class mixed-effect modeling. Multinominal logistic regressions revealed that for individuals with higher CD-RISC scores, greenspace was associated with a greater likelihood of assignment in a resilient trajectory compared with nonremitting high (Wald z test = -3.92; P < .001), nonremitting moderate (Wald z test = -2.24; P = .03), or slow recovery (Wald z test = -2.27; P = .02) classes. Greenspace was also associated with greater neural reactivity to reward in the amygdala (n = 288; t277 = 2.83; adjusted P value = 0.02); however, reward reactivity did not differ by PTSD trajectory. Conclusions and Relevance: In this cohort study, greenspace and self-reported individual resources were significantly associated with PTSD trajectories. These findings suggest that factors at multiple ecological levels may contribute to the likelihood of resiliency to PTSD after trauma.