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The generalized risk-adjusted cost-effectiveness (GRACE) analysis method modifies standard cost-effectiveness analysis (CEA), the primary method currently used worldwide to value health improvements arising from healthcare interventions. Generalizing standard CEA, GRACE allows for decreasing or even increasing returns to health. Previous presentations of GRACE have relied extensively on Taylor Series expansion methods to specify key model parameters, including those that properly adjust for illness severity and preexisting disability, consequences of uncertain treatment outcomes, and the marginal rate of substitution between life expectancy and health-related quality of life. Standard CEA cannot account for these sources of value or cost in its valuation of medical treatments. However, calculations of GRACE measures based on Taylor Series are approximations, which may be poorly behaved in some contexts. This paper provides a new approach for implementing GRACE, using exact utility functions instead of Taylor Series approximations. While any proper utility function will suffice, we illustrate with three well-known functions: constant relative risk aversion (CRRA) utility; hyperbolic absolute risk aversion (HARA) utility, of which CRRA is a special case; and expo-power (EP) utility, of which constant absolute risk aversion (CARA) is a special case. The analysis then extends from two-period to multiperiod models. We discuss methods to estimate parameters of HARA and EP functions using two different types of data, one from discrete choice experiments and the other from “happiness economics” methods. We conclude with some reflections on how this analysis might affect benefit-cost analysis studies of healthcare interventions.

As recently as fifty years ago, Melbourne's new suburban communities were constructed with unpaved roads and lacked many basic services. Today they often come not just with roads but virtually complete with most of the facilities and amenities needed on a daily basis. Yet architectural, planning and design professionals remain uneasy about the design and the environmental, social, and economic sustainability of the newest suburbs built in some instances up to 60 kilometres from the central business district. We locate this unease in the systemic nature of the planning and building of these new communities by an enormous public–private industry complex. Melbourne's outer suburbs could be thought to be administered rather than planned.

Christian congregations strive to be caring and inspirational communities, but women who lead them often face challenges to their well-being not experienced by their male counterparts. We conducted a study of leadership challenges among female pastors, administering a survey to a sample of 102 Evangelical Lutheran Church in America (ELCA) pastors. The results suggest that pastors are not isolated from the types of gender discrimination females experience outside of the church. The insights gained can be useful to church leaders, clergy, seminarians, congregants, and those generally interested in gender dynamics and effective leadership strategies.

OBJECTIVE To review ordering patterns, positivity rates, and outcome data for a subset of consecutive samples submitted for a commercially available, blood-based multicancer early-detection liquid biopsy test for dogs using next-generation sequencing at 1 laboratory. SAMPLE 1,500 consecutively submitted blood samples from client-owned dogs with and without clinical suspicion and/or history of cancer for prospective liquid biopsy testing between December 28, 2021, and June 28, 2022. PROCEDURES We performed a retrospective observational study, reviewing data from 1,500 consecutive clinical samples submitted for liquid biopsy testing. Outcome data were obtained via medical record review, direct communication with the referring clinic, and/or a patient outcome survey through October 16, 2022. RESULTS Sixty-four percent (910/1,419) of reportable samples were submitted for cancer screening, 26% (366/1,419) for aid in diagnosis, and 10% (143/1,419) for other indications. The positivity rate was 25.4% (93/366) in aid-in-diagnosis patients and 4.5% (41/910) in screening patients. Outcome data were available for 33% (465/1,401) of patients, and outcomes were classifiable for 428 patients. The relative observed sensitivity was 61.5% (67/109) and specificity was 97.5% (311/319). The positive predictive value was 75.0% (21/28) for screening patients and 97.7% (43/44) for aid-in-diagnosis patients, and the time to diagnostic resolution following a positive result was < 2 weeks in most cases. CLINICAL RELEVANCE Liquid biopsy using next-generation sequencing represents a novel tool for noninvasive detection of cancer in dogs. Real-world clinical performance meets or exceeds expectations established in the test’s clinical validation study.

The influence of extracellular and intracellular calcium on smooth muscle contractile activity varies between organs. In response to G protein-coupled receptor (GPCR) stimulation, the urinary bladder detrusor muscle has shown a 70% dependence on extracellular calcium, whereas the urothelium and lamina propria (U&LP) has a 20%–50% dependence. However, as this only accounts for partial contractile activity, the contribution of intracellular calcium and calcium sensitization pathways remains unclear. This study assessed the role of intracellular signaling pathways on GPCR-mediated urinary bladder U&LP contraction. Porcine U&LP responses to activation of the Gq/11-coupled muscarinic, histamine, 5-hydroxytryptamine (serotonin), neurokinin, prostaglandin, and angiotensin II receptors were assessed with three selective inhibitors of store-released intracellular calcium, 2-aminoethyl diphenylborinate (2-APB), cyclopiazonic acid (CPA), and ruthenium red, and three Rho kinase inhibitors, fasudil, Y-27632, and GSK269962. There was no discernible impact on receptor agonist-induced contractions of the U&LP after blocking intracellular calcium pathways, suggesting that this tissue is more sensitive to alterations in the availability of extracellular calcium. However, an alternative mechanism of action for GPCR-mediated contraction was identified to be the activation of Rho kinase, such as when Y-27632 significantly reduced the GPCR-mediated contractile activity of the U&LP by approximately 50% ( P < 0.05, n = 8). This suggests that contractile responses of the bladder U&LP do not involve a significant release of calcium from intracellular stores, but that Gq/11-coupled receptor activation causes calcium sensitization via Rho kinase. This study highlights a key role for Rho kinase in the urinary bladder, which may provide a novel target in the future pharmaceutical management of bladder contractile disorders.

OBJECTIVESWe aimed to describe the quality of sedation and additional clinically-meaningful outcomes associated with different intranasal dexmedetomidine-based regimens in children undergoing nonpainful procedures.METHODSA multicenter prospective observational study of children aged 2 months to 17 years undergoing intranasal dexmedetomidine sedation for MRI, auditory brainstem response testing, echocardiogram, EEG, or computed tomography scan. Regimens varied by dose of dexmedetomidine and use of adjunct sedatives. Quality of sedation was assessed using the Pediatric Sedation State Scale and by determining proportion of children who achieved an acceptable sedation state. Procedure completion, time-based outcomes, and adverse events were assessed.RESULTSWe enrolled 578 children across 7 sites. Median age was 2.5 years (interquartile range 1.6–3) and 37.5% were female. The most common procedures were auditory brainstem response testing (54.3%) and MRI (22.8%). The most common dose was 3 to 3.9 mcg/kg (55%), with 25.1% and 14.2% of children receiving oral or intranasal midazolam, respectively. Acceptable sedation state and procedure completion was achieved in 81.1% and 91.3% of children, and mean time to onset of sedation and total sedation time were 32.3 and 114.8 minutes, respectively. Twelve interventions were performed in 10 patients in response to an event; no patients required a serious airway, breathing, or cardiovascular intervention.CONCLUSIONSIntranasal dexmedetomidine-based regimens can achieve acceptable sedation states and high rates of procedure completion in children undergoing sedation for nonpainful procedures. Our findings delineate clinical outcomes associated with intranasal dexmedetomidine-based sedation that can be used to guide the implementation and optimization of such regimens.

Although vocalizations are essential to mammalian sociosexual behaviours, little is known about female preferences for male vocal displays in non-model mammalian species. Here, we characterized female preferences for the advertisement songs of male Alston’s singing mice (Scotinomys teguina). We developed procedures for inducing oestrus, using vaginal perforation as a morphological indicator of oestrus. We then broadcasted ‘high-effort’ and ‘low-effort’ songs recorded from wild-caught males to virgin laboratory-reared females, using a two-choice experiment. Our results indicate that females spent more time investigating speakers playing high-effort songs; surprisingly, this phonotactic response is independent of oestrus status. In wild singing mice, acoustic characteristics of high-effort male songs positively correlate with body condition. Our data suggest that females could use acoustic cues to select mates in good condition, thus providing preliminary support for adaptive mate choice hypotheses. More generally, our results support the hypothesis that elaborate Scotinomys song may be shaped by female choice.

9 pages, 6 figures, 1 table, supplement https://doi.org/10.5194/essd-15-511-2023-supplement.-- Data availability: Data are archived in the data repository PANGAEA (https://doi.org/10.1594/PANGAEA.929968) (Strydom et al., 2022).-- Code availability: R scripts used to generate figures and maps can be found in the Supplement, Seagrass meadows provide valuable socio-ecological ecosystem services, including a key role in climate change mitigation and adaption. Understanding the natural history of seagrass meadows across environmental gradients is crucial to deciphering the role of seagrasses in the global ocean. In this data collation, spatial and temporal patterns in seagrass meadow structure, biomass and production data are presented as a function of biotic and abiotic habitat characteristics. The biological traits compiled include measures of meadow structure (e.g. percent cover and shoot density), biomass (e.g. above-ground biomass) and production (e.g. shoot production). Categorical factors include bioregion, geotype (coastal or estuarine), genera and year of sampling. This dataset contains data extracted from peer-reviewed publications published between 1975 and 2020 based on a Web of Science search and includes 11 data variables across 12 seagrass genera. The dataset excludes data from mesocosm and field experiments, contains 14 271 data points extracted from 390 publications and is publicly available on the PANGAEA® data repository (https://doi.org/10.1594/PANGAEA.929968; Strydom et al., 2021). The top five most studied genera are Zostera, Thalassia, Cymodocea, Halodule and Halophila (84 % of data), and the least studied genera are Phyllospadix, Amphibolis and Thalassodendron (2.3 % of data). The data hotspot bioregion is the Tropical Indo-Pacific (25 % of data) followed by the Tropical Atlantic (21 %), whereas data for the other four bioregions are evenly spread (ranging between 13 and 15 % of total data within each bioregion). From the data compiled, 57 % related to seagrass biomass and 33 % to seagrass structure, while the least number of data were related to seagrass production (11 % of data). This data collation can inform several research fields beyond seagrass ecology, such as the development of nature-based solutions for climate change mitigation, which include readership interested in blue carbon, engineering, fisheries, global change, conservation and policy, Anna Lafratta was supported by Environmental Protection Authority (SA)/Water SA and Edith Cowan University (ECU) Industry Engagement Scholarship. Cristian Salinas was funded by ECU Higher Degree by Research Scholarship. Oscar Serrano was supported by I+D+i projects RYC2019-027073-I and PIE HOLOCENO 20213AT014 funded by MCIN/AEI/10.13039/501100011033 and FEDER, With the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event ( Clinical Trial Registration: NCT01719055 ( ClinicalTrials.gov )

Antibodies targeting insulin-like growth factor 1 receptor (IGF-1R) induce objective responses in only 5% to 15% of children with sarcoma. Understanding the mechanisms of resistance may identify combination therapies that optimize efficacy of IGF-1R–targeted antibodies. Sensitivity to the IGF-1R–targeting antibody TZ-1 was determined in rhabdomyosarcoma and Ewing sarcoma cell lines. Acquired resistance to TZ-1 was developed and characterized in sensitive Rh41 cells. The BRD4 inhibitor, JQ1, was evaluated as an agent to prevent acquired TZ-1 resistance in Rh41 cells. The phosphorylation status of receptor tyrosine kinases (RTK) was assessed. Sensitivity to TZ-1 in vivo was determined in Rh41 parental and TZ-1–resistant xenografts. Of 20 sarcoma cell lines, only Rh41 was sensitive to TZ-1. Cells intrinsically resistant to TZ-1 expressed multiple (>10) activated RTKs or a relatively less complex set of activated RTKs (∼5). TZ-1 decreased the phosphorylation of IGF-1R but had little effect on other phosphorylated RTKs in all resistant lines. TZ-1 rapidly induced activation of RTKs in Rh41 that was partially abrogated by knockdown of SOX18 and JQ1. Rh41/TZ-1 cells selected for acquired resistance to TZ-1 constitutively expressed multiple activated RTKs. TZ-1 treatment caused complete regressions in Rh41 xenografts and was significantly less effective against the Rh41/TZ-1 xenograft. Intrinsic resistance is a consequence of redundant signaling in pediatric sarcoma cell lines. Acquired resistance in Rh41 cells is associated with rapid induction of multiple RTKs, indicating a dynamic response to IGF-1R blockade and rapid development of resistance. The TZ-1 antibody had greater antitumor activity against Rh41 xenografts compared with other IGF-1R–targeted antibodies tested against this model.

Background/Aim: There exists considerably large interpatient variability in pharmacokinetic exposure of high dose melphalan in multiple myeloma patients with hematopoietic stem-cell transplantation. In this study, we aimed to evaluate the potential impacts of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) variations on pharmacokinetic properties of melphalan and clinical outcomes in multiple myeloma (MM) patients. Patients and Methods: Genotypes of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) were determined by validated gene-specific real-time PCR (RT-PCR) assays using DNA samples from 108 MM patients; plasma concentrations of melphalan at different time points were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/ΜS). Results: CYP3A4*1B/*1B and CYP3A5*3/*3 carriers appeared to have a short median progression-free survival time and a higher maximum melphalan plasma concentration than non-carriers [792 vs. over 950 days, p=0.08; 9.91 (2.67, 34.03) vs. 8.66 (4.46, 17.61) mg/l, p=0.039]. Conclusion: CYP3A4*1B/*1B and CYP3A5*3/*3 variations might influence melphalan therapy in MM patients through yet-to-be-identified mechanisms.

Based on presentations across two days as part of an Urban Studies Foundation-funded seminar series, we elaborate a thematic agenda for considering the centrality of urban peripheries. We move beyond a typology of suburban centres to depict senses of peripheral centrality in terms of: their pervasiveness; their visibility across multiple scales; their underlying social relations; the agency exerted in their imagining and production, and the associated policy mobility.

Objective To describe the perinatal and neonatal outcomes of fetal laser ablation (FLA) for the treatment of twin-twin transfusion syndrome (TTTS) in our single center institution. Study design Retrospective study of 76 treated pregnant women. Procedural complications, perinatal and neonatal outcomes analyzed. Differences in outcomes between two procedural techniques, selective and Solomon, compared. Results FLA occurred at median gestational age (GA) of 20.8 weeks (IQR 18.1–22.9) with low incidence of procedural complications (5.3%). High survival rate with delivery of at least one neonate (96%) [95% CI: 88.9–99.2%]; 73.7% [95% CI: 62.3–83.1%] were twins. Median GA at birth was 33.1 weeks (IQR 28.0–35.0). Neonatal mortality and morbidities were 9.4% and 48.3% of cases respectively, and associated with lower GA. Solomon cases had comparatively higher median GA, and lower incidences of neonatal morbidities. Conclusion Our small single center study showed favorable outcomes for using the Solomon technique in the treatment of TTTS.

Results produced from randomized controlled trials (RCTs) help guide clinical decision making and health policy. Therefore, it is essential that RCT outcomes- including harms (eg, adverse events)-are adequately reported such that clinicians, patients, and policy makers are equipped with all necessary information to complete risk-benefit assessment of the RCT's intervention. Here, we evaluated the quality of reporting of harms (eg, adverse events) in RCTs cited as supporting evidence for recommendations in the American Academy of Orthopaedic Surgeons (AAOS) Management of Rotator Cuff Injuries clinical practice guidelines (CPGs) using the Consolidated Standards of Reporting Trials (CONSORT) Extension for Harms Checklist.To quantify adherence to CONSORT Extension for Harms items, each RCT was screened for pertinent information satisfying each checklist item. Screening of CPG reference sections for RCTs underpinning CPG recommendations, as well as data extraction from each of the included RCTs, was performed in a blind and duplicate manner. Descriptive statistics-including frequencies, percentages, and 95% confidence intervals-were used to summarize overall percent adherence to checklist items. A linear regression model assessed the relationship of CONSORT Harms reporting over time.Ninety-nine RCTs were included in our final sample. Fifty-seven RCTs (of 99; 57.6%) were conducted at a single center. Common funding sources included private (nonindustry) (17/99; 17.2%), private (industry) (8/99; 8.1%), and public (7/99; 7.1%) sources. Sample size for each trial most often consisted of50 participants (29/99; 29.3%) or 51-100 participants (50/99; 50.5%). The average number of CONSORT Extension for Harms items adequately reported across all included RCTs was 5.7 (of 18; 31.7%). None of the included trials reported all 18 items. Twenty-six RCTs (of 99; 26.3%) adequately reported ≥50% of eligible checklist items. Fifty-nine RCTs (of 99; 59.6%) adequately reported ≤33% of eligible checklist items. Items with ≥50% adherence included item 2, item 7a, and item 8a. Items with ≤20% adherence included item 3b, item 4d, and item 5. Results from our linear regression demonstrated a slight, yet nonsignificant, improvement in adherence to the Harms Extension over time (ROur results illustrate the poor state of harms reporting within RCTs cited as supporting evidence for the AAOS Management of Rotator Cuff Injuries CPG. Efforts to address these gaps in reporting are warranted, as complete knowledge of potential harms is critical to patients, clinicians, and health policy makers when determining best practice decisions in orthopedic surgery.

Trace element zoning is often used to unravel the crystallization history of phenocrysts in magmatic systems, but interpretation requires quantifying the relative importance of equilibrium versus disequilibrium. Published partition coefficients for phosphorous (P) in olivine vary by more than a factor of ten. After considering kinetic effects, a new equilibrium partition coefficient was extrapolated from a re-examination of natural and experimental systems, indicating that P partition coefficients in olivine are significantly over-estimated. These new partitioning constraints allow us to establish a theoretical P Equilibrium Fractionation Array (PEFA) for mid-ocean ridge basalts (MORBs), revealing that most olivines from MORBs have excess P (2–15 times PEFA) and are thus in disequilibrium. Using an independent case study of natural dendritic olivines, we show that such P enrichments can be explained by diffusion-limited incorporation of P during rapid crystal growth. If growth rate can be related to cooling, the rapid growth rates of olivines have implications for magma system dynamics, such as the size of magma bodies or where crystallization occurs within the body.

This paper presents a reconstruction of natural environmental dynamics, wildfires and vegetation change in northwest Putorana Plateau during the last 1300 years. The study area is a remote and poorly investigated region of subarctic Siberia, relatively untouched by human impacts, which offers a unique opportunity to examine natural environmental dynamics and climate-vegetation-fire relationships. The paleoenvironmental reconstructions are based on multi-proxy analysis of the Gervi peatland including pollen, plant macrofossil, testate amoebae and charcoal analysis, loss on ignition measurements and AMS radiocarbon dating. The results revealed the main phases of regional paleoenvironmental change: a warm period between 680 and 1200 C.E. (Common Era) corresponding to the Mediaeval Climate Anomaly (MCA), followed by climate cooling during the Little Ice Age (LIA, 1200–1850 C.E.) and subsequent centuries. Climate amelioration during the MCA led to afforestation of northwestern Putorana Plateau and an expansion of spruce extending 70 km northeast of its present geographical range. A quantitative water-table reconstruction was generated using a testate amoebae transfer function and suggested that relatively dry climate conditions during the MCA triggered high fire frequencies. The LIA appeared in the study area as a period of pronounced climate cooling and moderate moistening, which caused an extension of tundra vegetation and a dramatic decline of fire activity. Distinct environmental changes at the study site were detected since 1990 C.E., characterized by a high peat accumulation rate and rising water table. Since 1990 C.E., the macroscopic charcoal accumulation rate in the peat core increased abruptly, suggesting a recent increase in the fire frequency in the study region.

A patient admitted to the ICU with shock and acute kidney injury required continuous renal replacement therapy (CRRT). CRRT was initiated using regional citrate anticoagulation (RCA) with an initial magnesium (Mg) level of 1.7 mg/dL. Over 12 days the patient received 68 g of Mg sulfate. After 58 g the patient’s Mg level was 1.4 mg/dL. On day 13, CRRT was changed to a heparin circuit from concerns of citrate toxicity. Over the next 7 days the patient required no Mg replacement with a mean Mg level of 2.22. This was significantly higher than the final 7 days on RCA (1.99; P = .00069). This case illustrates the challenges in maintaining Mg stores during CRRT. RCA is now the preferred method of circuit anticoagulation, with prolonged filter life and fewer bleeding complication compared to heparin circuits. Citrate inhibits coagulation within the circuit by chelating ionized calcium (Ca2+). Free Ca2+ and Ca-citrate complexes diffuse across the hemofilter with a percentual calcium loss as high as 70%, requiring continuous post-filter infusions of calcium to prevent systemic hypocalcemia. Magnesium loss during CRRT is also significant and may approach 15% to 20% of the total body pool within a week. Citrate chelates Mg with percentual losses comparable to calcium. Twenty-two CRRT patients on RCA had median losses >6 g/day. Doubling the Mg content in the dialyzate of 45 CRRT patients significantly improved Mg balance, but with the potential risk of increased citrate toxicity. A major obstacle to replacing Magnesium loss with the same precision as calcium is few hospitals can measure ionized Mg++ levels and must rely on total magnesium levels to guide replacement, despite a literature showing poor correlation with total body stores. Post-circuit continuous replacement of magnesium, as with calcium, in the absence of ionized magnesium levels would likely be very inexact and arduous. Being aware of the losses that can occur with CRRT, especially with RCA, and adjusting magnesium replacement empirically on rounds may be the only pragmatic action plan for this clinical issue.

Purpose: Pharmacists play a key role in preventing medication errors during transitions of care and preventing hospital readmissions through medication reconciliation (MR) programs. This study retrospectively evaluated the implementation of a standardized pharmacy residentdriven MR program for patients at high risk for readmission as defined by the Hospital Readmissions Reduction Program (HRRP). Methods: This was a single-center, retrospective cross sectional study of a pharmacy resident-driven MR program including patients at high risk of readmission defined by HRRP. The primary objective was to determine the number of inpatient regimen interventions identified during the MR. Secondary objectives include severity of interventions, number of medication discrepancies identified, types of interventions and discrepancies identified, and all-cause hospital readmission rates within 30 days of discharge.. Results: Fifty-three high-risk patients were included in the study. Pharmacy intervention recommendations were accepted by prescribers for nine patients (9/53; 17.0%) with a total of 13 accepted inpatient regimen interventions. The two most commonly identified medication classes for interventions were anticonvulsants (3/13; 23.1%) and antidepressants (6/13; 46.2%). Discrepancies on the admission MR were identified for 46 (46/53; 86.8%) patients with a median of three discrepancies per patient (interquartile range 2-4). The most common type of discrepancy was an incorrect or unnecessary drug. The 30-day all-cause readmission rate was 35.8% (19/53) for the total patient Conclusion: A pharmacy-resident driven MR program provided value in clarifying prior to admission medications and may help prevent drugrelated adverse events.

Lumbar synovial cysts (LSCs) can cause painful radiculopathy and sensory and/or motor deficits. Historically, first-line surgical treatment has been decompression with fusion. Recently, minimally invasive laminectomy without fusion has shown equal or superior results to traditional decompression and fusion methods.This study investigates the long-term efficacy of minimally invasive laminectomy without fusion in the treatment of LSC as it relates to the rate of subsequent fusion surgery.A retrospective review was performed over a 10-year period of patients undergoing minimally invasive laminectomy for symptomatic LSCs. The primary end point was the rate of revision surgery requiring fusion.Eighty-five patients with symptomatic LSCs underwent minimally invasive laminectomy alone January 2010-August 2020 at our institution. The most common location was L4-5 (72%). Preoperative imaging identified spondylolisthesis (grade 1) in 43 patients (57%), none of which was unstable on available dynamic radiographs. Average procedure duration was 93 minutes, with 78% of patients discharged home on the same day of surgery. Over 46 months of mean follow-up, 17 patients (20%) required 19 revision operations. Of those operations, 16 were spinal fusions (17.6%). Median time to fusion surgery was 36 months. There were no identifiable risk factors on multivariate regression analysis that predicted the need for fusion.Minimally invasive laminectomy is an effective first-line treatment for symptomatic LSCs and avoids the need for fusion in most treated patients. Of our patients, 18% required a fusion over 46 months, suggesting that further studies are required to guide patient selection.

Antibody responses are critical for protection against pathogens. However, diseases such as allergic rhinitis or food allergy result from aberrant production of IgE antibodies against otherwise innocuous environmental antigens. The production of allergen-specific IgE requires interaction between B cells and CD4sup+/supT cells, and a granular understanding of these interactions is required to develop novel therapies for allergic disease. CD4sup+/supT cells are exceptionally heterogeneous in their transcriptional, epigenetic, and proteomic profiles, which poses significant challenges when attempting to define subsets relevant to the study of allergy among a continuum of cells. Defining subsets such as the T follicular helper (TsubFH/sub) cell cluster provides a shorthand to understand the functions of CD4sup+/supT cells in antibody production and supports mechanistic experimentation for hypothesis-driven discovery. With a focus on allergic disease, this Rostrum article broadly discusses heterogeneity among CD4sup+/supT cells and provides a rationale for subdividing TsubFH/subcells into both functional and cytokine-skewed subsets. Further, it highlights the plasticity demonstrated by TsubFH/subcells during the primary response and after recall, and it explores the possibility of harnessing this plasticity to reprogram immunity for therapeutic benefit in allergic disease.

Deregulation of neuroblastoma-derived myc (N-myc) is a leading cause of malignant brain tumors in children. To target N-myc-driven medulloblastoma, most research has focused on identifying genomic alterations or on the analysis of the medulloblastoma transcriptome. Here, we have broadly characterized the translatome of medulloblastoma and shown that N-myc unexpectedly drives selective translation of transcripts that promote protein homeostasis. Cancer cells are constantly exposed to proteotoxic stress associated with alterations in protein production or folding. It remains poorly understood how cancers cope with proteotoxic stress to promote their growth. Here, our data revealed that N-myc regulates the expression of specific components (∼5%) of the protein folding machinery at the translational level through the major cap binding protein, eukaryotic initiation factor eIF4E. Reducing eIF4E levels in mouse models of medulloblastoma blocked tumorigenesis. Importantly, targeting Hsp70, a protein folding chaperone translationally regulated by N-myc, suppressed tumor growth in mouse and human medulloblastoma xenograft models. These findings reveal a previously hidden molecular program that promotes medulloblastoma formation and identify new therapies that may have impact in the clinic. Significance: Translatome analysis in medulloblastoma shows that N-myc drives selective translation of transcripts that promote protein homeostasis and that represent new therapeutic vulnerabilities.