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Abstract The location of a patient’s colorectal cancer (CRC) influences their outcome but inherited factors may also be involved. We studied 1899 patients with advanced CRC (514 had proximal colonic, 493 distal colonic and 892 rectal tumours) and carried out genome-wide association studies for survival. Single nucleotide polymorphisms (SNPs) suggestive of association (P

Abstract Background (S)-4-(3-18F-Fluoropropyl)-ʟ-glutamic acid ([18F]FSPG) is a positron emission tomography radiotracer used to image system xc −, an antiporter that is upregulated in several cancers. Not only does imaging system xc − with [18F]FSPG identify tumours, but it can also provide an early readout of response and resistance to therapy. Unfortunately, the clinical production of [18F]FSPG has been hampered by a lack of robust, cGMP-compliant methods. Here, we report the automated synthesis of [18F]FSPG on the Trasis AllinOne™, overcoming previous limitations to provide a user-friendly method ready for clinical adoption. Results The optimised method provided [18F]FSPG in 33.5 ± 4.9% radiochemical yield in just 35 min when starting with 18–25 GBq. Importantly, this method could be scaled up to > 100 GBq starting activity with only a modest reduction in radiochemical yield, providing [18F]FSPG with a molar activity of 372 ± 65 GBq/µmol and excellent radiochemical purity (96.8 ± 1.1%). The formulated product was stable when produced with these high starting activities. Conclusions We have developed the first automated synthesis of [18F]FSPG on the Trasis AllinOne™. The method produces [18F]FSPG with excellent radiochemical purity and in high amounts suitable for large clinical trials and off-site distribution. The method expands the number of synthesis modules capable of producing [18F]FSPG and has been carefully designed for cGMP compliance to simplify regulatory approval for clinical production. The methods developed for the purification of high-activity [18F]FSPG are transferrable and should aid the development of clinical [18F]FSPG productions on other synthesis modules.

Background: The purpose of this study was to examine long-term, greater-than-ten-year outcomes of patients with full-thickness rotator cuff tears treated nonoperatively. Methods: Patients with a chronic, full-thickness rotator cuff tear (demonstrated on imaging) who were referred by their physician for shoulder surgery were enrolled in this prospective study between October 2008 and September 2010. Patients then participated in a comprehensive nonoperative treatment program. After the three-month program, patients were defined as “successful” or “failed.” “Successful” patients were essentially asymptomatic and did not require surgery. “Failed” patients were symptomatic and consented to surgical repair. All patients were followed-up at 1 year, two years, and five years using a validated, disease-specific rotator cuff quality of life score (the RC-QOL) and whether or not they eventually underwent surgery during these time intervals. All of the patients who participated at the five-year follow-up were contacted for this study between 10 and 12 years (mean 11.4 years) after treatment. Results: Original results from this study showed that 75% of patients were treated successfully with the nonoperative program, while 25% failed and needed surgery. These numbers were maintained at the two-year follow-up and five-year follow-up (previously reported). At greater than ten years, 88 patients were contacted for follow-up. Only two patients crossed-over from “success” at 5 years to “failed” at 10 years. The nonoperative “success” group had a mean RC-QOL score of 80 (SD = 18) at the previously reported two-year follow-up and 82 (SD = 16) at five-year follow-up. Forty-one patients provided follow-up RC-QOL data at a mean of 11.4 years. The mean RC-QOL scores of the successfully treated nonoperative group were actually higher than those who required surgery during the course of the study (success group mean 86, SD = 12; “failed”/surgery group mean 78, SD = 24), although this was not statistically different (P = .27). Two patients had crossed over from the successful group to undergo surgery between 5 and 11 years (one had an acute traumatic injury and the other reported aggravation with activity). Conclusion: Nonoperative treatment is an effective and lasting option for many patients with a chronic, full-thickness rotator cuff tear. While some may argue that nonoperative treatment delays inevitable surgical repair, this long-term study shows that patients can do very well over time.

Abstract Objective Osteoarthritis (OA) is a disease impacting the synovial joint complex, yet transcriptional changes specific to shoulder OA remain underexplored. This study aims to profile transcriptomic changes in periarticular tissues from patients undergoing shoulder replacement for OA. By correlating these profiles with QuickDASH scores—a validated measure of worsening shoulder function—this research seeks to understand the gene expression changes associated with clinical decline. Capsular tissue biopsies from shoulder OA patients were compared with those from a control group undergoing shoulder stabilization for recurrent instability. This investigation forms part of a larger transcriptomic analysis of painful shoulder conditions which will address the current gap in knowledge regarding the molecular and genetic underpinnings of shoulder OA, rotator cuff tears and cuff-tear arthropathy. Results The analysis revealed that genes most strongly associated with increasing QuickDASH scores across tissues were linked to inflammation and stress response. Key pathways involved interleukins, chemokines, complement components, nuclear response factors, and immediate early response genes, reflecting a balance between pro- and anti-inflammatory signalling. Additionally, this study identified unique gene expression patterns in shoulder OA not previously observed in hip and knee OA, along with novel genes implicated in shoulder OA, highlighting areas for future targeted investigation. Trial registration This investigation has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), registered on the 26th of March 2018, registration number: 12618000431224, accessible from: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374665&isReview=true

Abstract Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system xc − radiotracer, [18F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC. We found a NRF2-related gene expression signature in a large cohort of NSCLC patients, suggesting an opportunity to preselect patients prior to [18F]FSPG imaging. Furthermore, we reveal that system xc − is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [18F]FSPG as a predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

Abstract Phytolith have been recognized as an important soil bioavailable Si source for plants, as well as a sink of C and heavy metals in soils. Though the impacts of fire and heat on phytolith sequestration of some nutrients (phosphorus, potassium) and heavy metals have been addressed, little attention has been paid to fire’s effects on phytolith carbon sequestration. In this study, the carbon and dissolved Si content of phytoliths extracted from 6 common grass species and their burned ashes, as well as phytoliths collected from different areas (burned, transitional, and unburned) of a pine forest, were compared to characterize the effects of open fire on phytolith carbon content, solubility, and carbon sequestration. The carbon content and Si dissolution of ashed phytoliths varied between plant species, and differed with phytoliths from modern plants. The topsoil phytoliths had increased carbon content, and generally decreased solubility across the gradient of unburned, transitional, and burned pine forest. We therefore conclude that open fire can cause changes in phytolith related carbon content and solubility, as well as its preservation in soils. This study provides new perspective on the effects of open fire on phytolith carbon sequestration and its estimation.

Increases in power output and maximal oxygen consumption (V˙O2max) occur in response to sprint interval exercise (SIE), but common use of “all-out” intensities presents a barrier for many adults. Furthermore, lower-body SIE is not feasible for all adults. We compared physiological and perceptual responses to supramaximal, but “non-all-out” SIE between leg and arm cycling exercise. Twenty-four active adults (mean ​± ​SD age: [25 ​± ​7] y; cycling V˙O2max: [39 ​± ​7] mL·kg−1·min−1) performed incremental exercise using leg (LCE) and arm cycle ergometry (ACE) to determine V˙O2max and maximal work capacity (Wmax). Subsequently, they performed four 20 ​s bouts of SIE at 130% Wmax on the LCE or ACE at cadence ​= ​120–130 ​rev/min, with 2 ​min recovery between intervals. Gas exchange data, heart rate (HR), blood lactate concentration (BLa), rating of perceived exertion (RPE), and affective valence were acquired. Data showed significantly lower (p ​ ​0.42), and lowest affective valence recorded (2.0 ​± ​1.8) was considered “good to fairly good”. Data show that non “all-out” ACE elicits lower absolute but higher relative HR and V˙O2 compared to LCE. Less aversive perceptual responses could make this non-all-out modality feasible for inactive adults.

Abstract Background Care of critically ill patients is complex, requiring effective collaboration co-ordination and communication across care teams and professions. Medicines are a fundamental component of the acute interventions intensive care unit (ICU) patients receive, requiring frequent review and optimisation according to patient needs. ICU patients recovering to transfer to a hospital ward are at risk of medication transition errors, contributing to poorer patient and health-system outcomes. We aimed to develop of a theory-informed intervention package to improve medication safety for ICU patients transferring to a hospital ward. Methods We conducted a qualitative study comprising two UK face-to-face focus group meetings in April and May 2022. There were ten participants in each meeting (7-8 healthcare professionals and 2-3 patient and public representatives). Each meeting had four foci: (i) What needs to change (intervention targets)? (ii) What are the core intervention components? (iii) What will the intervention components change and how (mechanisms of action), and what key outcomes will the changes impact on? (iv) What are the barriers and facilitators to intervention delivery? A background to the problem and previous intervention development work was provided. Meetings were digitally recorded and transcribed verbatim. Iterative analyses, informed by the Behaviour Change Wheel framework, were conducted to provide a behavioural diagnosis, identify key behaviour change techniques and outline the mechanisms of action through which the intervention might impact on key outcome. Results We identified what needs to change to improve medication safety for UK ICU patients on this care transition. A theory-informed intervention package was developed, based on seven core intervention components (e.g., medication review (targeted), task organisation and prioritisation). For each intervention component the mechanism of action, targeted change, and key outcomes were identified (e.g., medication review (targeted); action planning; decreases problematic polypharmacy; decreased preventable adverse drug events). Barriers and facilitators to intervention component delivery were described. Conclusions We developed a theory-informed core intervention package to address the limitations in medication safety for ICU patients transferring to a hospital ward. Understanding what needs to change, and the accompanying facilitators provides a basis for intervention feasibility testing and refinement prior to future evaluation of effectiveness.

Abstract Background Medication overuse headache (MOH) is the most common secondary headache disorder, resulting from chronic and excessive use of medication to treat headaches, for example, sumatriptan. In a recent study, we have shown that the peripheral C-C motif ligand 2 (CCL2), C-C motif chemokine receptor 2 (CCR2) and calcitonin-gene-related peptide (CGRP) signaling pathways interact with each other and play critical roles in the development of chronic migraine-related behavioral and cellular sensitization. In the present study, we investigated whether CCL2-CCR2 and CGRP signaling pathways play a role in the development of sumatriptan overuse-induced sensitization, and whether they are involved in its resolution by the low-dose interleukin-2 (LD-IL-2) treatment. Methods Mice received daily sumatriptan administration for 12 days. MOH-related behavioral sensitization was assessed by measuring changes of periorbital mechanical thresholds for 3 weeks. CCL2-CCR2 and CGRP signaling pathways were inhibited by targeted gene deletion or with an anti-CCL2 antibody. Ca2+-imaging was used to examine whether repetitive sumatriptan treatment enhances CGRP and pituitary adenylate cyclase–activating polypeptide (PACAP) signaling in trigeminal ganglion (TG) neurons. LD-IL-2 treatment was initiated after the establishment of sumatriptan-induced sensitization. Immunohistochemistry and flow cytometry analyses were used to examine whether CCL2-CCR2 signaling controls regulatory T (Treg) cell proliferation and/or trafficking. Results CCL2, CCR2 and CGRPα global KO mice exhibited robust sumatriptan-induced behavioral sensitization comparable to wild-type controls. Antibody neutralization of peripheral CCL2 did not affect sumatriptan-induced behaviors either. Repeated sumatriptan administration did not enhance the strength of CGRP or PACAP signaling in TG neurons. Nevertheless, LD-IL-2 treatment, which facilitated the resolution of sumatriptan-induced sensitization in wild-type and CGRPα KO mice, was completely ineffective in mice with compromised CCL2-CCR2 signaling. In CCL2 KO mice, we observed normal LD-IL-2-induced Treg expansion in peripheral blood, but the increase of Treg cells in dura and TG tissues was significantly reduced in LD-IL-2-treated CCL2 KO mice relative to wild-type controls. Conclusions These results indicate that the endogenous CCL2-CCR2 and CGRP signaling pathways are not involved in sumatriptan-induced behavioral sensitization, suggesting that distinct molecular mechanisms underlie chronic migraine and MOH. On the other hand, peripheral CCL2-CCR2 signaling is required for LD-IL-2 to reverse chronic headache-related sensitization. Graphical abstract

Background: MicroRNAs (miRNAs) show promise as blood-based tumor markers for germ cell tumors (GCTs), with miRNA-371-3p being the most studied. The marginal benefit of including other candidate miRNAs to aid with the management of testicular GCTs remains unclear. Objective: To assess the performance of our combined miRNA assay (371a-3p and 372-3p) in patients with clinically localized testicular masses. Design, setting, and participants: This was a retrospective review of patients prospectively enrolled in an ongoing protocol collecting serum miR-371a-3p and miR-372-3p levels (together, Memorial Sloan Kettering Cancer Center [MSK] miRNA assay [MMA]) in patients with a suspected or diagnosed testicular GCT. Outcome measurements and statistical analysis: The coprimary outcomes of interest were sensitivity and specificity of miR-371a-3p and 372-3p, individually and together, to detect nonteratomatous GCTs in the orchiectomy specimen. Secondary outcomes included additional assay diagnostic parameters, the relationship of patient and disease factors with variations in miRNA levels, and temporal patterns of miRNA normalization after orchiectomy. Results and limitations: Sixty-two patients were included, 52 had a viable GCT at orchiectomy, and ten had no cancer or a non-GCT. Forty-six patients with a GCT had positive preorchiectomy MMA (sensitivity 88.5% [95% confidence interval {CI}: 79.8, 97.2]), and one patient had positive preorchiectomy MMA but no GCT (specificity 90.0% [95% CI: 71.4, 100]). The diagnostic performance of miR-371a-3-p and miR-372-3p was similar. The time for miRNA to decrease to undetectable levels varied, with some patients having positive levels up to 3 wk after orchiectomy. Conclusions: The biomarkers miR-371a-3p and miR-372-3p demonstrated high sensitivity and specificity for localized testicular GCTs, but causes of variation in relative miRNA levels and time to normalization for individual patients remain unclear. Patient summary: We studied the ability of the blood-based biomarkers miR-371a-3p and miR-372-3p to detect testicular cancer (germ cell tumors) in patients with small testicular masses. We found that together and individually these were sensitive and specific for testicular cancer.

Abstract Testicular germ cell tumours (TGCT), which comprise seminoma and non-seminoma subtypes, are the most common cancers in young men. In this study, we present a comprehensive whole genome sequencing analysis of adult TGCTs. Leveraging samples from participants recruited via the UK National Health Service and data from the Genomics England 100,000 Genomes Project, our results provide an extended description of genomic elements underlying TGCT pathogenesis. This catalogue offers a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genome features, including mutational signatures and analysis of extrachromosomal DNA amplification. This study establishes correlations between genomic alterations and histological diversification, revealing divergent evolutionary trajectories among TGCT subtypes. By reconstructing the chronological order of driver events, we identify a subgroup of adult TGCTs undergoing relatively late whole genome duplication. Additionally, we present evidence that human leukocyte antigen loss is a more prevalent mechanism of immune disruption in seminomas. Collectively, our findings provide valuable insights into the developmental and immune modulatory processes implicated in TGCT pathogenesis and progression.

Abstract Brain microvascular dysfunction is an important feature of Alzheimer’s disease (AD). To better understand the brain microvascular molecular signatures of AD, we processed and analyzed isolated human brain microvessels by data-independent acquisition liquid chromatography with tandem mass spectrometry (DIA LC–MS/MS) to generate a quantitative dataset at the peptide and protein level. Brain microvessels were isolated from parietal cortex grey matter using protocols that preserve viability for downstream functional studies. Our cohort included 23 subjects with clinical and neuropathologic concordance for Alzheimer’s disease, and 21 age-matched controls. In our analysis, we identified 168 proteins whose abundance was significantly increased, and no proteins that were significantly decreased in AD. The most highly increased proteins included amyloid beta, tau, midkine, SPARC related modular calcium binding 1 (SMOC1), and fatty acid binding protein 7 (FABP7). Additionally, Gene Ontology (GO) enrichment analysis identified the enrichment of increased proteins involved in cellular detoxification and antioxidative responses. A systematic evaluation of protein functions using the UniProt database identified groupings into common functional themes including the regulation of cellular proliferation, cellular differentiation and survival, inflammation, extracellular matrix, cell stress responses, metabolism, coagulation and heme breakdown, protein degradation, cytoskeleton, subcellular trafficking, cell motility, and cell signaling. This suggests that AD brain microvessels exist in a stressed state of increased energy demand, and mount a compensatory response to ongoing oxidative and cellular damage that is associated with AD. We also used public RNAseq databases to identify cell-type enriched genes that were detected at the protein level and found no changes in abundance of these proteins between control and AD groups, indicating that changes in cellular composition of the isolated microvessels were minimal between AD and no-AD groups. Using public data, we additionally found that under half of the proteins that were significantly increased in AD microvessels had concordant changes in brain microvascular mRNA, implying substantial discordance between gene and protein levels. Together, our results offer novel insights into the molecular underpinnings of brain microvascular dysfunction in AD.

Abstract With an interest in monitoring the patency of stents that are used to treat strictures in the bile duct, this paper reports the investigation of a wireless sensing system to interrogate a microsensor integrated into the stent. The microsensor is comprised of a 28-μm-thick magnetoelastic foil with 8.25-mm length and 1-mm width. Magnetic biasing is provided by permanent magnets attached to the foil. These elements are incorporated into a customized 3D polymeric package. The system electromagnetically excites the magnetoelastic resonant sensor and measures the resulting signal. Through shifts in resonant frequency and quality factor, the sensor is intended to provide an early indication of sludge accumulation in the stent. This work focuses on challenges associated with sensor miniaturization and placement, wireless range, drive signal feedthrough, and clinical use. A swine specimen in vivo experiment is described. Following endoscopic implantation of the sensor enabled plastic stent into the bile duct, at a range of approximately 17 cm, the signal-to-noise ratio of ~106 was observed with an interrogation time of 336 s. These are the first reported signals from a passive wireless magnetoelastic sensor implanted in a live animal.

Abstract There is limited access to molecular genetic testing in most low- and middle-income countries. The iHope program provides clinical genome sequencing (cGS) to underserved individuals with signs or symptoms of rare genetic diseases and limited or no access to molecular genetic testing. Here we describe the performance and impact of cGS in 247 patients from three clinics in Peru. Although most patients had at least one genetic test prior to cGS (70.9%), the most frequent was karyotyping (53.4%). The diagnostic yield of cGS was 54.3%, with candidate variants reported in an additional 22.3% of patients. Clinical GS results impacted clinician diagnostic evaluation in 85.0% and genetic counseling in 72.1% of cases. Changes in management were reported in 71.3%, inclusive of referrals (64.7%), therapeutics (26.3%), laboratory or physiological testing (25.5%), imaging (19%), and palliative care (17.4%), suggesting that increased availability of genomic testing in Peru would enable improved patient management.

Purpose: Subretinal fibrosis has been reported as a presumed late sequela of orbital trauma in those with Stargardt disease (STGD). This case report highlights the sequential pathologic changes in response to trauma utilizing multimodal imaging. Observations: An asymptomatic 19-year-old female with no significant ocular history presented for possible drusen. Initial imaging noted yellow-white pisciform perifoveal flecks in both eyes with corresponding hyper-and hypo-fluorescent lesions on fundus autofluorescence and hyperreflective deposits on near-infrared and spectral-domain optical coherence tomography (SD-OCT). A few months later, the patient presented with a new onset “black shadow” in the right eye after a traumatic periorbital injury, with multi-modal imaging revealing sequelae of commotio retinae superotemporally. Follow-up imaging three months later revealed a large patch of hyperpigmented chorioretinal scar corresponding to the region of commotio. SD-OCT delineated findings consistent with subretinal fibrosis. Given the constellation of findings and subsequent genetic testing, the patient was diagnosed with STGD. Conclusions and importance: Multimodal imaging allows for the detection of traumatic transformation of STGD and monitoring for early signs of massive lipofuscin release within the immediate post-traumatic period. Given the impact of minor orbital trauma on prognosis, caution should be taken to minimize and prevent orbital trauma in patients with STGD.

Background: Primary arthroscopic-assisted anterior cruciate ligament (ACL) reconstruction using a bone–patellar tendon–bone (BTB) graft offers excellent long-term results for patients with ACL tears. When concurrent meniscal damage is present, the preferred treatment is repair of the meniscus. However, meniscectomy may be needed, which can result in insufficient meniscal function. Indications: ACL reconstruction performed concomitantly with meniscal allograft transplantation (MAT) is indicated for patients with ACL tears and meniscal insufficiency. This procedure is typically reserved for younger, active patients, such as the 38-year-old woman in this presentation. Technique Description: The patient was placed in the supine position. The BTB graft was harvested first using a standard medial midline incision. A posterior meniscus root tunnel was drilled, followed by drilling of the femoral tunnel for ACL reconstruction. The tibial tunnel for ACL reconstruction was subsequently created, after which tapping was performed for anterior meniscus root fixation. The meniscal allograft was secured using alternating vertical mattress inside-out sutures. Finally, the BTB graft was passed through the tibial and femoral tunnels. Results: Outcomes following ACL reconstruction with BTB autograft and MAT are positive, with a 5-year survival between 84% and 91%. ACL reinjury and long-term development of osteoarthritis are the most common complications. In this case, the patient returned to work within 7 months and reported 0 out of 10 pain. Discussion/Conclusion: ACL reconstruction with BTB autograft and concomitant MAT is a viable treatment option for patients with ACL tears in the context of meniscal deficiency. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

We apply moral foundations theory (MFT) to explore how the public conceptualizes the first eight months of the conflict between Ukraine and the Russian Federation (Russia). Our analysis includes over 1.1 million English tweets related to the conflict over the first 36 weeks. We used linguistic inquiry word count (LIWC) and a moral foundations dictionary to identify tweets’ moral components (care, fairness, loyalty, authority, and sanctity) from the United States, pre- and post-Cold War NATO countries, Ukraine, and Russia. Following an initial spike at the beginning of the conflict, tweet volume declined and stabilized by week 10. The level of moral content varied significantly across the five regions and the five moral components. Tweets from the different regions included significantly different moral foundations to conceptualize the conflict. Across all regions, tweets were dominated by loyalty content, while fairness content was infrequent. Moral content over time was relatively stable, and variations were linked to reported conflict events.

Abstract Microsatellite instability high (MSI-H) and mismatch repair deficient (dMMR) tumor status have been demonstrated to predict patient response to immunotherapies. We developed and validated a next-generation sequencing (NGS)-based companion diagnostic (CDx) to detect MSI-H solid tumors via a comprehensive genomic profiling (CGP) assay, FoundationOne®CDx (F1CDx). To determine MSI status, F1CDx calculates the fraction of unstable microsatellite loci across >2000 loci using a fraction-based (FB) analysis. Across solid tumor types, F1CDx demonstrated a high analytical concordance with both PCR (n = 264) and IHC (n = 279) with an overall percent agreement (OPA) of 97.7% and 97.8%, respectively. As part of a retrospective bridging clinical study from KEYNOTE-158 Cohort K and KEYNOTE-164, patients with MSI-H tumors as determined by F1CDx demonstrated an objective response rate (ORR) of 43.0% to pembrolizumab. In real-world cancer patients from a deidentified clinicogenomic database, F1CDx was at least equivalent in assessing clinical outcome following immunotherapy compared with MMR IHC. Demonstrated analytical and clinical performance of F1CDx led to the pan-tumor FDA approval in 2022 of F1CDx to identify MSI-H solid tumor patients for treatment with pembrolizumab. F1CDx is an accurate, reliable, and FDA-approved method for the identification of MSI-H tumors for treatment with pembrolizumab.

Abstract The neocortex varies in size and complexity among mammals due to the tremendous variability in the number and diversity of neuronal subtypes across species. The increased cellular diversity is paralleled by the expansion of the pool of neocortical progenitors and the emergence of indirect neurogenesis during brain evolution. The molecular pathways that control these biological processes and are disrupted in neurological disorders remain largely unknown. Here we show that the transcription factors BRN1 and BRN2 have an evolutionary conserved function in neocortical progenitors to control their proliferative capacity and the switch from direct to indirect neurogenesis. Functional studies in mice and ferrets show that BRN1/2 act in concert with NOTCH and primary microcephaly genes to regulate progenitor behavior. Analysis of transcriptomics data from genetically modified macaques provides evidence that these molecular pathways are conserved in non-human primates. Our findings thus demonstrate that BRN1/2 are central regulators of gene expression programs in neocortical progenitors critical to determine brain size during evolution.

Abstract Background The performance and availability of invasive and non-invasive investigations for the diagnosis of Pneumocystis jirovecii pneumonia (PCP) vary across clinical settings. Estimating the pre-test probability of PCP is essential to the optimal selection and interpretation of diagnostic tests, such as the 1,3-β-D-glucan assay (BDG), for the prioritization of bronchoscopy, and to guide empiric treatment decisions. We aimed to develop a multivariable risk score to estimate the pre-test probability of PCP. Methods The score was developed from a cohort of 626 individuals who underwent bronchoscopy for the purposes of identifying PCP in a Canadian tertiary-care centre, between 2015 and 2018. We conducted a nested case-control study of 57 cases and 228 unmatched controls. Demographic, clinical, laboratory, and radiological data were included in a multivariable logistic regression model to estimate adjusted odds ratios for PCP diagnosis. A clinical risk score was derived from the multivariable model and discrimination was assessed by estimating the score’s receiver operating characteristic curve. Results Participants had a median age of 60 years (interquartile range [IQR] 49–68) and 115 (40%) were female; 40 (14%) had HIV and 49 (17%) had a solid organ transplant (SOT). The risk score included prior SOT or HIV with CD4 ≤ 200/µL (+ 2), serum lactate dehydrogenase ≥ 265.5 IU/mL (+ 2), radiological pattern typical of PCP on chest x-ray (+ 2) or CT scan (+ 2.5), and PCP prophylaxis with trimethoprim-sulfamethoxazole (-3) or other antimicrobials (-2). The median score was 4 points (IQR, 2-4.5) corresponding to a 28% probability of PCP. The risk prediction model had good discrimination with a c-statistic of 0.79 (0.71–0.84). Given the operating characteristics of the BDG assay, scores ≤ 3 in patients without HIV, and ≤ 5.5 in those with HIV, paired with a negative BDG, would be expected to rule out PCP with 95% certainty. Conclusion We propose the PCP Score to estimate pre-test probability of PCP. Once validated, it should help clinicians determine which patients to refer for invasive investigations, when to rely on serological testing, and in whom to consider pre-emptive treatment.

Medically important ixodid ticks often carry multiple pathogens, with individual ticks frequently coinfected and capable of transmitting multiple infections to hosts, including humans. Acquisition of multiple zoonotic pathogens by immature blacklegged ticks (Ixodes scapularis) is facilitated when they feed on small mammals, which are the most competent reservoir hosts for Anaplasma phagocytophilum (which causes anaplasmosis in humans), Babesia microti (babesiosis) and Borrelia burgdorferi (Lyme disease). Here, we used data from a large-scale, long-term experiment to ask whether patterns of single and multiple infections in questing nymphal I. scapularis ticks from residential neighbourhoods differed from those predicted by independent assortment of pathogens, and whether patterns of coinfection were affected by residential application of commercial acaricidal products. Quantitative polymerase chain reaction was used for pathogen detection in multiplex reactions. In control neighbourhoods and those treated with a fungus-based biopesticide deployed against host-seeking ticks (Met52), ticks having only single infections of either B. microti or B. burgdorferi were significantly less common than expected, whereas coinfections with these 2 pathogens were significantly more common. However, use of tick control system bait boxes, which kill ticks attempting to feed on small mammals, eliminated the bias towards coinfection. Although aimed at reducing the abundance of host-seeking ticks, control methods directed at ticks attached to small mammals may influence human exposure to coinfected ticks and the probability of exposure to multiple tick-borne infections.

Abstract The retina is light-sensitive neuronal tissue in the back of the eye. The phospholipid composition of the retina is unique and highly enriched in polyunsaturated fatty acids, including docosahexaenoic fatty acid (DHA). While it is generally accepted that a high DHA content is important for vision, surprisingly little is known about the mechanisms of DHA enrichment in the retina. Furthermore, the biological processes controlled by DHA in the eye remain poorly defined as well. Here, we combined genetic manipulations with lipidomic analysis in mice to demonstrate that acyl-CoA synthetase 6 (Acsl6) serves as a regulator of the unique composition of retinal membranes. Inactivation of Acsl6 reduced the levels of DHA-containing phospholipids, led to progressive loss of light-sensitive rod photoreceptor neurons, attenuated the light responses of these cells, and evoked distinct transcriptional response in the retina involving the Srebf1/2 (sterol regulatory element binding transcription factors 1/2) pathway. This study identifies one of the major enzymes responsible for DHA enrichment in the retinal membranes and introduces a model allowing an evaluation of rod functioning and pathology caused by impaired DHA incorporation/retention in the retina.

Abstract The ability to image early treatment response to radiotherapy in head and neck squamous cell carcinoma (HNSCC) will enable the identification of radioresistant tumor volumes suitable for treatment intensification. Here, we propose the system xc − radiotracer (4S)-4-(3-[18F]fluoropropyl)-L-glutamate ([18F]FSPG) as a non-invasive method to monitor radiation response in HNSCC. We assessed temporal changes in cell death, antioxidant status, and [18F]FSPG retention following a single dose of 10 Gy irradiation in FaDU HNSCC cells. Next, using a fractionated course of radiotherapy, we assessed tumor volume changes and performed [18F]FSPG-PET imaging in FaDU-bearing mouse xenografts, followed by ex vivo response assessment. In cells, 10 Gy irradiation reduced [18F]FSPG retention, coinciding with the induction of apoptosis and the production of reactive oxygen species. In vivo, [18F]FSPG tumor retention was halved seven days after the start of treatment, which preceded radiotherapy-induced tumor shrinkage, thereby confirming [18F]FSPG-PET as an early and sensitive marker of radiation response.

Abstract Background Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. Methods An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. Results CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. Conclusions To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.

Abstract Robustness is the reproducible development of a phenotype despite stochastic noise. It often involves tradeoffs with other performance metrics, but the mechanisms underlying such tradeoffs were largely unknown. An Arabidopsis flower robustly develops four sepals from four precisely positioned auxin maxima. The development related myb-like 1 (drmy1) mutant generates noise in auxin signaling that disrupts robustness in sepal initiation. Here, we find that increased expression of CUP-SHAPED COTYLEDON1 (CUC1), a boundary specification transcription factor, in drmy1 underlies this loss of robustness. CUC1 surrounds and amplifies stochastic auxin noise in drmy1 to form variably positioned auxin maxima and sepal primordia. Removing CUC1 from drmy1 provides time for noisy auxin signaling to resolve into four precisely positioned auxin maxima, restoring robust sepal initiation. However, removing CUC1 decreases the intensity of auxin maxima and slows down sepal initiation. Thus, CUC1 increases morphogenesis speed but impairs robustness against auxin noise. Further, using a computational model, we find that the observed phenotype can be explained by the effect of CUC1 in repolarizing PIN FORMED1 (PIN1), a polar auxin transporter. Lastly, our model predicts that reducing global growth rate improves developmental robustness, which we validate experimentally. Thus, our study illustrates a tradeoff between speed and robustness during development.

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients.

Objective: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in India. There is no laboratory-based CVD risk data among Indians from different regions and backgrounds. This study estimated laboratory-based 10-year CVD risk across different population sub-groups. Methods: Data from UDAY derived from cross-sectional surveys of rural and urban populations of northern (Haryana) and southern (Andhra Pradesh) India were analysed. World Health Organization/International Society of Hypertension laboratory-based equations calculated 10-year CVD risk among participants without CVD history. Wilcoxon rank sum test analyzed average CVD risk across subgroups. Chi-square test compared population proportions in different CVD risk categories. Regression analysis assessed the association between CVD risk and participant characteristics. Results: The mean (SD) age of the participants (n = 8448) was 53.2 (9.2) years. Males in Haryana had increased CVD risk compared to those in Andhra Pradesh (p

In recent years, soil-transmitted helminthiases, including strongyloidiasis have become a prominent public health concern in the southeastern United States of America (USA). While there is ongoing human soil-transmitted helminths (STH) surveillance in Mississippi and Alabama, very little attention has been paid to potentially zoonotic STH from dogs in this region. We microscopically examined faecal samples collected from 252 shelter dogs in Mississippi using the formalin-ethyl acetate sedimentation method. Extracted DNA were subjected to three multiplex real-time polymerase chain reaction (qPCR) assays targeting canine STH (canine hookworm species, Strongyloides spp., Toxocara species and Baylisascaris procyonis). The combined prevalence of STH by microscopy and qPCRs in Mississippi dogs was 62.7 %, with hookworms at 50.0 % and Toxocara at 24.2 %. qPCR identified Ancylostoma caninum (44.4 %), Toxocara canis (22.2 %), Strongyloides spp. (1.2 %), and Uncinaria stenocephala (0.8 %). No other canine hookworm species, Baylisascaris procyonis, or Toxocara cati were detected by qPCR. Seven additional intestinal parasites were identified by microscopy, including Trichuris vulpis (13.5 %), Physaloptera sp. (6.4 %), Cystoisospora sp. (3.2 %), Dipylidium caninum (1.2 %). Giardia duodenalis (0.8 %), Alaria sp. (0.4 %), and Macracanthorhynchus sp. (0.4 %). These findings, combined with recent human cases in Mississippi, highlight the need for targeted public health messaging to promote regular anthelmintic treatment for dogs and their owners.

Summary: Background: Polycystic ovary syndrome (PCOS) is a common endocrinopathy with significant reproductive, metabolic, and psychological complications. Consensus on PCOS clinical research priorities across end-users is fundamental and necessitates a robust co-development of a clinical research roadmap to guide international research efforts. Methods: A multistage process included: i) international surveys of women and healthcare providers to identify research priorities and unmet needs; ii) interrogation of systematic reviews conducted for the International PCOS Guideline to identify research gaps; iii) International PCOS Guideline Network consensus generated clinical research roadmap; and iv) international peer review for external validation. Findings: A codesigned survey engaging 1278 women with PCOS and 1474 healthcare providers found general concordance on research priorities. International PCOS Guideline development processes identified gaps in the literature and coproduced over 150 research priorities throughout the women’s life course, affirmed in international peer review. Key themes included: 1) Optimizing PCOS diagnosis; understanding natural history across diverse populations and life stages; detecting and preventing complications, and integrating and interrogating large data assets; 2) developing evidence-based resources, exploring optimal modes for information provision and models of care; 3) exploring effective lifestyle and weight management strategies; minimising weight stigma; 4) exploring intervention effects (including treatment efficacy, safety, cost-effectiveness, and long-term follow-up) on diverse features of PCOS across subgroups; and 5) optimising preconception care and fertility treatments in PCOS. Interpretation: This rigorously coproduced International PCOS Guideline clinical research roadmap addresses stakeholder priorities to guide future clinical research in this common yet neglected condition. The roadmap complements the established PCOS Core Outcome Set to enhance research quality, and tackles evidence-practice gaps to improve health outcomes for women with PCOS throughout their life course. Funding: The survey, International PCOS Guideline Network and 2018 and 2023 International PCOS Guidelines were funded by the Australian National Health and Medical Research Council (NHMRC) Centres of Research excellence in PCOS (APP1078444) and in Women’s Health in Reproductive life (APP1171592). Guideline partners, American Society for Reproductive Medicine (ASRM), Endocrine Society, European Society of Human Reproduction and Embryology (ESHRE), and European Society of Endocrinology (ESE), provided additional funding and assisted in guideline development. HT and AM are NHMRC Research Fellows. LM was funded by a Heart Foundation Future Leader and Veski Fellowship and CTT by the NHMRC Centres of Research excellence in Women’s Health in Reproductive life. All disclosures of interest were declared before commencing GDG involvement and updated before all major milestones and are available alongside the PCOS Guideline (https://www.monash.edu/__data/assets/pdf_file/0009/3371292/Register-of-disclosures-of-interest.pdf).

Intra-abdominal arterial reconstructions in the setting of reoperative, contaminated, or frankly infected fields can be a challenging undertaking for even the most experienced vascular surgeons. Open surgical arterial transpositions have been less commonly performed than other methods of reconstruction in the current era of vascular surgery despite many historical reports of successful outcomes. Autologous artery transpositions represent a viable option in the case of an infected or a contaminated operative field. We have described the cases of three patients treated at our institution who had required intra-abdominal revascularization in a contaminated or frankly infected surgical field. All three patients were successfully treated using open native visceral artery transposition procedures. These cases presented multiple challenges secondary to the ongoing infections, infected operative field, and, sometimes, a history of multiple vascular bypasses involving the aorta and visceral arteries. In such circumstances, we have demonstrated the effectiveness of native visceral arterial transposition as a feasible technique.

Epigenomic annotations for the rat lag far behind those of human and mouse, despite the rat’s immense utility in pharmacological and behavioral studies and the need to understand their epigenetic mechanisms. We have designed a targeted-enrichment method followed by next-generation sequencing (Methyl-Seq) to identify DNA methylation (DNAm) signatures across the rat genome. The design reflected an attempt to create a more comprehensive investigation of the rat epigenome, as it included promoters, CpG islands, and island shores of all RefSeq genes. In this study, we implemented the rat Methyl-Seq platform and tested its ability to distinguish differentially methylated regions (DMRs) among three different tissue types, three distinct brain regions, and, in the hippocampus, between males and females. These comparisons yielded DNAm differences of differing magnitudes, many of which were independently validated by bisulfite pyrosequencing, including autosomal regions that were predicted to show the least degree of difference in DNAm between males and females. Quantitative reverse transcription PCR revealed that most genes associated with the DMRs showed tissue-, brain region-, and sex-specific differences in expression. In particular, we found evidence for sex-specific DNAm and expression differences at Tubb6, Lrrn2, Tex26, and Sox5l1, all of which play important roles in neurodevelopment and have been implicated in studies examining sex differences. Our results demonstrate the utility of the rat Methyl-Seq platform and suggest the presence of DNAm differences between the male and female hippocampus. The rat Methyl-Seq has the potential to provide epigenomic insights into pharmacological and behavioral studies performed in the rat.

Abstract. Objectives:. Does degree of comminution affect femoral version after intramedullary nailing of femoral shaft fractures? Design:. Retrospective. Setting:. Standard of care, Level II Trauma Center, Hospital. Patients/Participants:. We reviewed electronic medical records of consecutive patients from 2000 to 2009 with diaphyseal femoral shaft fractures treated with intramedullary nailing and with available early postoperative computed tomography scanograms. Four hundred seventeen patients were identified, and 307 met inclusion criteria. Intervention:. Intramedullary nailing of the femur. Main Outcome Measurements:. Our primary study measure, determined before data collection, was the difference in femoral version between the uninjured limb and the injured limb. Femoral version was determined on postoperative computed tomography scanograms and reviewed by a fellowship trained musculoskeletal radiologist and a senior orthopaedic surgeon. Results:. Fractures were classified by an experienced orthopaedic trauma attending surgeon. OTA/AO type A fractures were the most common (51.5%), followed by type B (30.0%) and type C (18.5%). When categorized according to the Winquist system, 49.5% were type 1, 14.7% were type 2, 21.2% were type 3, and 14.7% were type 4. In univariate analysis, none of the classification systems were predictive of postoperative difference in femoral version (OTA/AO types and subtypes, OTA/AO types only, all Winquist types, and low-grade vs. high-grade Winquist; P > 0.05 for all). Subsequently, multivariate models did not yield any significant predictors. Conclusions:. Increasing degree of comminution based on fracture classifications had no significant impact on obtaining acceptable femoral version after intramedullary nailing. Level of Evidence:. Level III.

This article has been withdrawn at the request of the editor and publisher.The publisher regrets that an error occurred which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error.The full Elsevier Policy on Article Withdrawal can be found at (https://www.elsevier.com/about/policies/article-withdrawal).

Summary: Division plane orientation contributes to cell shape and topological organization, playing a key role in morphogenesis, but the precise physical and molecular mechanism influencing these processes remains largely obscure in plants. In particular, it is less clear how the placement of the new walls occurs in relation to the walls of neighboring cells. Here, we show that genetic perturbation of the actin cytoskeleton results in more rectangular cell shapes and higher incidences of four-way junctions, perturbing the global topology of cells in the shoot apical meristem of Arabidopsis thaliana. Actin mutants also exhibit changes in the expansion rate of the new versus the maternal cell wall after division, affecting the evolution of internal angles at tricellular junctions. Further, the increased width of the preprophase band in the actin mutant contributes to inaccuracy in the placement of the new cell wall. Computational simulation further substantiates this hypothesis and reproduces the observed cell shape defects.

The use of ligand conjugation onto nanoparticle surfaces as an active targeting strategy has gained significant attention in the pursuit of improving tumor‐specific delivery and retention. However, the chemical conjugation of targeting moieties often induces alterations in the physicochemical properties of nanoparticles, including size, conformation, charge‐to‐mass ratio, and hydrophilicity/lipophilicity, resulting in unexpected biodistribution and pharmacokinetic profiles. Here, the enhanced active targeting efficiency achieved by integrating cyclic arginine–glycine–aspartic acid (cRGD) peptides onto ultrasmall nanocarrier H‐dot while preserving its essential physicochemical and pharmacokinetic attributes is investigated. The resulting cRGD/H‐dots demonstrate improved cellular uptake via integrin αvβ3 receptors, accompanied by negligible cytotoxicity. Notably, the active targeting efficacy of cRGD/H‐dots compared to unmodified H‐dots (1.2%ID/g, two‐fold increase) is quantitatively evaluated, validated through fluorescence imaging and histological analysis. The findings highlight that cRGD/H‐dots offer enhanced tumor targetability and prolonged tumoral retention while maintaining active renal clearance of unbound molecules.

The sunk-cost effect (SCE) refers to the tendency to continue pouring resources into a venture due to unrecoverable prior investments, despite a potentially unfavorable outcome ahead. In the two studies reported here, we aimed to explore the issue of whether the SCE is susceptible to the involvement of others by differentiating the individual who would incur the cost (i.e., self vs. someone close vs. stranger) as well as the modality of the primary decision maker's involvement (i.e., making a decision vs. a prediction vs. a suggestion). To measure the magnitude of the SCE, we used eight vignettes about everyday personal decisions adapted from Strough et al. (2014) in Experiment 1 and developed a new scale with 20 vignettes in Experiment 2. Our main findings showed that predictions indicate a greater SCE than suggestions for someone close and strangers. However, we did not find evidence in either experiment supporting the hypothesis that the SCE would be greater for self than for someone close for either decisions or predictions. We discuss the implications of these findings in terms of five competing interpretations of the SCE, namely, mental accounting, gain-loss framing, wishful thinking, opportunity costs, and conflicting objectives.

ObjectiveThe impact of chronic exposure to stress or glucocorticoids on psychiatric symptoms has been exemplified by cases of iatrogenic or endogenous hypercortisolism such as Cushing’s syndrome (CS). The amygdala plays an important role in mediating both stress and affective responses, and one of the key factors that link stress response and psychiatric symptoms is the corticotropin-releasing factor (CRF). Epigenetic changes, especially those occurring on CpG dinucleotides in DNA of glucocorticoid target genes in blood, have been previously implicated as potential predictors of glucocorticoid-related events in the central nervous system (CNS). In this study, we examined amygdala volume and mood symptoms in CS patients and aimed at evaluating whether these parameters were associated with blood DNA methylation of CRF.MethodsIn this cross-sectional study, 32 CS patients and 32 healthy controls matched for age, sex, and years of education underwent an MRI scan, a Beck Depression Inventory-II, and a State-Trait Anxiety Inventory. Genomic DNA extracted from total leukocytes were used for DNA methylation analysis of several CpG dinucleotides at the CRF promoter region.ResultsSignificant associations between CRF methylation vs. amygdala volume (CpG-1, P = 0.006) and depression scores (CpG-2, P = 0.01) were found. To assess whether the promoter CpG methylation has functional consequences, we examined RNA and DNA extracted from non-CS, postmortem amygdala tissues. A significant association between CpG methylation and gene expression (CpG-1, P = 0.004) was observed.ConclusionThese results demonstrate that methylation levels of the CRF promoter CpGs are associated with amygdala volume in CS and related mood symptoms. Methylation levels may also be associated with CRF expression. This finding supports the feasibility of using epigenetic patterns in blood as a surrogate for assessing GC-related pathologies in the brain.

IntroductionSepsis is a complex clinical syndrome characterized by a heterogenous host immune response. Historically, static protein and transcriptomic metrics have been employed to describe the underlying biology. Here, we tested the hypothesis that ex vivo functional TNF expression as well as an immunologic endotype based on both IFNγ and TNF expression could be used to model clinical outcomes in sepsis patients.MethodsThis prospective, observational study of patient samples collected from the SPIES consortium included patients at five health systems enrolled over 17 months, with 46 healthy control patients, 68 ICU patients without sepsis, and 107 ICU patients with sepsis. Whole blood was collected on day 1, 4, and 7 of ICU admission. Outcomes included in-hospital and 180-day mortality and non-favorable discharge disposition defined by skilled nursing facility, long-term acute care facility, or hospice. Whole blood ELISpot assays were conducted to quantify TNF expression [stimulated by lipopolysaccharide (LPS)] and IFNγ expression (stimulated by anti-CD3/CD28 mAb), which were then used for assignment to one of four subgroups including an ‘immunocompetent’, ‘immunosuppressed endotype’, and two ‘mixed’ endotypes.ResultsWhole blood TNF spot-forming units were significantly increased in septic and CINS patients on days 4 and 7 compared to healthy subjects. In contrast, TNF expression per cell on days 1, 4, and 7 was significantly lower in both septic and critically ill non-septic (CINS) patients compared to healthy subjects. Early increases in total TNF expression were associated with favorable discharge disposition and lower in-hospital mortality. ‘Immunocompetent’ endotype patients on day 1 had a higher proportion of favorable to non-favorable discharges compared to the ‘immunosuppressed’ endotype. Similarly, ‘immunocompetent’ endotype patients on day 4 had a higher in-hospital survival compared to the ‘immunosuppressed’ endotype patients. Finally, among septic patients, decreased total TNF and IFNγ expression were associated with 180-day mortality.ConclusionsIncreased ex vivo whole blood TNF expression is associated with improved clinical outcomes. Further, the early ‘immunocompetent’ endotype is associated with favorable discharge and improved in-hospital and 180-day survival. The ability to functionally stratify septic patients based on blood cell function ex vivo may allow for identification of future immune modulating therapies.

Abstract New approaches are needed to resolve persistent geographic gaps and biases in paleofire research. Most sedimentary paleofire research relies on lake and peat sediments. We present an unconventional sedimentary charcoal record preserved in a modern, post‐bomb bat guano deposit and compare its accumulation to historical fire data. We find strong correlations between charcoal accumulation rates (CHAR) and non‐winter prescribed burns. CHAR in bat guano is more strongly correlated with prescribed fire than wildfire or total area burned, likely due to bats seeking out areas burned by prescribed fire for better foraging opportunities and/or bats avoiding wildfire. We attribute the CHAR in guano being a better recorder of area burned during non‐winter months to winter bat hibernation. Our analyses show that charcoal preserved in bat guano is a reliable paleofire proxy system, which has important implications for the paleofire field and encourages future research using bat guano as a viable archive.

Abstract Lyme disease, the most prevalent tick‐borne disease in North America, is caused by the bacterium Borrelia burgdorferi, and in the eastern and central United States, it is spread to humans by the black‐legged tick (Ixodes scapularis). Due to the complex, multiyear and multihost life cycle of this species, a matrix modeling approach is needed to effectively estimate subseasonal, multistage survival and transition dynamics in order to better understand and predict when population growth is high. Of the three questing tick life stages (larvae, nymphs, and adults), nymphs are most often associated with transmitting the bacteria to humans, and previous work suggests a mix of abiotic and biotic drivers are associated with nymph abundance. However, understanding tick population growth requires understanding mortality and transition probabilities for each stage and each stage may be individually and uniquely impacted by climate and host availability. A larval tick, for example, may experience warming temperatures differently than nymph or adults, because they are present on the landscape at different times. Here, we describe and validate a model that accounts for field sampling design and evaluates abiotic (temperature, relative humidity, precipitation) and biotic (host abundance) drivers of variation in tick population growth. To account for the drivers of subseasonal and interannual variability in demography, phenology, and population density, we built stage‐structured population models that account for variability in meteorology and host population abundance throughout the full tick lifecycle. Our model is fit and validated with 11 years of tick and host data from the northeastern United States. In this context, we found that a four‐stage model that includes unique transitions to and from a dormant, overwintering nymph state outperforms a model that only includes the three questing stages, and that incorporating the abundance of the predominant host species, Peromyscus leucopus, and weather variables improved predictions and model fit. Additionally, the model accurately predicted all three questing stages at sites different than where they were calibrated, showing that this model structure is generally transferable. Overall, this model lays a foundation for the real‐time iterative forecasting of tick populations needed to effectively protect public health.

Dana James and Evan Bowness’ book, Growing and eating sustainably: Agroecology in action, provides a portrayal of existing sites of a radically different food system than our present industrial one. The authors explore the origin of agroecology as a social movement, before expanding on the ways in which grower-eater relations can and are being strengthened in southern Brazil. Finally, they envision a future of global food systems that centre the justice and intersectionality explicit within the agroecological movement. The authors’ presentation of both photography and text draws individual stories out from abstract notions of ideal futures and brings them to life with their particularities.

A fecal survey in Tamil Nadu, India, revealed 2 persons passed schistosome eggs, later identified as Schistosoma incognitum, a parasite of pigs, dogs, and rats. We investigated those cases and reviewed autochthonous schistosomiasis cases from India and Nepal. Whether the 2 new cases represent true infection or spurious passage is undetermined.

Abstract Lower body negative pressure (LBNP) has been proposed as a countermeasure to mitigate the cephalad fluid shift occurring during spaceflight, which may be associated with the development of Spaceflight Associated Neuro-ocular Syndrome (SANS). This study quantifies the effect of LBNP on intraocular pressure (IOP), mean arterial pressure at eye level (MAPeye), and ocular perfusion pressure (OPP). Twenty-four subjects (12 male, 12 female) were subjected to graded LBNP in 0° supine and 15° head-down tilt (HDT) postures from 0 mmHg to –50 mmHg in 10 mmHg increments. IOP decreased significantly with LBNP pressure in 0° supine (by 0.7 ± 0.09 mmHg per 10 mmHg LBNP pressure, p

Abstract Intrinsic breast cancer molecular subtyping (IBCMS) provides significant prognostic information for patients with breast cancer and helps determine treatment. This study compared IBCMS methods on various gene-expression platforms in PALOMA-2 and PALLET trials. PALOMA-2 tumor samples were profiled using EdgeSeq and nanostring and subtyped with AIMS, PAM50, and research-use-only (ruo)Prosigna. PALLET tumor biopsies were profiled using mRNA sequencing and subtyped with AIMS and PAM50. In PALOMA-2 (n = 222), a 54% agreement was observed between results from AIMS and gold-standard ruoProsigna, with AIMS assigning 67% basal-like to HER2-enriched. In PALLET (n = 224), a 69% agreement was observed between results from PAM50 and AIMS. Different IBCMS methods may lead to different results and could misguide treatment selection; hence, a standardized clinical PAM50 assay and computational approach should be used. Trial number: NCT01740427

Abstract Background Patient outcomes following low-trauma hip fracture are suboptimal resulting in increased healthcare costs and poor functional outcomes at 1 year. Providing early and intensive in-hospital physiotherapy could help improve patient outcomes and reduce costs following hip fracture surgery. The HIP fracture Supplemental Therapy to Enhance Recovery (HIPSTER) trial will compare usual care physiotherapy to intensive in-hospital physiotherapy for patients following hip fracture surgery. The complex environments in which the intervention is implemented present unique contextual challenges that may impact intervention effectiveness. This study aims to complete a process evaluation to identify barriers and facilitators to implementation and explore the patient, carer and clinician experience of intensive therapy following hip fracture surgery. Methods and analysis The process evaluation is embedded within a two-arm randomised, controlled, assessor-blinded trial recruiting 620 participants from eight Australian hospitals who have had surgery for a hip fracture sustained via a low-trauma injury. A theory-based mixed method process evaluation will be completed in tandem with the HIPSTER trial. Patient and carer semi-structured interviews will be completed at 6 weeks following hip fracture surgery. The clinician experience will be explored through online surveys completed pre- and post-implementation of intensive therapy and mapped to domains of the Theoretical Domains Framework (TDF). Translation and behaviour change success will be assessed using the Reach Effectiveness-Adoption Implementation Maintenance (RE-AIM) framework and a combination of qualitative and quantitative data collection methods. These data will assist with the development of an Implementation Toolkit aiding future translation into practice. Discussion The embedded process evaluation will help understand the interplay between the implementation context and the intensive therapy intervention following surgery for low-trauma hip fracture. Understanding these mechanisms, if effective, will assist with transferability into other contexts and wider translation into practice. Trial registration ACTRN 12622001442796.