Post-traumatic lipid inclusion cyst.

Post-traumatic lipid inclusion cysts are a rare entity seen following fractures in paediatric patients. They often occur in the distal radius, developing 1-3 months following an extra-articular fracture. Although benign and self-limiting in nature, adequate awareness and accurate radiographic interpretation is key in avoiding further unnecessary non-invasive or invasive investigations. We report on a case of post-traumatic lipid inclusion cyst and review the literature.

Disaggregating trends in alcohol involvement among Hispanic, Black, and White female and male U.S. adolescents: 2002 to 2019.

OBJECTIVE: Alcohol involvement is declining among U.S. adolescents, however studies examining population-level trends in alcohol involvement among females and males from diverse racial and ethnic backgrounds are scarce. Therefore, the current study examined alcohol involvement from 2002 to 2019 among Hispanic, Black, and White U.S. adolescent females and males. METHOD: Data were from the National Survey on Drug Use and Health, years 2002-2019. Participants were between 12 to 17 years old and Hispanic, non-Hispanic Black, or non-Hispanic White. Annualized change estimates within each subgroup were analyzed separately for four alcohol variables: 1) lifetime alcohol use; 2) age at alcohol initiation; 3) past-year drinking days; 4) respondent's perceived risk of alcohol misuse. RESULTS: Lifetime alcohol use decreased for all groups, and the decrease was strongest for Hispanic males. Age at alcohol initiation similarly increased for Hispanic and White females and males, with no change in age at alcohol initiation for Black adolescents. Past-year drinking days declined for all groups but was not significant for Black females. Perceiving alcohol misuse as a "great risk" increased only for Hispanic males and females. CONCLUSIONS: Although alcohol involvement is declining among U.S. adolescents, results from this study highlight that engaging with alcohol is normative among many adolescent groups. Also, when considering sex as well as race and ethnicity, there are important distinctions in patterns of decline in alcohol involvement that should be accounted for to inform future research and screening.

Modeling epithelial homeostasis and perturbation in three-dimensional human esophageal organoids.

Background: Esophageal organoids from a variety of pathologies including cancer are grown in Advanced Dulbecco's Modified Eagle Medium-Nutrient Mixture F12 (hereafter ADF). However, the currently available ADF-based formulations are suboptimal for normal human esophageal organoids, limiting the ability to compare normal esophageal organoids with those representing a given disease state. Methods: We have utilized immortalized normal human esophageal epithelial cell (keratinocyte) lines EPC1 and EPC2 and endoscopic normal esophageal biopsies to generate three-dimensional (3D) organoids. To optimize ADF-based medium, we evaluated the requirement of exogenous epidermal growth factor (EGF) and inhibition of transforming growth factor-(TGF)-ß receptor-mediated signaling, both key regulators of proliferation of human esophageal keratinocytes. We have modeled human esophageal epithelial pathology by stimulating esophageal 3D organoids with interleukin (IL)-13, an inflammatory cytokine, or UAB30, a novel pharmacological activator of retinoic acid signaling. Results: The formation of normal human esophageal 3D organoids was limited by excessive EGF and intrinsic TGFß receptor-mediated signaling. In optimized HOME0, normal human esophageal organoid formation was improved, whereas IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis. Conclusions: HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media.

ACR Appropriateness Criteria® Urinary Tract Infection-Child: 2023 Update.

Urinary tract infection (UTI) is a frequent infection in childhood. The diagnosis is usually made by history and physical examination and confirmed by urine analysis. Cystitis is infection or inflammation confined to the bladder, whereas pyelonephritis is infection or inflammation of kidneys. Pyelonephritis can cause renal scarring, which is the most severe long-term sequela of UTI and can lead to accelerated nephrosclerosis, leading to hypertension and chronic renal failure. The role of imaging is to guide treatment by identifying patients who are at high risk to develop recurrent UTIs or renal scarring. This document provides initial imaging guidelines for children presenting with first febrile UTI with appropriate response to medical management, atypical or recurrent febrile UTI, and follow-up imaging for children with established vesicoureteral reflux. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Mesial temporal lobe spiking reveals distinct patterns of blood oxygen level-dependent functional magnetic resonance imaging activation using simultaneous intracranial electroencephalography-functional magnetic resonance imaging.

OBJECTIVE: Temporal lobe epilepsy (TLE) has a high probability of becoming drug resistant and is frequently considered for surgical intervention. However, 30% of TLE cases have nonlesional magnetic resonance imaging (MRI) scans, which is associated with worse surgical outcomes. Characterizing interactions between temporal and extratemporal structures in these patients may help understand these poor outcomes. Simultaneous intracranial electroencephalography-functional MRI (iEEG-fMRI) can measure the hemodynamic changes associated with interictal epileptiform discharges (IEDs) recorded directly from the brain. This study was designed to characterize the whole brain patterns of IED-associated fMRI activation recorded exclusively from the mesial temporal lobes of patients with nonlesional TLE. METHODS: Eighteen patients with nonlesional TLE undergoing iEEG monitoring with mesial temporal IEDs underwent simultaneous iEEG-fMRI at 3 T. IEDs were marked, and statistically significant clusters of fMRI activation were identified. The locations of IED-associated fMRI activation for each patient were determined, and patients were grouped based on the location and pattern of fMRI activation. RESULTS: Two patterns of IED-associated fMRI activation emerged: primarily localized (n = 7), where activation was primarily located within the ipsilateral temporal lobe, and primarily diffuse (n = 11), where widespread bilateral extratemporal activation was detected. The primarily diffuse group reported significantly fewer focal to bilateral tonic-clonic seizures and had better postsurgical outcomes. SIGNIFICANCE: Simultaneous iEEG-fMRI can measure the hemodynamic changes associated with focal IEDs not visible on scalp EEG, such as those arising from the mesial temporal lobe. Significant fMRI activation associated with these IEDs was observed in all patients. Two distinct patterns of IED-associated activation were seen: primarily localized to the ipsilateral temporal lobe and more widespread, bilateral activation. Patients with widespread IED associated-activation had fewer focal to bilateral tonic-clonic seizures and better postsurgical outcome, which may suggest a neuroprotective mechanism limiting the spread of ictal events.

DEVELOPING A THROMBOELASTOGRAPHY ASSAY IN ELASMOBRANCHS.

Thromboelastography (TEG) is a hemostatic assay evaluating clot initiation time, kinetics, strength, and extent of fibrinolysis. Hemostatic assays in nonmammalian species have been less extensively studied because of lack of taxon-specific reagents and unique physiology. Hemostatic or hemorrhagic disease has been described postmortem in elasmobranchs, but antemortem detection of coagulopathies is limited in this taxon. The study aimed to establish an elasmobranch TEG protocol to improve hemostatic evaluation and facilitate advanced treatment options for animals under human care. Multiple clotting initiators were assessed for efficacy with frozen-thawed citrated plasma, fresh citrated plasma, and fresh whole citrated blood: RapidTEGTM, citrated kaolin, Reptilase®, and species brain-derived thromboplastin prepared by two different methods. Initial evaluation found plasma samples clot inconsistently, but TEG analyses using fresh whole blood consistently led to measurable TEG reactions using multiple clotting initiators. The most reliable elasmobranch TEG results were observed using citrated fresh whole blood and the RapidTEG clot initiation reagent.

QM/MM Simulations of Afatinib-EGFR Addition: The Role of ß-Dimethylaminomethyl Substitution.

Acrylamides are the most commonly used warheads of targeted covalent inhibitors (TCIs) directed at cysteines; however, the reaction mechanisms of acrylamides in proteins remain controversial, particularly for those involving protonated or unreactive cysteines. Using the combined semiempirical quantum mechanics (QM)/molecular mechanics (MM) free energy simulations, we investigated the reaction between afatinib, the first TCI drug for cancer treatment, and Cys797 in the EGFR kinase. Afatinib contains a ß-dimethylaminomethyl (ß-DMAM) substitution which has been shown to enhance the intrinsic reactivity and potency against EGFR for related inhibitors. Two hypothesized reaction mechanisms were tested. Our data suggest that Cys797 becomes deprotonated in the presence of afatinib, and the reaction proceeds via a classical Michael addition mechanism, with Asp800 stabilizing the ion-pair reactant state ß-DMAM+/C797- and the transition state of the nucleophilic attack. Our work elucidates an important structure-activity relationship of acrylamides in proteins.

The immune response behind peptide vaccination in diffuse midline glioma.

A first-in-human trial demonstrated that a vaccine targeting the histone mutation H3K27M can induce an immune response, in a mutation-specific manner, in patients with diffuse midline glioma. In a recent study by Boschert et al., the same group now dissects the functional immune response triggered after effective vaccination of one of the patients, who has been in remission for over 3 years. The H3K27M peptide vaccine, named H3-vac, induces a CD4+ T-cell-specific immune response in this patient and expands the repertoire of polyclonal H3K27M-specific T-cell receptors. A clonal H3K27M-reactive B-cell population was also detected in the patient's cerebrospinal fluid. Importantly, the immune response is induced across various human leukocyte antigen alleleotypes, indicating the potential efficacy of the vaccine in diverse populations. By exploring in detail the immune response linked to this patient's long-term survival, the authors prove peptide vaccinations as a viable therapeutic approach. This paves the way for personalised therapies harnessing immunogenic T- and B-cell responses against different tumour types.

Electrocochleography-Based Tonotopic Map: II. Frequency-to-Place Mismatch Impacts Speech-Perception Outcomes in Cochlear Implant Recipients.

OBJECTIVES: Modern cochlear implants (CIs) use varying-length electrode arrays inserted at varying insertion angles within variably sized cochleae. Thus, there exists an opportunity to enhance CI performance, particularly in postlinguistic adults, by optimizing the frequency-to-place allocation for electrical stimulation, thereby minimizing the need for central adaptation and plasticity. There has been interest in applying Greenwood or Stakhovskaya et al. function (describing the tonotopic map) to postoperative imaging of electrodes to improve frequency allocation and place coding. Acoustically-evoked electrocochleography (ECochG) allows for electrophysiologic best-frequency (BF) determination of CI electrodes and the potential for creating a personalized frequency allocation function. The objective of this study was to investigate the correlation between early speech-perception performance and frequency-to-place mismatch. DESIGN: This retrospective study included 50 patients who received a slim perimodiolar electrode array. Following electrode insertion, five acoustic pure-tone stimuli ranging from 0.25 to 2 kHz were presented, and electrophysiological measurements were collected across all 22 electrode contacts. Cochlear microphonic tuning curves were subsequently generated for each stimulus frequency to ascertain the BF electrode or the location corresponding to the maximum response amplitude. Subsequently, we calculated the difference between the stimulus frequency and the patient's CI map's actual frequency allocation at each BF electrode, reflecting the frequency-to-place mismatch. BF electrocochleography-total response (BF-ECochG-TR), a measure of cochlear health, was also evaluated for each subject to control for the known impact of this measure on performance. RESULTS: Our findings showed a moderate correlation (r = 0.51; 95% confidence interval: 0.23 to 0.76) between the cumulative frequency-to-place mismatch, as determined using the ECochG-derived BF map (utilizing 500, 1000, and 2000 Hz), and 3-month performance on consonant-nucleus-consonant words (N = 38). Larger positive mismatches, shifted basal from the BF map, led to enhanced speech perception. Incorporating BF-ECochG-TR, total mismatch, and their interaction in a multivariate model explained 62% of the variance in consonant-nucleus-consonant word scores at 3 months. BF-ECochG-TR as a standalone predictor tended to overestimate performance for subjects with larger negative total mismatches and underestimated the performance for those with larger positive total mismatches. Neither cochlear diameter, number of cochlear turns, nor apical insertion angle accounted for the variability in total mismatch. CONCLUSIONS: Comparison of ECochG-BF derived tonotopic electrode maps to the frequency allocation tables reveals substantial mismatch, explaining 26.0% of the variability in CI performance in quiet. Closer examination of the mismatch shows that basally shifted maps at high frequencies demonstrate superior performance at 3 months compared with those with apically shifted maps (toward Greenwood and Stakhovskaya et al.). The implications of these results suggest that electrophysiological-based frequency reallocation might lead to enhanced speech-perception performance, especially when compared with conventional manufacturer maps or anatomic-based mapping strategies. Future research, exploring the prospective use of ECochG-based mapping techniques for frequency allocation is underway.

The structure of the monobactam-producing thioesterase domain of SulM forms a unique complex with the upstream carrier protein domain.

Nonribosomal peptide synthetases (NRPSs) are responsible for the production of important biologically active peptides. The large, multidomain NRPSs operate through an assembly line strategy in which the growing peptide is tethered to carrier domains that deliver the intermediates to neighboring catalytic domains. While most NRPS domains catalyze standard chemistry of amino acid activation, peptide bond formation and product release, some canonical NRPS catalytic domains promote unexpected chemistry. The paradigm monobactam antibiotic sulfazecin is produced through the activity of a terminal thioesterase domain of SulM, which catalyzes an unusual ß-lactam forming reaction in which the nitrogen of the C-terminal N-sulfo-2,3-diaminopropionate residue attacks its thioester tether to release the monobactam product. We have determined the structure of the thioesterase domain as both a free-standing domain and a didomain complex with the upstream holo peptidyl-carrier domain. The position of variant lid helices results in an active site pocket that is quite constrained, a feature that is likely necessary to orient the substrate properly for ß-lactam formation. Modeling of a sulfazecin tripeptide into the active site identifies a plausible binding mode identifying potential interactions for the sulfamate and the peptide backbone with Arg2849 and Asn2819, respectively. The overall structure is similar to the ß-lactone forming thioesterase domain that is responsible for similar ring closure in the production of obafluorin. We further use these insights to enable bioinformatic analysis to identify additional, uncharacterized ß-lactam-forming biosynthetic gene clusters by genome mining.

Pre-intervention wait time and survival in people with rheumatic heart disease in Uganda.

BACKGROUND: There is an unmet surgical burden among people living with rheumatic heart disease (RHD) in Uganda. Nevertheless, risk factors associated with time to first intervention and preoperative mortality is poorly understood. METHODS: Individuals with RHD who met indications for valve surgery were identified using the Uganda National RHD Registry (Jan. 2010- Aug. 2022). Kaplan-Meier estimates and multivariable Cox proportional hazard models were utilized. RESULTS: 64% of the cohort with clinical RHD (1452 of 2269) met criteria for index operation. Of those, 13.5% obtained surgical intervention while 30.6% died before surgery. The estimated likelihood of first surgery was 50% at 9.3 years of follow up (95% CI 8.1-upper limit not reached). Intervention was more likely in men vs. women (hazard ratio [HR] 1.78; 95% CI 1.21-2.64), those with post-secondary education vs. primary school or less (HR 3.60; 95% CI 1.88-6.89), and those with history of atrial fibrillation (HR 2.78; 95% CI 1.63-4.76). Surgery was less likely for adults (vs. those <18 years; HR 0.49; 95% CI 0.32-0.77) and those with NYHA class III/IV (vs. I/II; HR 0.51; 95% CI 0.32-0.83). The median preoperative survival time among those awaiting surgery was 4.6 years (95% CI, 3.9-5.7). History of infective endocarditis, RV dysfunction, pericardial effusion, atrial fibrillation, and having surgical indications for multiple valves were associated with increased mortality. CONCLUSIONS: Our analysis revealed a prolonged time to first surgical intervention and high pre-intervention mortality for RHD in Uganda, with factors such as age, sex, and education level remaining barriers to obtaining surgery.

Association of EEG characteristics with outcomes following pediatric ICU cardiac arrest: A secondary analysis of the ICU-RESUScitation trial.

BACKGROUND AND OBJECTIVES: There are limited tools available following cardiac arrest to prognosticate neurologic outcomes. Prior retrospective and single center studies have demonstrated early EEG features are associated with neurologic outcome. This study aimed to evaluate the prognostic value of EEG for pediatric in-hospital cardiac arrest (IHCA) in a prospective, multicenter study. METHODS: This cohort study is a secondary analysis of the ICU-Resuscitation trial, a multicenter randomized interventional trial conducted at 18 pediatric and pediatric cardiac ICUs in the United States. Patients who achieved return of circulation (ROC) and had post-ROC EEG monitoring were eligible for inclusion. Patients < 90 days old and those with pre-arrest Pediatric Cerebral Performance Category (PCPC) scores > 3 were excluded. EEG features of interest included EEG Background Category, and presence of focal abnormalities, sleep spindles, variability, reactivity, periodic and rhythmic patterns, and seizures. The primary outcome was survival to hospital discharge with favorable neurologic outcome. Associations between EEG features and outcomes were assessed with multivariable logistic regression. Prediction models with and without EEG Background Category were developed and receiver operator characteristic curves compared. RESULTS: Of the 1129 patients with an index cardiac arrest who achieved ROC in the parent study, 261 had EEG within 24 h of ROC, of which 151 were evaluable. The cohort included 57% males with a median age of 1.1 years (IQR 0.4, 6.8). EEG features including EEG Background Category, sleep spindles, variability, and reactivity were associated with survival with favorable outcome and survival, (all p < 0.001). The addition of EEG Background Category to clinical models including age category, illness category, PRISM score, duration of CPR, first documented rhythm, highest early post-arrest arterial lactate improved the prediction accuracy achieving an AUROC of 0.84 (CI 0.77-0.92), compared to AUROC of 0.76 (CI 0.67-0.85) (p = 0.005) without EEG Background Category. CONCLUSION: This multicenter study demonstrates the value of EEG, in the first 24 h following ROC, for predicting survival with favorable outcome after a pediatric IHCA.

In vivo editing of lung stem cells for durable gene correction in mice.

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.

Expectation of pain and relief: A dynamical model of the neural basis for pain-trauma co-morbidity.

Posttraumatic Stress Disorder (PTSD) is highly co-morbid with chronic pain conditions. When present, PTSD significantly worsens chronic pain outcomes. Likewise, pain contributes to a more severe PTSD as evidenced by greater disability, more frequent use of harmful opioid analgesics and increased pain severity. The biomechanism behind this comorbidity is incompletely understood, however recent work strongly supports the widely-accepted role of expectation, in the entanglement of chronic pain and trauma symptoms. This work has shown that those with trauma have a maladaptive brain response while expecting stress and pain, whereas those with chronic pain may have a notable impairment in brain response while expecting pain relief. This dynamical expectation model of the interaction between neural systems underlying expectation of pain onset (traumatic stress) and pain offset (chronic pain) is biologically viable and may provide a biomechanistic insight into pain-trauma comorbidity. These predictive mechanisms work through interoceptive pathways in the brain critically the insula cortex. Here we highlight how the neural expectation-related mechanisms augment the existing models of pain and trauma to better understand the dynamics of pain and trauma comorbidity. These ideas will point to targeted complementary clinical approaches, based on mechanistically separable neural biophenotypes for the entanglement of chronic pain and trauma symptoms.

Emergent robot-to-open conversion - Multidisciplinary simulation training in crisis management.

Anticipating and addressing unexpected intraoperative events and anatomies are some of the most challenging aspects of pediatric urologic practice; uncontrolled hemorrhage is one of the most anxiety provoking and precarious. The increasing application of the robotic platform in pediatric urology adds another layer of complexity as surgeons are not immediately at the patient's bedside. Should hemorrhage occur in robotic cases, clear communication and seamless coordination between members of the operating room team are paramount to optimize patient safety and minimize errors. This is especially important in pediatric cases for which the margin of error is narrow. Non-technical skills, including leadership, decision-making, situational awareness, stress management, and team-communication, become increasingly critical. While many programs have focused on robotic training, few prepare the operating room team and surgical trainees to manage these unforeseen, emergent intraoperative scenarios. This review discusses the role of a multidisciplinary, in situ robot-to-open conversion simulation program in addressing this educational gap, ways to approach establishing these programs, and potential barriers.

International Consensus Statements on Intraoperative Testing for Cochlear Implantation Surgery.

OBJECTIVES: A wide variety of intraoperative tests are available in cochlear implantation. However, no consensus exists on which tests constitute the minimum necessary battery. We assembled an international panel of clinical experts to develop, refine, and vote upon a set of core consensus statements. DESIGN: A literature review was used to identify intraoperative tests currently used in the field and draft a set of provisional statements. For statement evaluation and refinement, we used a modified Delphi consensus panel structure. Multiple interactive rounds of voting, evaluation, and feedback were conducted to achieve convergence. RESULTS: Twenty-nine provisional statements were included in the original draft. In the first voting round, consensus was reached on 15 statements. Of the 14 statements that did not reach consensus, 12 were revised based on feedback provided by the expert practitioners, and 2 were eliminated. In the second voting round, 10 of the 12 revised statements reached a consensus. The two statements which did not achieve consensus were further revised and subjected to a third voting round. However, both statements failed to achieve consensus in the third round. In addition, during the final revision, one more statement was decided to be deleted due to overlap with another modified statement. CONCLUSIONS: A final core set of 24 consensus statements was generated, covering wide areas of intraoperative testing during CI surgery. These statements may provide utility as evidence-based guidelines to improve quality and achieve uniformity of surgical practice.

The Bead Maze Hand Function Test for Children.

IMPORTANCE: There is a need for a pediatric hand function test that can be used to objectively assess movement quality. We have developed a toy-based test, the Bead Maze Hand Function (BMHF) test, to quantify how well a child performs an activity. This is achieved by assessing the control of forces applied while drawing a bead over wires of different complexity. OBJECTIVE: To study the psychometric properties of the BMHF test and understand the influence of age and task complexity on test measures. DESIGN: A cross-sectional, observational study performed in a single visit. SETTING: Clinical research laboratory. PARTICIPANTS: Twenty-three participants (ages 4-15 yr) were recruited locally. They were typically developing children with no illness or conditions that affected their movement. Interventions/Assessments: Participants performed the BMHF test and the Box and Block test with both hands. OUTCOMES AND MEASURES: Total force and completion time were examined according to age and task complexity using a linear mixed-effects model. We calculated intraclass correlation coefficients to measure interrater reliability of the method and estimated concurrent validity using the Box and Block test. RESULTS: Total force and completion time decreased with age and depended on task complexity. The total force was more sensitive to task complexity. The Box and Block score was associated with BMHF completion time but not with total force. We found excellent interrater reliability. CONCLUSIONS AND RELEVANCE: A familiar toy equipped with hidden sensors provides a sensitive tool to assess a child's typical hand function. Plain-Language Summary: We developed the Bead Maze Hand Function (BMHF) test to determine how well a child performs an activity with their hands. The BMHF test is a toy equipped with hidden sensors. Twenty-three typically developing children with no illnesses or conditions that affected their hand movement participated in the study. We asked the children to perform the BMHF test with both hands. Our study found that occupational therapists can reliably use the BMHF test to assess a child's hand function.

Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.

BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown. METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles. RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively. CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).

Influenza virus infection exacerbates gene expression related to neurocognitive dysfunction in brains of old mice.

BACKGROUND: Age > 65 years is a key risk factor for poor outcomes after human influenza infection. Specifically, in addition to respiratory disease, non-neurotropic influenza A virus (IAV) causes neuro-cognitive complications, e.g. new onset depression and increases the risk of dementia after hospitalization. This study aimed to identify potential mechanisms of these effects by determining differences between young and old mice in brain gene expression in a mouse model of non-neurotropic IAV infection. METHODS: Young (12 weeks) and old (70 weeks) C57Bl/6J mice were inoculated intranasally with 200 PFU H1N1 A/PR/34/8 (PR8) or sterile PBS (mock). Gene expression in lung and brain was measured by qRT-PCR and normalized to ß-actin. Findings were confirmed using the nCounter Mouse Neuroinflammation Array (NanoString) and analyzed with nSolver 4.0 and Ingenuity Pathway Analysis (IPA, Qiagen). RESULTS: IAV PR8 did not invade the central nervous system. Young and old mice differed significantly in brain gene expression at baseline and during non-neurotropic IAV infection. Expression of brain Ifnl, Irf7, and Tnf mRNAs was upregulated over baseline control at 3 days post-infection (p.i.) only in young mice, but old mice expressed more Ifnl than young mice 7 days p.i. Gene arrays showed down-regulation of the Epigenetic Regulation, Insulin Signaling, and Neurons and Neurotransmission pathways in old mice 3 days p.i. while young mice demonstrated no change or induction of these pathways at the same time point. IPA revealed marked baseline differences between old and young mice. Gene expression related to Cognitive Impairment, Memory Deficits and Learning worsened in old mice relative to young mice during IAV infection. Aged mice demonstrate more severe changes in gene expression related to memory loss and cognitive dysfunction by IPA. CONCLUSIONS: These data suggest the genes and pathways related to learning and cognitive performance that were worse at baseline in old mice were further worsened by IAV infection, similar to old patients. Early events in the brain triggered by IAV infection portend downstream neurocognitive pathology in old adults.