Hip Osteoarthritis in Patients Undergoing Surgery for Severe Adult Spinal Deformity: Prevalence and Impact on Spine Surgery Outcomes.

BACKGROUND: Hip osteoarthritis (OA) is common in patients with adult spinal deformity (ASD). Limited data exist on the prevalence of hip OA in patients with ASD, or on its impact on baseline and postoperative alignment and patient-reported outcome measures (PROMs). Therefore, this paper will assess the prevalence and impact of hip OA on alignment and PROMs. METHODS: Patients with ASD who underwent L1-pelvis or longer fusions were included. Two independent reviewers graded hip OA with the Kellgren-Lawrence (KL) classification and stratified it by severity into non-severe (KL grade 1 or 2) and severe (KL grade 3 or 4). Radiographic parameters and PROMs were compared among 3 patient groups: Hip-Spine (hip KL grade 3 or 4 bilaterally), Unilateral (UL)-Hip (hip KL grade 3 or 4 unilaterally), or Spine (hip KL grade 1 or 2 bilaterally). RESULTS: Of 520 patients with ASD who met inclusion criteria for an OA prevalence analysis, 34% (177 of 520) had severe bilateral hip OA and unilateral or bilateral hip arthroplasty had been performed in 8.7% (45 of 520). A subset of 165 patients had all data components and were examined: 68 Hip-Spine, 32 UL-Hip, and 65 Spine. Hip-Spine patients were older (67.9 ± 9.5 years, versus 59.6 ± 10.1 years for Spine and 65.8 ± 7.5 years for UL-Hip; p < 0.001) and had a higher frailty index (4.3 ± 2.6, versus 2.7 ± 2.0 for UL-Hip and 2.9 ± 2.0 for Spine; p < 0.001). At 1 year, the groups had similar lumbar lordosis, yet the Hip-Spine patients had a worse sagittal vertebral axis (SVA) measurement (45.9 ± 45.5 mm, versus 25.1 ± 37.1 mm for UL-Hip and 19.0 ± 39.3 mm for Spine; p = 0.001). Hip-Spine patients also had worse Veterans RAND-12 Physical Component Summary scores at baseline (25.7 ± 9.3, versus 28.7 ± 9.8 for UL-Hip and 31.3 ± 10.5 for Spine; p = 0.005) and 1 year postoperatively (34.5 ± 11.4, versus 40.3 ± 10.4 for UL-Hip and 40.1 ± 10.9 for Spine; p = 0.006). CONCLUSIONS: This study of operatively treated ASD revealed that 1 in 3 patients had severe hip OA bilaterally. Such patients with severe bilateral hip OA had worse baseline SVA and PROMs that persisted 1 year following ASD surgery, despite correction of lordosis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Thermal profiles of Cicindelidia haemorrhagica (Coleoptera: Cicindelidae) activity in hot springs in Yellowstone National Park.

The wetsalts tiger beetle, Cicindelidia haemorrhagica (LeConte) (Coleoptera: Cicindelidae), is found in several active thermal hot spring areas in Yellowstone National Park (YNP) where substrate surface temperatures can exceed 50 °C. However, relationships between surface temperatures and the time adults spend on them remain poorly understood. Therefore, we characterized thermal profiles of Dragon Spring and Rabbit Creek, 2 thermally active research sites containing C. haemorrhagica in YNP, to quantify the time adults spend at different surface temperatures. We took 58 thermal video recordings of adults over 6 total days of observation ranging from 10 to 15 min for each adult. Thermal video analysis results indicated a positive relationship between the total time adult beetles spent on surface temperatures from Dragon Spring and Rabbit Creek as temperatures increased from 20 °C. Once surface temperatures exceeded 40 °C, the total time spent at those surface temperatures declined. Adults were recorded on substrates exceeding 50 °C at one of the 2 research locations. Rabbit Creek had substantially more instances of adults present with surface temperatures exceeding 40 °C, including one individual on a surface temperature of 61.5 °C. There were 3 instances of beetles spending more than 4 min at a particular surface temperature, all within the preferred range of 30-40 °C. Our thermal profile results and previous behavioral observations suggest that adults may be resistant to the heat produced from the thermal waters that influence the substrate temperatures but may not be subject to high surface temperatures as previously reported.

Schizophrenia-Like Deficits and Impaired Glutamate/Gamma-aminobutyric acid Homeostasis in Zfp804a Conditional Knockout Mice.

BACKGROUND AND HYPOTHESIS: Zinc finger protein 804A (ZNF804A) was the first genome-wide associated susceptibility gene for schizophrenia (SCZ) and played an essential role in the pathophysiology of SCZ by influencing neurodevelopment regulation, neurite outgrowth, synaptic plasticity, and RNA translational control; however, the exact molecular mechanism remains unclear. STUDY DESIGN: A nervous-system-specific Zfp804a (ZNF804A murine gene) conditional knockout (cKO) mouse model was generated using clustered regularly interspaced short palindromic repeat/Cas9 technology and the Cre/loxP method. RESULTS: Multiple and complex SCZ-like behaviors, such as anxiety, depression, and impaired cognition, were observed in Zfp804a cKO mice. Molecular biological methods and targeted metabolomics assay validated that Zfp804a cKO mice displayed altered SATB2 (a cortical superficial neuron marker) expression in the cortex; aberrant NeuN, cleaved caspase 3, and DLG4 (markers of mature neurons, apoptosis, and postsynapse, respectively) expressions in the hippocampus and a loss of glutamate (Glu)/γ-aminobutyric acid (GABA) homeostasis with abnormal GAD67 (Gad1) expression in the hippocampus. Clozapine partly ameliorated some SCZ-like behaviors, reversed the disequilibrium of the Glu/GABA ratio, and recovered the expression of GAD67 in cKO mice. CONCLUSIONS: Zfp804a cKO mice reproducing SCZ-like pathological and behavioral phenotypes were successfully developed. A novel mechanism was determined in which Zfp804a caused Glu/GABA imbalance and reduced GAD67 expression, which was partly recovered by clozapine treatment. These findings underscore the role of altered gene expression in understanding the pathogenesis of SCZ and provide a reliable SCZ model for future therapeutic interventions and biomarker discovery.

Hormonal differences in perpetrators of intimate partner violence.

Objective: In order to gain a better understanding of the individual and joint impact of testosterone and cortisol on behavior, the present study was developed to test the differences in each hormone alone and conjointly between perpetrators of IPV and non-violent controls. Method: Perpetrators of IPV on probation were compared to a control group of non-aggressive males from Hidalgo County in the Rio Grande Valley on baseline testosterone and cortisol, as well as several relevant questionnaires measuring aggression and trait anger. Differences in cortisol following exposure to a stressful event were also examined. Procedures included two laboratory visits consisting of questionnaires, a number of salivary testosterone and cortisol collections, and exposure to a stressor. Results: Perpetrators had higher basal testosterone and post stressor cortisol levels than non- violent controls as well as a higher T/C ratio. In addition, trait anger moderated the relationship between both testosterone alone, and the testosterone/cortisol ratio and perpetration of IPV. Conclusion: Results are consistent with the hypothesis that testosterone leads to antisocial behavior, including perpetration of violence. The results are also consistent with the dual hormone hypothesis, i.e., that testosterone and cortisol work together to jointly regulate social dominance and aggression. Both the increased freestanding testosterone and the increased cortisol following exposure to stress places these men at risk for perpetrating violence. Clinical implications are discussed.

Diagnosis and Management of Osgood Schlatter Disease.

Osgood Schlatter disease is the inflammation of the tibial tubercle, right below the patella. It is prevalent in athletic adolescents experiencing growth plate maturation due to puberty. This case study highlights the main causes and symptoms of Osgood Schlatter disease (OSD) and relates them to a case about a 10-year-old girl who runs daily and is going through puberty. The authors also discuss recent research regarding OSD, which suggests that OSD will typically conclude after the child stops growing. Surgery is only needed in extreme cases where the growth or inflammation at the tibia continues to push onto the shinbone, even after puberty.

Patient and Caregiver Experience With the Hope and Prognostic Uncertainty of Immunotherapy: A Qualitative Study.

PURPOSE: Immunotherapy has improved survival for patients with melanoma and non-small cell lung cancer (NSCLC). Yet, as responses vary widely, immunotherapy also introduces challenges in prognostic communication. In this study, we sought to explore how patients and caregivers learned about the goal of immunotherapy and their experience of living with uncertainty. MATERIALS AND METHODS: We conducted a qualitative study of patients with stage III or IV melanoma or stage IV NSCLC within 12 weeks of initiating or 12 months of discontinuing immunotherapy, and their caregivers. We conducted in-depth interviews with participants to explore how they learned about immunotherapy from oncology clinicians and how they experienced uncertainty. We used a framework approach to analyze interview transcripts and synthesized concepts into themes. RESULTS: Forty-two patients and 10 caregivers participated; median age was 67 years and most were male (68%), white (95%), married (61%), and had melanoma (62%). We identified four themes: (1) the oncology team shaped participants' hopeful expectations of immunotherapy, including as a potential cure among those with melanoma; (2) distress related to prognostic uncertainty particularly affected patients who experienced toxicity or progressive disease; (3) patients who did not have long-term responses experienced overwhelming disappointment; and (4) some patients and caregivers had conflicting preferences for prognostic information. Participants provided suggestions to improve education and underscored unmet psychosocial needs. CONCLUSION: Patients and caregivers held optimistic expectations of immunotherapy, which resulted in heightened disappointment among the subset with progression or toxicity. Clinicians should elicit information preferences of both patients and caregivers, as these may be disparate. Our results highlight the need to optimize prognostic communication and support for living with uncertainty among patients receiving immunotherapy.

RBM10 loss induces aberrant splicing of cytoskeletal and extracellular matrix mRNAs and promotes metastatic fitness.

RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon-inclusion events included vinculin (VCL), tenascin C (TNC) and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon-inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse Hras G12V /Rbm1O KO thyrocytes develop metastases that are reversed by RBM10 or by combined knockdown of VCL, CD44 and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusions in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFkB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.

The Tobacco Industry Has No Business Funding Continuing Medical Education.

This Viewpoint explores tobacco industry­funded continuing medical education and concerns regarding the precedents this funding sets in relation to commercial bias and influence and conflicts of interest.

What Is the Carbon Footprint of Adult Spinal Deformity Surgery?

Background/Objectives: While the economic cost of adult spinal deformity (ASD) surgery has been studied extensively, its environmental impact is unknown. The aim of this study is to determine the carbon footprint (CF) associated with ASD surgery. Methods: ASD patients who underwent > four levels of corrective surgery between 2017 and 2021 were included. The open group included a posterior-only, single-stage technique, while the minimally invasive surgery (MIS) group was defined as the use of lateral interbody fusion and percutaneous posterior screw fixation. The two groups were propensity-score matched to adjust for baseline demographic, surgical, and radiographic characteristics. Data on all disposables and reusable instruments, anesthetic gas, and non-gas medications used during surgery were collected from medical records. The CF of transporting, using, and disposing of each product and the footprint of energy use in operating rooms were calculated. The CF produced was evaluated using the carbon dioxide equivalent (CO2e), which is relative to the amount of CO2 with an equivalent global warming potential. Results: Of the 175 eligible patients, 15 pairs (65 ± 9 years, 47% female) were properly matched and analyzed for all variables. The average CF generated per case was 147.7 ± 37.3 kg-CO2e, of which 54% was attributable to energy used to sterilize reusable instruments, followed by anesthetic gas released into the environment (17%) and operating room air conditioning (15%). Conclusions: The CF generated during ASD surgery should be reduced using a multidisciplinary approach, taking into account that different surgical procedures have different impacts on carbon emission sources.

Moldable Plastics (Polycaprolactone) can be Acutely Toxic to Developing Zebrafish and Activate Nuclear Receptors in Mammalian Cells.

Popularized on social media, hand-moldable plastics are formed by consumers into tools, trinkets, and dental prosthetics. Despite the anticipated dermal and oral contact, manufacturers share little information with consumers about these materials, which are typically sold as microplastic-sized resin pellets. Inherent to their function, moldable plastics pose a risk of dermal and oral exposure to unknown leachable substances. We analyzed 12 moldable plastics advertised for modeling and dental applications and determined them to be polycaprolactone (PCL) or thermoplastic polyurethane (TPU). The bioactivities of the most popular brands advertised for modeling applications of each type of polymer were evaluated using a zebrafish embryo bioassay. While water-borne exposure to the TPU pellets did not affect the targeted developmental end points at any concentration tested, the PCL pellets were acutely toxic above 1 pellet/mL. The aqueous leachates of the PCL pellets demonstrated similar toxicity. Methanolic extracts from the PCL pellets were assayed for their bioactivity using the Attagene FACTORIAL platform. Of the 69 measured end points, the extracts activated nuclear receptors and transcription factors for xenobiotic metabolism (pregnane X receptor, PXR), lipid metabolism (peroxisome proliferator-activated receptor γ, PPARγ), and oxidative stress (nuclear factor erythroid 2-related factor 2, NRF2). By nontargeted high-resolution comprehensive two-dimensional gas chromatography (GC × GC-HRT), we tentatively identified several compounds in the methanolic extracts, including PCL oligomers, a phenolic antioxidant, and residues of suspected antihydrolysis and cross-linking additives. In a follow-up zebrafish embryo bioassay, because of its stated high purity, biomedical grade PCL was tested to mitigate any confounding effects due to chemical additives in the PCL pellets; it elicited comparable acute toxicity. From these orthogonal and complementary experiments, we suggest that the toxicity was due to oligomers and nanoplastics released from the PCL rather than chemical additives. These results challenge the perceived and assumed inertness of plastics and highlight their multiple sources of toxicity.

BECC-engineered live-attenuated Shigella vaccine candidates display reduced endotoxicity with robust immunogenicity in mice.

Shigella spp. infection contributes significantly to the global disease burden, primarily affecting young children in developing countries. Currently, there are no FDA-approved vaccines against Shigella, and the prevalence of antibiotic resistance is increasing, making therapeutic options limited. Live-attenuated vaccine strains WRSs2 (S. sonnei) and WRSf2G12 (S. flexneri 2a) are highly immunogenic, making them promising vaccine candidates, but possess an inflammatory lipid A structure on their lipopolysaccharide (LPS; also known as endotoxin). Here, we utilized bacterial enzymatic combinatorial chemistry (BECC) to ectopically express lipid A modifying enzymes in WRSs2 and WRSf2G12, as well as their respective wild-type strains, generating targeted lipid A modifications across the Shigella backgrounds. Dephosphorylation of lipid A, rather than deacylation, reduced LPS-induced TLR4 signaling in vitro and dampened endotoxic effects in vivo. These BECC-modified vaccine strains retained the phenotypic traits of their parental strains, such as invasion of epithelial cells and immunogenicity in mice without adverse endotoxicity. Overall, our observations suggest that BECC-engineered live attenuated vaccines are a promising approach to safe and effective Shigella vaccines.

PDX1+ cell budding morphogenesis in a stem cell-derived islet spheroid system.

Remarkable advances in protocol development have been achieved to manufacture insulin-secreting islets from human pluripotent stem cells (hPSCs). Distinct from current approaches, we devised a tunable strategy to generate islet spheroids enriched for major islet cell types by incorporating PDX1+ cell budding morphogenesis into staged differentiation. In this process that appears to mimic normal islet morphogenesis, the differentiating islet spheroids organize with endocrine cells that are intermingled or arranged in a core-mantle architecture, accompanied with functional heterogeneity. Through in vitro modelling of human pancreas development, we illustrate the importance of PDX1 and the requirement for EphB3/4 signaling in eliciting cell budding morphogenesis. Using this new approach, we model Mitchell-Riley syndrome with RFX6 knockout hPSCs illustrating unexpected morphogenesis defects in the differentiation towards islet cells. The tunable differentiation system and stem cell-derived islet models described in this work may facilitate addressing fundamental questions in islet biology and probing human pancreas diseases.

Interpreting the role of antioxidants in vivo: A cautionary tale.

Bacteria have a remarkable ability to sense environmental stresses and to respond to these stressors by adapting their metabolism and physiology. In recent publications, investigators have suggested that multiple stresses that cause cell death share the mechanistic feature of stimulating the formation of reactive oxygen species (ROS). A central piece of evidence cited in these claims is the ability of exogenous antioxidant compounds to mitigate stress-related cell death. The validity of attributing a positive effect of exogenous antioxidants to ROS-mediated stress is challenged by an important study by Korshunov and Imlay in this issue of Molecular Microbiology. This study reports biochemical data that convincingly show that some commonly used antioxidants quench oxidants orders of magnitude too slowly to have a significant effect on the concentration of ROS in the cell. Under conditions where antioxidants minimize cell death, they also slow growth. Significantly, slowing cell growth by other means has the same restorative effect as adding an antioxidant. Based on the solid biochemical and genetic data, Korshunov and Imlay make the case for discarding the use of antioxidants to diagnose conditions that generate increased internal ROS production.

Triptolide and its pro-drug Minnelide target high-risk MYC amplified medulloblastoma in preclinical models.

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic dataset that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor five-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB patients.

Laparoscopy experience in East, Central, and Southern Africa: insights from operative case volume analysis.

BACKGROUND: With the primary objective of addressing the disparity in global surgical care access, the College of Surgeons of East, Central, and Southern Africa (COSECSA) trains surgeons. While sufficient operative experience is crucial for surgical training, the extent of utilization of minimally invasive techniques during COSECSA training remains understudied. METHODS: We conducted an extensive review of COSECSA general surgery trainees' operative case logs from January 1, 2015, to December 31, 2020, focusing on the utilization of minimally invasive surgical procedures. Our primary objective was to determine the prevalence of laparoscopic procedures and compare this to open procedures. We analyzed the distribution of laparoscopic cases across common indications such as cholecystectomy, appendicitis, and hernia operations. Additionally, we examined the impact of trainee autonomy, country development index, and hospital type on laparoscopy utilization. RESULTS: Among 68,659 total cases, only 616 (0.9%) were laparoscopic procedures. Notably, 34 cases were conducted during trainee external rotations in countries like the United Kingdom, Germany, and India. Gallbladder and appendix pathologies were most frequent among the 582 recorded laparoscopic cases performed in Africa. Laparoscopic cholecystectomy accounted for 29% (276 of 975 cases), laparoscopic appendectomy for 3% (76 of 2548 cases), and laparoscopic hernia repairs for 0.5% (26 of 5620 cases). Trainees self-reported lower autonomy for laparoscopic (22.5%) than open cases (61.5%). Laparoscopy usage was more prevalent in upper-middle-income (2.7%) and lower-middle-income countries (0.8%) compared with lower-income countries (0.5%) (p < 0.001). Private (1.6%) and faith-based hospitals (1.5%) showed greater laparoscopy utilization than public hospitals (0.5%) (p < 0.001). CONCLUSIONS: The study highlights the relatively low utilization of minimally invasive techniques in surgical training within the ECSA region. Laparoscopic cases remain a minority, with variations observed based on specific diagnoses. The findings suggest a need to enhance exposure to minimally invasive procedures to ensure well-rounded training and proficiency in these techniques.

Gene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down".

Viral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca2+ sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.

Opening Side of Unilateral Open-Door Laminoplasty Does Not Impact Improvement in Arm Pain or Space Available for the Spinal Cord.

Background/Objectives: There exists limited data guiding open-door laminoplasty. The objective of this study is to determine if open-door laminoplasty affects radiographic decompression or arm pain outcomes. Methods: Adult patients who underwent unilateral open-door laminoplasty cervical myelopathy were included. The side opened was dependent on surgeon discretion. We recorded preoperative side of symptoms, side of radiographic compression, arm pain scores, and canal diameter. Patients with open-side ipsilateral or contralateral to dominant symptoms or compression were compared to determine any effect on arm pain outcomes or spinal canal diameter. If the symptoms were equal bilaterally, patients were neutral. Results: A total of 167 patients were included, with an average age of 64 ± 11 years and average follow-up time of 64.5 ± 72 weeks. The average preoperative arm pain visual analog score (VAS) was 2.13 ± 2.86, and the average arm VAS after 6 months was 1.52 ± 2.68. For dominant symptoms, the ipsilateral, contralateral, and neutral groups had a significant improvement in arm VAS at >6 months postoperatively. For dominant compression, the ipsilateral and contralateral groups had a significant improvement in both arm VASs and canal diameter at >6 months postoperatively. No differences were seen between groups for either. We observed a significant correlation between size of plate and change in canal diameter; however, no differences were noted for arm pain. Conclusions: Laminoplasty may be effective in addressing radicular arm pain by increasing the spinal canal's diameter and space available for the cord. The laterality of open-door laminoplasty did not affect arm pain improvement or canal expansion.

Vaccination with a Protective Ipa Protein-Containing Nanoemulsion Differentially Alters the Transcriptomic Profiles of Young and Elderly Mice following Shigella Infection.

Shigella spp. are responsible for bacillary dysentery or shigellosis transmitted via the fecal-oral route, causing significant morbidity and mortality, especially among vulnerable populations. There are currently no licensed Shigella vaccines. Shigella spp. use a type III secretion system (T3SS) to invade host cells. We have shown that L-DBF, a recombinant fusion of the T3SS needle tip (IpaD) and translocator (IpaB) proteins with the LTA1 subunit of enterotoxigenic E. coli labile toxin, is broadly protective against Shigella spp. challenge in a mouse lethal pulmonary model. Here, we assessed the effect of LDBF, formulated with a unique TLR4 agonist called BECC470 in an oil-in-water emulsion (ME), on the murine immune response in a high-risk population (young and elderly) in response to Shigella challenge. Dual RNA Sequencing captured the transcriptome during Shigella infection in vaccinated and unvaccinated mice. Both age groups were protected by the L-DBF formulation, while younger vaccinated mice exhibited more adaptive immune response gene patterns. This preliminary study provides a step toward identifying the gene expression patterns and regulatory pathways responsible for a protective immune response against Shigella. Furthermore, this study provides a measure of the challenges that need to be addressed when immunizing an aging population.

National Institute of Mental Health Support for Cognitive Treatment Development in Schizophrenia: A Narrative Review.

For several decades the National Institute of Mental Health (NIMH) has supported basic and translational research into cognitive impairment in schizophrenia. This article describes the Institute's ongoing commitment to cognitive assessment and intervention research, as reflected by three signature initiatives-Measurement and Treatment Research to Improve Cognition in Schizophrenia; Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia; and Research Domain Criteria-and related funding announcements that span basic experimental studies, efficacy and comparative effectiveness trials, and implementation research designed to promote cognitive healthcare in real-world treatment settings. We discuss how trends in science and public health policy since the early 2000s have influenced NIMH treatment development activities, resulting in greater attention to (1) inclusive teams that reflect end-user perspectives on the utility of proposed studies; (2) measurement of discrete neurocognitive processes to inform targeted interventions; (3) clinical trials that produce useful information about putative illness mechanisms, promising treatment targets, and downstream clinical effects; and (4) "productive urgency" in pursuing feasible and effective cognitive interventions for psychosis. Programs employing these principles have catalyzed cognitive measurement, drug development, and behavioral intervention approaches that aim to improve neurocognition and community functioning among persons with schizophrenia. NIMH will maintain support for innovative and impactful investigator-initiated research that advances patient-centered, clinically effective, and continuously improving cognitive health care for persons with psychotic disorders.