Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3.

Fetal hematopoietic stem and progenitor cells (HSPCs) hold promise to cure a wide array of hematological diseases, and we previously found a role for the RNA-binding protein (RBP) Lin28b in respecifying adult HSPCs to resemble their fetal counterparts. Here we show by single-cell RNA sequencing that Lin28b alone was insufficient for complete reprogramming of gene expression from the adult toward the fetal pattern. Using proteomics and in situ analyses, we found that Lin28b (and its closely related paralog, Lin28a) directly interacted with Igf2bp3, another RBP, and their enforced co-expression in adult HSPCs reactivated fetal-like B-cell development in vivo more efficiently than either factor alone. In B-cell progenitors, Lin28b and Igf2bp3 jointly stabilized thousands of mRNAs by binding at the same sites, including those of the B-cell regulators Pax5 and Arid3a as well as Igf2bp3 mRNA itself, forming an autoregulatory loop. Our results suggest that Lin28b and Igf2bp3 are at the center of a gene regulatory network that mediates the fetal-adult hematopoietic switch. A method to efficiently generate induced fetal-like hematopoietic stem cells (ifHSCs) will facilitate basic studies of their biology and possibly pave a path toward their clinical application.

The space between notes: emerging roles for translationally silent ribosomes.

In addition to their central functions in translation, ribosomes can adopt inactive structures that are fully assembled yet devoid of mRNA. We describe how the abundance of idle eukaryotic ribosomes is influenced by a broad range of biological conditions spanning viral infection, nutrient deprivation, and developmental cues. Vacant ribosomes may provide a means to exclude ribosomes from translation while also shielding them from degradation, and the variable identity of factors that occlude ribosomes may impart distinct functionality. We propose that regulated changes in the balance of idle and active ribosomes provides a means to fine-tune translation. We provide an overview of idle ribosomes, describe what is known regarding their function, and highlight questions that may clarify their biological roles.

IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer.

CD40 is a central costimulatory receptor implicated in productive antitumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway has demonstrated dose-limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe a role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of transpresented IL-15/IL-15Rα surface complexes, particularly by cross-presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment of activated CD8 T cells. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, although they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, including the fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Collectively, these data reveal an important role for IL-15 in mediating antitumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use of Fc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to develop combinations of these promising therapeutics for the treatment of patients with bladder cancer.

A novel mouse strain optimized for chronic human antibody administration.

Therapeutic human IgG antibodies are routinely tested in mouse models of oncologic, infectious, and autoimmune diseases. However, assessing the efficacy and safety of long-term administration of these agents has been limited by endogenous anti-human IgG immune responses that act to clear human IgG from serum and relevant tissues, thereby reducing their efficacy and contributing to immune complex­mediated pathologies, confounding evaluation of potential toxicity. For this reason, human antibody treatment in mice is generally limited in duration and dosing, thus failing to recapitulate the potential clinical applications of these therapeutics. Here, we report the development of a mouse model that is tolerant of chronic human antibody administration. This model combines both a human IgG1 heavy chain knock-in and a full recapitulation of human Fc receptor (FcγR) expression, providing a unique platform for in vivo testing of human monoclonal antibodies with relevant receptors beyond the short term. Compared to controls, hIgG1 knock-in mice mount minimal anti-human IgG responses, allowing for the persistence of therapeutically active circulating human IgG even in the late stages of treatment in chronic models of immune thrombocytopenic purpura and metastatic melanoma.

Inhibition of Nonsense-Mediated Decay Induces Nociceptive Sensitization through Activation of the Integrated Stress Response.

RNA stability is meticulously controlled. Here, we sought to determine whether an essential post-transcriptional regulatory mechanism plays a role in pain. Nonsense-mediated decay (NMD) safeguards against translation of mRNAs that harbor premature termination codons and controls the stability of ∼10% of typical protein-coding mRNAs. It hinges on the activity of the conserved kinase SMG1. Both SMG1 and its target, UPF1, are expressed in murine DRG sensory neurons. SMG1 protein is present in both the DRG and sciatic nerve. Using high-throughput sequencing, we examined changes in mRNA abundance following inhibition of SMG1. We confirmed multiple NMD stability targets in sensory neurons, including ATF4. ATF4 is preferentially translated during the integrated stress response (ISR). This led us to ask whether suspension of NMD induces the ISR. Inhibition of NMD increased eIF2-α phosphorylation and reduced the abundance of the eIF2-α phosphatase constitutive repressor of eIF2-α phosphorylation. Finally, we examined the effects of SMG1 inhibition on pain-associated behaviors. Peripheral inhibition of SMG1 results in mechanical hypersensitivity in males and females that persists for several days and priming to a subthreshold dose of PGE2. Priming was fully rescued by a small-molecule inhibitor of the ISR. Collectively, our results indicate that suspension of NMD promotes pain through stimulation of the ISR.SIGNIFICANCE STATEMENT Nociceptors undergo long-lived changes in their plasticity which may contribute to chronic pain. Translational regulation has emerged as a dominant mechanism in pain. Here, we investigate the role of a major pathway of RNA surveillance called nonsense-mediated decay (NMD). Modulation of NMD is potentially beneficial for a broad array of diseases caused by frameshift or nonsense mutations. Our results suggest that inhibition of the rate-limiting step of NMD drives behaviors associated with pain through activation of the ISR. This work reveals complex interconnectivity between RNA stability and translational regulation and suggests an important consideration in harnessing the salubrious benefits of NMD disruption.

Disentangling sex-dependent effects of APOE on diverse trajectories of cognitive decline in Alzheimer's disease.

Current diagnostic systems for Alzheimer's disease (AD) rely upon clinical signs and symptoms, despite the fact that the multiplicity of clinical symptoms renders various neuropsychological assessments inadequate to reflect the underlying pathophysiological mechanisms. Since putative neuroimaging biomarkers play a crucial role in understanding the etiology of AD, we sought to stratify the diverse relationships between AD biomarkers and cognitive decline in the aging population and uncover risk factors contributing to the diversities in AD. To do so, we capitalized on a large amount of neuroimaging data from the ADNI study to examine the inflection points along the dynamic relationship between cognitive decline trajectories and whole-brain neuroimaging biomarkers, using a state-of-the-art statistical model of change point detection. Our findings indicated that the temporal relationship between AD biomarkers and cognitive decline may differ depending on the synergistic effect of genetic risk and biological sex. Specifically, tauopathy-PET biomarkers exhibit a more dynamic and age-dependent association with Mini-Mental State Examination scores (p<0.05), with inflection points at 72, 78, and 83 years old, compared with amyloid-PET and neurodegeneration (cortical thickness from MRI) biomarkers. In the landscape of health disparities in AD, our analysis indicated that biological sex moderates the rate of cognitive decline associated with APOE4 genotype. Meanwhile, we found that higher education levels may moderate the effect of APOE4, acting as a marker of cognitive reserve.

Identification of an X-Band Clock Transition in Cp'3Pr- Enabled by a 4f25d1 Configuration.

Molecular qubits offer an attractive basis for quantum information processing, but challenges remain with regard to sustained coherence. Qubits based on clock transitions offer a method to improve the coherence times. We propose a general strategy for identifying molecules with high-frequency clock transitions in systems where a d electron is coupled to a crystal-field singlet state of an f configuration, resulting in an MJ = ±1/2 ground state with strong hyperfine coupling. Using this approach, a 9.834 GHz clock transition was identified in a molecular Pr complex, [K(crypt)][Cp'3PrII], leading to 3-fold enhancements in T2 relative to other transitions in the spectrum. This result indicates the promise of the design principles outlined here for the further development of f-element systems for quantum information applications.

Investigating the dissociative subtype of post-traumatic stress disorder in single- and multi-event trauma-exposed youth: Prevalence, course, prognosis, severity and functional impairment.

OBJECTIVES: This study aimed, following both single- and multi-event trauma, to ascertain prevalence and course of the dissociative subtype of post-traumatic stress disorder (PTSD-DS) in youth; how well early PTSD-DS predicts later PTSD; and whether dissociation accounts for unique variance in post-traumatic stress symptoms (PTSS) and functional impairment over and above the effect of other post-trauma cognitive processing factors and PTSS respectively. DESIGN AND METHODS: This study is a secondary analysis of data from the Acute Stress Programme for Children and Teenagers study (n = 234) and the Coping in Care After Trauma study (n = 110) in which children had experienced single- and multi-event trauma respectively. RESULTS: PTSD-DS diagnosis was common in children with PTSD regardless of trauma experienced (>39.0%). PTSD-DS showed a similar trajectory of natural recovery to PTSD, and it was similarly predictive of later PTSD following single-event trauma. Finally, dissociation was a significant factor in PTSS and functional impairment. CONCLUSIONS: These results should be viewed in the context of several limitations including narrow sample of participants which reduces the generalizability of results, concerns around children's ability to conceptualize challenging concepts such as dissociation and the use of self-report measures to form diagnostic groups. The PTSD-DS diagnosis may offer clinical utility to the extant PTSD diagnosis in children and adolescents, as dissociation has been shown to be a contributory factor in the maintenance of both PTSS and functional impairment. Further research is required to inform further editions of the DSM and other diagnostic systems.

Access to best-evidenced mental health support for care-experienced young people: Learnings from the implementation of cognitive therapy for PTSD.

OBJECTIVES: Rates of PTSD are up to 12 times higher in care-experienced young people (CEYP) compared to their peers. Trauma-focused CBTs (tf-CBT) are the best-evidenced treatment for youth with PTSD, yet, in practice, CEYP often struggle to access this treatment. We worked alongside services to understand barriers and facilitators of the implementation of cognitive therapy for PTSD (a type of tf-CBT) to CEYP. DESIGN: This was an active, open implementation trial. METHODS: We recruited 28 mental health teams across England, including general CAMHS, targeted CAMHS for CEYP and social care-based teams. From these teams, participants were 243 mental health professionals, from a wide variety of professional backgrounds. Following recruitment/intervention training, teams participated in rolling three monthly focus groups and individual interviews, to understand what helped and hindered implementation. Data were analysed using a framework analysis conducted using CFIR 2.0. RESULTS: Almost half of the teams were able to implement, but only approximately one quarter with CEYP, specifically. Universal barriers that were discussed by almost all teams particularly highlighted service structures and poor resourcing as major barriers to delivery to CEYP, as well as the complexities of the young person and their network. Unique factors that differentiated teams who did and did not implement included commissioning practices, the culture of the team, leadership engagement and style, and the development of supervision structures. CONCLUSIONS: Findings offer key considerations for mental health teams, service leads, commissioners and policy-makers to enhance delivery of best-evidenced mental health treatments like CT-PTSD, for CEYP.

Healthcare workers' views on decentralized primary health care management in Lesotho: a qualitative study.

BACKGROUND: Lesotho experienced high rates of maternal (566/100,000 live births) and under-five mortality (72.9/1000 live births). A 2013 national assessment found centralized healthcare management in Ministry of Health led to fragmented, ineffective district health team management. Launched in 2014 through collaboration between the Ministry of Health and Partners In Health, Lesotho's Primary Health Care Reform (LPHCR) aimed to improve service quality and quantity by decentralizing healthcare management to the district level. We conducted a qualitative study to explore health workers' perceptions regarding the effectiveness of LPHCR in enhancing the primary health care system. METHODS: We conducted 21 semi-structured key informant interviews (KII) with healthcare workers and Ministry of Health officials purposively sampled from various levels of Lesotho's health system, including the central Ministry of Health, district health management teams, health centers, and community health worker programs in four pilot districts of the LPHCR initiative. The World Health Organization's health systems building blocks framework was used to guide data collection and analysis. Interviews assessed health care workers' perspectives on the impact of the LPHCR initiative on the six-health system building blocks: service delivery, health information systems, access to essential medicines, health workforce, financing, and leadership/governance. Data were analyzed using directed content analysis. RESULTS: Participants described benefits of decentralization, including improved efficiency in service delivery, enhanced accountability and responsiveness, increased community participation, improved data availability, and better resource allocation. Participants highlighted how the reform resulted in more efficient procurement and distribution processes and increased recognition and status in part due to the empowerment of district health management teams. However, participants also identified limited decentralization of financial decision-making and encountered barriers to successful implementation, such as staff shortages, inadequate management of the village health worker program, and a lack of clear communication regarding autonomy in utilizing and mobilizing donor funds. CONCLUSION: Our study findings indicate that the implementation of decentralized primary health care management in Lesotho was associated a positive impact on health system building blocks related to primary health care. However, it is crucial to address the implementation challenges identified by healthcare workers to optimize the benefits of decentralized healthcare management.

Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity.

Given the role of myeloid cells in T cell activation and in the antitumor response, targeting checkpoint molecules expressed on this population represents a promising strategy to augment antitumor immunity. However, myeloid checkpoints that can be effectively used as immunotherapy targets are still lacking. Here, we demonstrate the therapeutic potential of targeting the myeloid receptors Siglec-7 and Siglec-9 in vivo. By using a humanized immunocompetent murine model, we demonstrate that human Siglec-7 and Siglec-9, in addition to the murine homolog Siglec-E, inhibit the endogenous antitumor immune response, as well as the response to tumor-targeting and immune checkpoint inhibiting antibodies in vivo. The impact of these Siglecs on tumor progression is highly dependent on the anatomical distribution of the tumor and, as a consequence, the local tumor microenvironment, as tumors with a more immune-suppressive tumor microenvironment are less sensitive to Siglec perturbation. Finally, to assess the potential of these two receptors as targets for immunotherapy, we developed Fc engineered blocking antibodies to Siglec-7 and Siglec-9 and demonstrate that Siglec-7 and Siglec-9 blockade can significantly reduce tumor burden in vivo, demonstrating the therapeutic potential of targeting these two receptors.

Less Subsequent Revision Anterior Cruciate Ligament (ACL) Reconstruction Following Primary Bone-Patellar Tendon-Bone ACL Reconstruction with Suture Tape Augmentation-A Retrospective Comparative Therapeutic Trial With 5-Year Follow-up.

PURPOSE: To investigate patient outcomes, including revision rate, following primary bone patellar-tendon bone autograft (BPTB) anterior cruciate ligament reconstruction (ACLR) with and without suture tape augmentation (STA) in a young and active cohort. METHODS: All eligible patients who received primary BPTB ACLR with a minimum of 2-year follow-up were included in this retrospective cohort study. All patients receiving STA were augmented with the same device. Patients completed the following patient-reported outcome measures (PROMs): the visual analog scale, the Single Assessment Numeric Evaluation, the Knee Injury and Osteoarthritis Outcome Score subscales, and the Tegner activity scale. Anteroposterior knee laxity was assessed using a KT-1000 arthrometer preoperatively and 1-year postoperatively. Posterior tibial slope, femoral tunnel angle, and tibial tunnel placement were calculated for all patients. Subsequent surgical interventions and return to sport (RTS) were obtained from each patient. RESULTS: One hundred fourteen patients (52 BPTB ACLR with STA, 62 traditional BPTB ACLR) with a mean patient age <19 years and a mean final follow-up of ≥5 years were included. Compared with the control group, the STA group demonstrated significantly less subsequent revision ACLR (0 vs. 5, P = .036). All PROMs and KT-1000 measurements improved at final follow-up (P < .001) and were comparable between groups. There were no differences seen in either posterior tibial slope or graft tunnel placement between groups. More than 85% of the patients were able to return to the sport that led to their injury at full capacity with no differences seen in RTS rate, time to RTS, or level of competition between groups. CONCLUSIONS: Compared with traditional BPTB ACLR, additional STA appeared to safely and effectively lead to less subsequent revision ACLR while maintaining acceptable PROMs and objective joint laxity measurements in a young and active patient population. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Primary All-Soft Tissue Quadriceps Tendon Autograft Anterior Cruciate Ligament Reconstruction With Suture Tape Augmentation Resulted in Satisfactory Patient Outcomes and a Low Graft Failure Rate in High School and Collegiate Athletes.

PURPOSE: To evaluate ≥2-year patient outcomes after primary all-soft tissue quadriceps tendon autograft (ASTQ) anterior cruciate ligament reconstruction (ACLR) with suture tape augmentation (STA) in skeletally mature high school and collegiate athletes. METHODS: All high school and collegiate athletes who underwent primary ASTQ ACLR with STA with a minimum of 2-year follow-up were analyzed retrospectively. Patients were administered validated patient-reported outcome measures (PROMs) pre- and postoperatively. The minimal clinically important difference was calculated for each PROM based on this study population and applied to the individual patient. Return to sport, subsequent surgical intervention including contralateral ACLR, and KT-1000 arthrometer measurements for knee laxity were collected. Complications were assessed by physical examination, radiologic studies, or obtained via telephone. RESULTS: In total, 60 patients were included in the final data analysis, with a mean age of 16.8 years (95% confidence interval 13-23) and mean final follow-up of 37.1 months (95% confidence interval 33.1-41.1). Twelve patients (20%) required subsequent surgery on the ipsilateral knee, which included 7 patients having a subsequent meniscal procedure and 3 patients who underwent arthrolysis. None sustained a graft failure, and 6 patients sustained a contralateral ACL injury necessitating surgery. All PROMs improved at the final follow-up (P < .001). In addition, KT-1000 arthrometer measurements significantly improved postoperatively at 1-year clinical follow-up (P < .001). Most patients obtained the minimal clinically important difference thresholds for each PROM at the final follow-up. There were 48 patients (80%) who participated in pivoting sports. The return-to-sport rate at same level was 54 patients (90%), with 6 patients (10%) not returning to the same level because of graduation. CONCLUSIONS: ASTQ ACLR with STA in a young athletic patient population may result in a low graft failure rate while maintaining satisfactory patient outcomes at short-term follow-up, including a return to sport at the same level of 90%. LEVEL OF EVIDENCE: Level IV, retrospective case series.

The patient journeys of children and adolescents with depression: a study of electronic health records.

In England, children and adolescents with depression can seek treatment from specialist mental health services. We know little about how they journey through these services, or whether healthcare providers collect sufficient data to accurately appraise this. We aimed to summarise the child and adolescent depression pathway for two healthcare providers. This cohort study used de-identified electronic health records extracted from Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) and South London and Maudsley NHS Foundation Trust (SLaM). We identified referrals between 2015 and 2019 during which the referred patient received their first depression diagnosis aged < 18 years. We described patient demographic and clinical characteristics, and features of the referral. In total, n = 296 (CPFT) and n = 2502 (SLaM) patients had a referral which met eligibility criteria. In both sites, patients were more frequently female (CPFT 79.3%; SLaM 69.3%) and White ethnicity (CPFT 88.9%; SLaM 57.9%) as compared to respective population estimates for the Trusts' catchment areas. Patients typically received their first depression diagnosis during adolescence (median ages 16 in CPFT and 15 in SLaM). The most common comorbidity was anxiety disorder. Referrals were usually routine, to community teams specialising in the child age group. Commonly mentioned interventions included antidepressant medication, cognitive behavioural therapy, and dialectical behaviour therapy. However, pathways varied within and between sites, and the quality and consistency of some data was poor. These findings provide an overview of service pathways experienced by children and adolescents with depression, but also highlight that pathways can vary according to individual need and healthcare provider. More systematic collection of some data, and standardisation in record systems used by different providers, would be beneficial.

Synthesis and Characterization of a Bridging Cerium(IV) Nitride Complex.

Complexes featuring lanthanide-ligand multiple bonds are rare and highly reactive. They are important synthetic targets to understand 4f/5d-bonding in comparison to d-block and actinide congeners. Herein, the isolation and characterization of a bridging cerium(IV)-nitride complex: [(TriNOx)Ce(Li2µ-N)Ce(TriNOx)][BArF4] is reported, the first example of a molecular cerium-nitride. The compound was isolated by deprotonating a monometallic cerium(IV)-ammonia complex: [CeIV(NH3)(TriNOx)][BArF4]. The average Ce═N bond length of [(TriNOx)Ce(Li2µ-N)Ce(TriNOx)][BArF4] was 2.117(3) Å. Vibrational studies of the 15N-isotopomer exhibited a shift of the Ce═N═Ce asymmetric stretch from ν = 644 cm-1 to 640 cm-1, and X-ray spectroscopic studies confirm the +4 oxidation state of cerium. Computational analyses showed strong involvement of the cerium 4f shell in bonding with overall 16% and 11% cerium weight in the σ- and π-bonds of the Ce═N═Ce fragment, respectively.

The Role of Exercise in Management of Mental Health Disorders: An Integrative Review.

A large and growing body of evidence suggests that physical activity (PA) may hold therapeutic promise in the management of mental health disorders. Most evidence linking PA to mental health outcomes has focused on the effects of aerobic exercise training on depression, although a growing body of work supports the efficacy of both aerobic and resistance exercise paradigms in the treatment of anxiety and post-traumatic stress disorder. Despite abundant evidence linking PA and mental health, use of exercise training as a mental health treatment remains limited due to three important sources of uncertainty: (a) large individual differences in response to exercise treatment within multiple mental health domains; (b) the critical importance of sustained PA engagement, not always achieved, for therapeutic benefit; and (c) disagreement regarding the relative importance of putative therapeutic mechanisms. Our review of treatment data on exercise interventions and mental health outcomes focuses primarily on depression and anxiety within a health neuroscience framework. Within this conceptual framework, neurobiological and behavioral mechanisms may have additiveor synergistic influences on key cognitive and behavioral processes that influence mental health outcomes. We therefore highlight sources of treatment heterogeneity by integrating the critical influences of (a) neurobiological mechanisms enhancing neuroplasticity and (b) behavioral learning of self-regulatory skills. Understanding the interrelationships between dynamic neurobiological and behavioral mechanisms may help inform personalized mental health treatments and clarify why, and for whom, exercise improves mental health outcomes. The review concludes with recommendations for future studies leveraging individual differences to refine treatment approaches to optimize mental health benefits.

Multidisciplinary Care in Heart Failure Services.

The American College of Cardiology/American Heart Association/Heart Failure Society of American 2022 guidelines for heart failure (HF) recommend a multidisciplinary team approach for patients with HF. The multidisciplinary HF team-based approach decreases the hospitalization rate for HF and health care costs and improves adherence to self-care and the use of guideline-directed medical therapy. This article proposes the optimal multidisciplinary team structure and each team member's delineated role to achieve institutional goals and metrics for HF care. The proposed HF-specific multidisciplinary team comprises cardiologists, surgeons, advanced practice providers, clinical pharmacists, specialty nurses, dieticians, physical therapists, psychologists, social workers, immunologists, and palliative care clinicians. A standardized multidisciplinary HF team-based approach should be incorporated to optimize the structure, minimize the redundancy of clinical responsibilities among team members, and improve clinical outcomes and patient satisfaction in their HF care.

Global analyses of mRNA expression in human sensory neurons reveal eIF5A as a conserved target for inflammatory pain.

Nociceptors are a type of sensory neuron that are integral to most forms of pain. Targeted disruption of nociceptor sensitization affords unique opportunities to prevent pain. An emerging model for nociceptors are sensory neurons derived from human stem cells. Here, we subjected five groups to high-throughput sequencing: human induced pluripotent stem cells (hiPSCs) prior to differentiation, mature hiPSC-derived sensory neurons, mature co-cultures containing hiPSC-derived astrocytes and sensory neurons, mouse dorsal root ganglion (DRG) tissues, and mouse DRG cultures. Co-culture of nociceptors and astrocytes promotes expression of transcripts enriched in DRG tissues. Comparisons of the hiPSC models to tissue samples reveal that many key transcripts linked to pain are present. Markers indicative of a range of neuronal subtypes present in the DRG were detected in mature hiPSCs. Intriguingly, translation factors were maintained at consistently high expression levels across species and culture systems. As a proof of concept for the utility of this resource, we validated expression of eukaryotic initiation factor 5A (eIF5A) in DRG tissues and hiPSC samples. eIF5A is subject to a unique posttranslational hypusine modification required for its activity. Inhibition of hypusine biosynthesis prevented hyperalgesic priming by inflammatory mediators in vivo and diminished hiPSC activity in vitro. Collectively, our results illuminate the transcriptomes of hiPSC sensory neuron models. We provide a demonstration for this resource through our investigation of eIF5A. Our findings reveal hypusine as a potential target for inflammation associated pain in males.

Timing of sedation and patient-reported pain outcomes during cardiac catheterization: Results from the UNTAP-intervention study.

BACKGROUND: Invasive cardiac catheterization (CC) temporarily increases pain, discomfort, and anxiety. Procedural sedation is deployed to mitigate these symptoms, though practice varies. Research evaluating peri-procedural patient-reported outcomes is lacking. METHODS AND RESULTS: We randomized 175 patients undergoing CC to short interval ([SI] group, <6 min) or long interval ([LI] group, ≥6 min) time intervals between initial intravenous sedation and local anesthetic administration. Outcomes included: (1) total pain medication use, (2) patient-reported and behaviorally assessed pain and (3) patient satisfaction during outpatient CC. Generalized linear mixed effect models were used to evaluate the impact of treatment time interval on total medication utilization, pain, and satisfaction. Among enrollees the mean age was 62 (standard deviation [SD] = 13.4), a majority were male (66%), white (74%), and overweight (mean body mass index = 28.5 [SD = 5.6]). Total pain medication use did not vary between treatment groups (p = 0.257), with no difference in total fentanyl (p = 0.288) or midazolam (p = 0.292). Post-treatment pain levels and nurse-observed pain were not statistically significant between groups (p = 0.324 & p = 0.656, respectively. No significant differences with satisfaction with sedation were found between the groups (p = 0.95) Patient-reported pain, satisfaction and nurse-observed measures of pain did not differ, after adjustment for demographic and procedural factors. Analyses of treatment effect modification revealed that postprocedure self-reported pain levels varied systematically between individuals undergoing percutaneous coronary intervention (PCI) (SI = 2.2 [0.8, 3.6] vs. LI = 0.7 [-0.6, 2.0]) compared with participants not undergoing PCI (SI = 0.4 [-0.8, 1.7] vs. LI = 0.7 [-0.3, 1.6]) (p = 0.043 for interaction). CONCLUSION: No consistent treatment differences were found for total medication dose, pain, or satisfaction regardless of timing between sedation and local anesthetic. Treatment moderations were seen for patients undergoing PCI. Further investigation of how procedural and individual factors impact the patient experience during CC is needed.

Child and adolescent anxiety as a risk factor for bipolar disorder: A systematic review of longitudinal studies.

OBJECTIVES: Several studies have suggested that anxiety disorders in childhood and adolescence often precede the onset of bipolar disorder. We therefore systematically reviewed the relationship between child and adolescent anxiety and later bipolar disorder. METHODS: Online databases (Medline [for Ovid], EMBASE and PsychINFO) were searched for original, peer-reviewed studies examining the relationship between child and adolescent anxiety and later bipolar disorder. Studies in both community samples and bipolar offspring samples were included. RESULTS: A total of 16 studies were included in the review. The results were broadly consistent and revealed that child and adolescent anxiety disorders are associated with later bipolar disorder in community samples. In bipolar offspring, child and adolescent anxiety disorders are a marker of increased risk and predict the onset of bipolar disorder and other major mood disorders. CONCLUSIONS: There is evidence that anxiety disorders in childhood and adolescence increase the risk of later bipolar disorder. Anxiety disorders may be a useful target for early intervention in those at high-risk of bipolar disorder.