Search

Introduction: Normative blood pressure (BP) values on preterm infants exist but are based on small cohorts of infants. Utilizing electronic medical records (EMR), we can explore earlier gestational ages (GA) and follow their progression to 40 weeks corrected gestational age (CGA)., Methods: A retrospective cohort study of infants within the SSM Health System from 7/01/2013 through 6/30/2023. Infants born at >22 0/7 weeks but < 41 weeks GA were included if any BP measurements existed (n=29,323 infants, 1.4 million BPs). Data was extracted electronically from EMR using Microsoft SQL. Systolic BP (SBP), mean arterial pressures (MAP), and Diastolic BP (DBP) were determined for each week of life from birth and percentile ranges (1st to 99th) for infants alive at CGA, and BP patterns for GA determined., Results: Percentiles for SBP, DBP and MAP are provided. There is a rapid increase in BP at all gestations during the first two weeks, thus BP values are higher at any CGA in infants born at an earlier GA than infants born at that GA. For MAP values between the 5th and 10th percentile, the GA is appropriate for first week then use CGA + 5 mmHg. After the first week, 2.8 X CGA is between 90 and 95 percentile for SBP. . ., Conclusions: The BP is dependent on the gestational age at birth and the corrected gestational age when it is measured. SBP, MAP, and DBP all increase rapidly in the two weeks of life prior to a gradual increase over time., (S. Karger AG, Basel.)

Purpose: Transcriptional profiling of pancreatic cancers has defined two main transcriptional subtypes: classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX and gemcitabine plus nab-paclitaxel by transcriptional subtype., Experimental Design: We examined 8,743 patients with RNA sequencing from pancreatic cancers performed at Caris Life Sciences. Classical and basal subtypes were identified using purity independent subtyping algorithm on RNA sequencing, and two cohorts were analyzed: (i) the biomarker cohort included patients with complete molecular profiling data (n = 7,250) and (ii) the outcome cohort included patients with metastatic disease with available survival outcomes (n = 5,335). A total of 3,842 patients were shared between the two cohorts. Kaplan-Meier curves and Cox proportional hazards regression were used to assess patient survival., Results: In the biomarker cohort, 3,063 tumors (42.2%) were strongly classical (SC) and 2,015 tumors (27.8%) were strongly basal (SB). SC and SB tumors showed strong associations with histologic phenotypes and biopsy sites. SB tumors had higher rates of KRAS, TP53, and ARID1A mutations, lower rates of SMAD4 mutation, and transcriptional evidence of epithelial-mesenchymal transition. Sixty of 77 cases (78%) maintained their transcriptional subtype between temporally and/or spatially disparate lesions. In the outcome cohort, the SB subtype was associated with shorter overall survival time, regardless of whether they received FOLFIRINOX or gemcitabine plus nab-paclitaxel as first-line chemotherapy. The mutant KRAS allele type was prognostic of outcomes; however, this impact was restricted to SC tumors, whereas all mutant KRAS alleles had similarly poor outcomes in SB tumors., Conclusions: The SB subtype is a strong independent predictor of worse outcomes, regardless of the up-front chemotherapy regimen used. Clinical trials should further investigate pancreatic cancer transcriptional subtypes as a prognostic and predictive biomarker., (©2024 American Association for Cancer Research.)

Objective: To evaluate the association between enteral sodium supplementation on growth and hypertension (HTN) in preterm infants., Study Design: A retrospective cohort study of infants born between 22-32 weeks and weighing 450-1500 grams (N = 821). Enteral sodium supplementation amounts, systolic blood pressures (SBP), weight gain, and other infant and maternal risk factors for HTN were electronically extracted., Results: Infants receiving sodium supplementation were smaller and less mature. Sodium supplementation improved serum sodium levels, weight gain, and head circumference growth without causing hypernatremia. There was no correlation between urine and serum sodium or urine sodium and weight gain. Although infants receiving sodium had higher average SBP and rates of HTN, analysis demonstrated sodium supplementation did not increase odds of hypertension (OR ADJ 1.02;0.64-1.64). Postnatal steroids were associated with HTN., Conclusions: In preterm infants with poor weight gain, enteral sodium supplementation improved growth without increasing hypertension or hypernatremia., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: TTN encodes a sarcomeric protein called titin. Pathogenic rare variants in TTN are the most common finding in patients with atrial fibrillation (AF) and positive genetic testing., Objectives: This study sought to define the characteristics and outcomes in patients with AF and pathogenic TTN variants compared with genotype-negative patients with AF., Methods: Patients who presented initially with AF were enrolled in an AF registry. Retrospectively they underwent research sequencing for cardiomyopathy and arrhythmia genes. TTN(+) AF cases were defined as participants with pathogenic or likely pathogenic (P/LP) rare variants located in exons with high cardiac expression. They were matched 1:2 with control subjects with no P/LP variants. Phenotyping used retrospective manual chart review., Results: Among 2794 participants; 57 (2.0%) TTN(+) AF cases were identified and matched with 114 control subjects. Low QRS complex voltage was present more often in TTN(+) AF cases (18% vs 5%; P < 0.01), with no difference in PR, QRS interval, or QTc. More TTN(+) AF cases had persistent AF at enrollment (44% vs 30%; P = 0.028) and had undergone multiple cardioversions (61% vs. 37%; P < 0.01). By end of follow-up (median 8.3 years; Q1, Q3: 4.5, 13.7 years), 11% of TTN(+) AF cases developed sustained ventricular tachycardia/ventricular fibrillation, 44% left ventricular (LV) systolic dysfunction (LV ejection fraction <50%), and 47% met a combined endpoint of sustained ventricular tachycardia/ventricular fibrillation or LV systolic dysfunction., Conclusions: TTN(+) AF patients undergo more cardioversions and have more persistent forms of AF. Approximately 50% develop LV systolic dysfunction and/or malignant ventricular arrhythmias. These results highlight the need for diagnostic evaluation and management in TTN(+) patients beyond the usual care for AF., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from the American Heart Association (AHA20SCG35540034 [to Dr Shoemaker] and AHA18SFRN34110369 [to Dr Roden]) and the National Institutes of Health (R01HL155197 [to Dr Shoemaker]); and was also supported by CTSA award (UL1TR000445) from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the AHA or National Institutes of Health. Dr Kanagasundram has received speaker fees from Biosense Webster and Janssen. Dr Montgomery has received research funding from Medtronic. Dr Ellis has received research funding from Boston Scientific, Medtronic, and Boehringer Ingelheim; and has received consulting fees from Medtronic, Boston Scientific, Abbott Medical, and Atricure. Dr Crossley has received consulting fees or honoraria from Bayer Healthcare, Boston Scientific, Janssen Pharmaceuticals, Medtronic, and Spectranetics. Dr Richardson has received research funding from Medtronic and Abbott; and has served as a consultant for Philips and Biosense Webster. Dr Tandri has received a research grant from Abbott. Dr Stevenson has received honoraria from Abbott, Boston Scientific, Medtronic, Johnson and Johnson, and Biotronik; and has received research funding from Adagio Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with rare, pathogenic cardiomyopathy (CM) and arrhythmia variants can present with atrial fibrillation (AF). The efficacy of AF ablation in these patients is unknown., Objective: This study tested the hypotheses that: 1) patients with a pathogenic variant in any CM or arrhythmia gene have increased recurrence following AF ablation; and 2) patients with a pathogenic variant associated with a specific gene group (arrhythmogenic left ventricular CM [ALVC], arrhythmogenic right ventricular CM, dilated CM, hypertrophic CM, or a channelopathy) have increased recurrence., Methods: We performed a prospective, observational, cohort study of patients who underwent AF catheter ablation and whole exome sequencing. The primary outcome measure was ≥30 seconds of any atrial tachyarrhythmia that occurred after a 90-day blanking period., Results: Among 1,366 participants, 109 (8.0%) had a pathogenic or likely pathogenic (P/LP) variant in a CM or arrhythmia gene. In multivariable analysis, the presence of a P/LP variant in any gene was not significantly associated with recurrence (HR 1.15; 95% CI 0.84-1.60; P = 0.53). P/LP variants in the ALVC gene group, predominantly LMNA, were associated with increased recurrence (n = 10; HR 3.75; 95% CI 1.84-7.63; P < 0.001), compared with those in the arrhythmogenic right ventricular CM, dilated CM, hypertrophic CM, and channelopathy gene groups. Participants with P/LP TTN variants (n = 46) had no difference in recurrence compared with genotype-negative-controls (HR 0.93; 95% CI 0.54-1.59; P = 0.78)., Conclusions: Our results support the use of AF ablation for most patients with rare pathogenic CM or arrhythmia variants, including TTN. However, patients with ALVC variants, such as LMNA, may be at a significantly higher risk for arrhythmia recurrence., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from the American Heart Association (AHA20SCG35540034 [Dr Shoemaker]) and the National Institutes of Health (R01HL155197 [Dr Shoemaker]). It was also supported by CTSA award (UL1TR000445) from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the AHA or NIH. Dr Shoemaker serves on the advisory board and has received sponsored research funds from Roche Diagnostics. Dr Kanagasundram has received speaking fees from Biosense Webster and Janssen. Dr Crossley has received consulting fees or honoraria from Bayer Healthcare, Boston Scientific, Janssen Pharmaceuticals, Medtronic, and Spectranetics. Dr Richardson has received research funding from Medtronic Inc, Abbott Inc and served as a consultant for Philips Inc and Biosense Webster. Dr Montgomery has received research funding from Medtronic Inc. Dr Ellis has received research funding from Boston Scientific, Medtronic, and Boehringer Ingelheim; and consulting fees from Medtronic, Boston Scientific, Abbott Medical, and Atricure. Dr Michaud has received consulting fees or honoraria from Boston Scientific, Medtronic, Biotronik, Abbott, and Biosense Webster. Vanderbilt receives fellowship support from Medtronic inc., Boston Scientific inc., Abbott Labs, Biotronik, and Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Enabling the examination of cell-cell relationships in tissue, spatially resolved omics technologies have revolutionised our perspectives on cancer biology. Clinically, the development of immune checkpoint inhibitors (ICI) has advanced cancer therapeutics. However, a major challenge of effective implementation is the identification of predictive biomarkers of response. In this review we examine the potential added predictive value of spatial biomarkers of response to ICI beyond current clinical benchmarks., (© 2024. The Author(s).)

Objective: Methicillin-resistant Staphylococcus aureus (MRSA) infection is a major cause of serious morbidity and mortality in the neonatal intensive care unit (NICU). There is no clear consensus on infection control measures. Some approaches to MRSA colonization management may be burdensome with unclear benefits. The objective of this study was to determine if stopping weekly MRSA surveillance with active detection and contact isolation (ADI) was associated with a change in infection rate., Study Design: This is a retrospective cohort study of infants admitted to two affiliated NICUs. The ADI cohort infants received weekly nasal MRSA cultures and were placed in contact isolation if MRSA colonized for the duration of their hospitalization. The No Surveillance cohort infants were only placed in isolation if there was active MRSA infection or if MRSA colonization was identified incidentally. The rates of infection were determined between the cohorts., Results: There were 8,406 neonates representing 193,684 NICU days in the comparison period. In the ADI cohort, MRSA colonization occurred in 3.4% of infants and infection occurred in 29 infants (0.4%). There were no differences between cohorts in the percent of infants with a MRSA infection at any site (0.5 vs. 0.5%, p  = 0.89), rate of MRSA infections per 1,000 patient-days (0.197 vs. 0.201, p  = 0.92), rate of bloodstream infections (0.12 vs. 0.26%, p  = 0.18), or in the overall mortality rate (3.7 vs. 3.0% p  = 0.13). ADI represented an annual cost of $590,000., Conclusion: The rates of MRSA infection did not change when weekly ADI was discontinued and was associated with a decrease in cost and resource utilization., Key Points: · Placing MRSA-colonized infants in contact isolation is a common practice.. · Data are limited with respect to efficacy in the NICU.. · This study provides evidence that active detection and contact isolation for MRSA colonization may not be beneficial.., Competing Interests: None declared., (Thieme. All rights reserved.)

Over the last 40 years, object recognition studies have moved from using simple line drawings, to more detailed illustrations, to more ecologically valid photographic representations. Researchers now have access to various stimuli sets, however, existing sets lack the ability to independently manipulate item format, as the concepts depicted are unique to the set they derive from. To enable such comparisons, Rossion and Pourtois (2004) revisited Snodgrass and Vanderwart's (1980) line drawings and digitally re-drew the objects, adding texture and shading. In the current study, we took this further and created a set of stimuli that showcase the same objects in photographic form. We selected six photographs of each object (three color/three grayscale) and collected normative data and RTs. Naming accuracy and agreement was high for all photographs and appeared to steadily increase with format distinctiveness. In contrast to previous data patterns for drawings, naming agreement (H values) did not differ between grey and color photographs, nor did familiarity ratings. However, grey photographs received significantly lower mental imagery agreement and visual complexity scores than color photographs. This suggests that, in comparison to drawings, the ecological nature of photographs may facilitate deeper critical evaluation of whether they offer a good match to a mental representation. Color may therefore play a more vital role in photographs than in drawings, aiding participants in judging the match with their mental representation. This new photographic stimulus set and corresponding normative data provide valuable materials for a wide range of experimental studies of object recognition., (© 2024. The Author(s).)

Background: Overexpression of HER2 plays an important role in cancer progression and is the target of multiple therapies in HER2-positive breast cancer. Recent studies have also highlighted the presence of activating mutations in HER2, and HER3 that are predicted to enhance HER2 downstream pathway activation in a HER2-dependent manner., Methods: In this report, we present two exceptional responses in hormone receptor-positive, HER2-nonamplified, HER2/HER3 co-mutated metastatic breast cancer patients who were treated with the anti-HER2-directed monoclonal antibodies, trastuzumab and pertuzumab., Results: Both patients acheived exceptional responses to treatment, suggesting that combined trastuzumab, pertuzumab, and endocrine therapy could be a highly effective therapy for these patients and our observations could help prioritize trastuzumab deruxtecan as an early therapeutic choice for patients whose cancers have activating mutations in HER2., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

This paper introduces a newly digitized, open-access version of the Food and Drug Administration's "Orange Book"-a linkage between approved small-molecule drugs and the patents that protect them. The Orange Book also reports any applicable regulatory exclusivity that prevents competitive entry. We summarize the Orange Book's coverage and discuss the opportunities and challenges associated with using these data for research. Empirical validations against various administrative datasets suggest that Orange Book records are, largely, complete and accurate. We conclude with a specific use case-calculating legal exclusivity periods for drugs-to highlight the types of choices that researchers must make when using this resource., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C. Scott Hemphill reports that he “has at various times served as an expert witness in litigation involving Orange Book-listed patents”. This relationship includes: paid expert testimony. Bhaven Sampat reports that he “has served as a consultant in litigation on issues relating to pharmaceutical patenting and innovation and to the Medicines Patent Pool for work on patents and access to medicines”. This relationship includes: consulting or advisory.

ABSTRACT We report three experiments designed to reveal the mechanisms that underlie subjective experiences of recognition by examining effects of how those experiences are measured. Prior research has explored the potential influences of collecting metacognitive measures on memory performance. Building on this work, here we systematically evaluated whether cross-measure contamination occurs when remember-know (RK) and/or confidence (C) judgments are made after old/new recognition decisions. In Experiment 1, making either RK or C judgments did not significantly influence recognition relative to a standard no-judgment condition. In Experiment 2, making RK judgments in addition to C judgments did not significantly affect recognition or confidence. In Experiment 3, making C judgments in addition to RK judgments did not significantly affect recognition or patterns of RK responses. Cross-contamination was not apparent regardless of whether items were studied using a shallow or deep levels-of-processing task - a manipulation that yielded robust effects on recognition, RK judgments, and C. Our results indicate that under some conditions, participants can independently evaluate their recognition, subjective recognition experience, and confidence. Though contamination across measures of metamemory and memory is always possible, it may not be inevitable. This has implications for the mechanisms that underlie subjective experiences that accompany recognition judgments.

Background: A subset of triple-negative breast cancers (TNBCs) have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. PIKTOR, a combination of TAK-228 (TORC1/2 inhibitor) and TAK-117 (PI3Kα inhibitor), is hypothesized to increase genomic instability and increase DNA damage repair (DDR) deficiency, leading to increased sensitivity to DNA-damaging chemotherapy and to immune checkpoint blockade inhibitors., Methods: 10 metastatic TNBC patients received 4 mg TAK-228 and 200 mg TAK-117 (PIKTOR) orally each day for 3 days followed by 4 days off, weekly, until disease progression (PD), followed by intravenous cisplatin 75 mg/m 2 plus nab paclitaxel 220 mg/m 2 every 3 weeks for up to 6 cycles. Patients received subsequent treatment with pembrolizumab and/or chemotherapy. Primary endpoints were objective response rate with cisplatin/nab paclitaxel and safety. Biopsies of a metastatic lesion were collected prior to and at PD on PIKTOR. Whole exome and RNA-sequencing and reverse phase protein arrays (RPPA) were used to phenotype tumors pre- and post-PIKTOR for alterations in DDR, proliferation, and immune response., Results: With cisplatin/nab paclitaxel (cis/nab pac) therapy post PIKTOR, 3 patients had clinical benefit (1 partial response (PR) and 2 stable disease (SD) ≥ 6 months) and continued to have durable benefit in progression-free survival with pembrolizumab post-cis/nab pac for 1.2, 2, and 3.6 years. Their post-PIKTOR metastatic tissue displayed decreased mismatch repair (MMR), increased tumor mutation burden, and significantly lower levels of 53BP1, DAG Lipase β, GCN2, AKT Ser473, and PKCzeta Thr410/403 compared to pre-PIKTOR tumor tissue., Conclusions: Priming patients' chemotherapy-pretreated metastatic TNBC with PIKTOR led to very prolonged response/disease control with subsequent cis/nab pac, followed by pembrolizumab, in 3 of 10 treated patients. Our multi-omics approach revealed a higher number of genomic alterations, reductions in MMR, and alterations in immune and stress response pathways post-PIKTOR in patients who had durable responses., Trial Registration: This clinical trial was registered on June 21, 2017, at ClinicalTrials.gov using identifier NCT03193853., (© 2023. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC., Significance: A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching., (©2022 American Association for Cancer Research.)

Purpose: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood., Design: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes., Results: In the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell-rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2-polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 72% showed a T cell-rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy, and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival., Conclusions: Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment toward an anti-tumorigenic state associated with improved patient survival., (©2022 American Association for Cancer Research.)

Background: Enteral nutrition is a critical intervention that supports the growth of children with pulmonary hypoplasia (PH). We explored the experiences of caregivers and providers caring for children with PH to better understand gaps in knowledge transfer and identify barriers and facilitators to caregiving to inform interventions that may improve support., Methods: This qualitative study included 10 interviews with caregivers and 10 clinical team members at a single integrated care program for children with PH. An inductive and iterative coding strategy was employed to produce a codebook. After cluster analysis, themes were generated to capture participant sentiments., Results: Themes were defined along a care continuum (1) initiation, (2) adaptation, and (3) maintenance that represented distinct phases of adjustment to enteral nutrition support (1) in the perinatal period and initial neonatal intensive care unit (NICU) admission, (2) from discharge planning through the family's first days at home and establishment of a stable feeding regime, and (3) through long-term follow-up and weaning. Notable subthemes included uncertainty, partnerships in training, and obstacles to adaptation., Conclusions: Among children with PH, the caregiver-provider relationship during the perinatal and NICU course is critical to promoting caregiver adaptation to the needs of the child. Ongoing considerations to support resource alignment and transition to a stable feeding regimen may facilitate caregiver adjustment to a "new normal," culminating in successful growth and/or weaning. These findings will inform interventions focused on training curricula, discharge planning, and the provision of follow-up in the context of an integrated care program for PH., (© 2022 American Society for Parenteral and Enteral Nutrition.)

Objective: To determine if extremely preterm (EPT) neonates receiving dexamethasone for the prevention of BPD have a higher incidence of presumed adrenal insufficiency (PAI)., Study Design: Retrospective cohort study of neonates <28 weeks gestation examining PAI after dexamethasone use and PAI after intratracheal budesonide with surfactant administration., Result: Of 332 neonates, 38% received dexamethasone. The incidence of PAI was higher in neonates who had received dexamethasone (20.8% vs 2.9%, p < 0.001). However, for intubated babies receiving surfactant, dexamethasone was not independently associated with increased PAI after adjusting for gestational age, birthweight, and race (aOR 2.92, 95% CI: 0.79-10.85). Dexamethasone was independently associated with increased PAI in infants previously receiving budesonide/surfactant treatment (aOR 5.38, 95% CI: 1.38-20.90)., Conclusion: The use of dexamethasone alone was not associated with increased PAI, when adjusted for prematurity-related factors. The combination of budesonide with dexamethasone was significantly associated with increased PAI., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The combination of surfactant and budesonide has been shown to decrease BPD rates and severity. Budesonide may be released systemically from lungs, and the effects on the immature adrenal glands are not known., Objective: The aim of this study was to determine if adrenal suppression rates are higher in preterm infants receiving budesonide with surfactant compared to surfactant alone., Methods: A retrospective chart review of 608 infants ≤1,250 g received intubation for surfactant therapy from 2013 through 2020. In August 2016, budesonide was added to surfactant for these infants. Indicators of adrenal suppression, including mean blood pressures, plasma electrolyte levels, hydrocortisone use, and the use of vasoactive medications, were analyzed for the first 14 days after birth. Respiratory variables, biochemical signs of adrenal insufficiency, and neonatal morbidities were analyzed., Results: There was no difference in hydrocortisone administration in the first 14 days between infants receiving budesonide with surfactant (n = 314) or surfactant alone (n = 294) (23% vs. 19%, p = 0.38). Budesonide exposed infants received hydrocortisone 3 days later than surfactant only infants (median DOL 5 vs. 2, p < 0.001). Infants receiving budesonide had higher blood pressures, required less dopamine (19% vs. 39%, p < 0.001) and dobutamine (2% vs. 6%, p = 0.02). Budesonide exposed infants were discharged home after a shorter NICU stay (85 days vs. 94 days, p = 0.02) and at a younger gestational age (39 vs. 40 weeks, p = 0.001)., Conclusions: The use of surfactant and budesonide does not alter the rate of hydrocortisone use, but does delay the timing of treatment initiation and decreases the use of vasoactive medications., (© 2022 S. Karger AG, Basel.)

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities., Competing Interests: Declaration of interests B.M.W. reports research support from Celgene and Eli Lilly and consulting for BioLineRx, Celgene, G1 Therapeutics, and GRAIL. W.C.H. is a consultant for Thermo Fisher, Solasta Ventures, MPM Capital, Tyra Biosciences, iTeos, Frontier Medicines, Function Oncology, KSQ Therapeutics, Jubilant Therapeutics, RAPPTA Therapeutics, and Paraxel. A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, Third Rock Ventures, Hovione, Relation Therapeutics, FL82, and Dahlia Biosciences. A.J.A. has consulted for Oncorus, Arrakis Therapeutics, and Merck & Co. and has research funding from Mirati Therapeutics, Syros, Deerfield, and Novo Ventures that are unrelated to this project. S.R.M. is a founder of Travera. S.R. has equity in Amgen. J.M.C. has received research funding from Merck, Tesaro, AstraZeneca, Bayer, and Esperas Pharma; has served as a consultant to Bristol Myers Squibb; and has received travel funding from Bristol Myers Squibb. A.R. is an employee of AstraZeneca and an equity holder in Celsius Therapeutics and NucleAI. Y.Y.L. reports equity from g.Root Biomedical Services. A.D. Cherniack reports research support from Bayer. R.J.S reports research support from Merck and consulting and/or SAB membership for Bristol Myers Squibb, Merck, Novartis, and Pfizer. G.I.S. reports sponsored research support from Eli Lilly, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology and has served on advisory boards for Pfizer, Eli Lilly, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines, and Kymera Therapeutics. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific; a co-Founder of Dragonfly Therapeutics and T2 Biosystems; serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics; and is the President of Break Through Cancer. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. T.J.’s laboratory currently also receives funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support the research described in this manuscript. K.N. reports research support from Revolution Medicines, Evergrande Group, Pharmavite, and Janssen; is a member of SABs for SeaGen, BiomX, and Bicara Therapeutics; and has consulted for X-Biotix Therapeutics and Redesign Health. A.K.S., P.S.W., A.W.N., S.R., W.C.H., A.J.A., B.W.M., and J.G.R. have filed a patent (Publication number WO/2021/081491; International application number PCT/US2020/057342) related to this work., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Early bubble continuous positive airway pressure (bCPAP) in the delivery room (DR) reduces early intubation, mechanical ventilation, and bronchopulmonary dysplasia. The RAM cannula, adopted for ease of patient care, is a high resistance nasal interface that, when used with bCPAP, only transmits a portion of set pressures and attenuates the bubble effects. This study aimed to review early bCPAP pressures and bCPAP failure with the RAM cannula interface over a 6-year period., Study Design: Retrospective, single-center study of infants delivered <1,250 g from 2013 to 2018 ( n  = 735) begun on bCPAP in the DR with the RAM cannula. In vitro testing of bCPAP pressure transmission was also performed for multiple nasal interfaces and nasal occlusion percentages., Results: The percentage of infants intubated in the DR decreased over time (59 to 42%), while the average bCPAP pressure increased from 5.3 to 6.8 cmH 2 O. A total of 355 infants (48%) were admitted to the neonatal intensive care unit (NICU) from the DR on BCPAP. The failure rate for bCPAP in NICU within 72 hours decreased from 45 to 24% as the maximum CPAP increased from 5.8 to 7.6 cmH 2 O. Pneumothorax rates did not change. CPAP pressure transmission decreased with all sizes of the RAM cannula., Conclusion: When utilizing the RAM cannula for bCPAP, higher CPAP levels were associated with decreases in DR intubations and CPAP failure within the first 72 hours. If clinicians choose to use the RAM cannula for bCPAP, they will need higher set pressures to achieve lung inflation and the beneficial oscillatory effect will be diminished., Key Points: · The transmission of the pressure oscillations from bubble CPAP is diminished with the RAM cannula.. · Increasing set CPAP pressures was associated with a decreased delivery room intubation rate and a decreased CPAP failure rate within 72 hours.. · Clinicians using the RAM cannula for bCPAP will need to increase pressures to obtain adequate lung inflation or change to a nasal interface designed for bCPAP.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: The addition of budesonide to surfactant in very-low-birth-weight infants with less severe RDS decreased bronchopulmonary dysplasia (BPD) severity. Long-term neurodevelopmental follow-up was needed to monitor for systemic effects of budesonide., Methods: Infants ≤1250 g who received intratracheal budesonide (0.25 mg/kg) with surfactant (n = 173) were compared to a historical cohort who received surfactant alone (n = 294). Peabody Developmental Motor Scales II at 4-6 months corrected age and Bayley Scales of Infant & Toddler Development III at 18-22 months corrected age were compared., Results: There were no differences in muscle tone or motor skills by Peabody exam. There were no differences in the cognitive, language, or motor domains between cohorts on Bayley III., Conclusions: In a cohort of infants treated with budesonide mixed with surfactant, there were no differences in developmental outcomes at 4-6 months or 18-22 months corrected age., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Histologic chorioamnionitis (HCA) is a placental inflammation linked to preterm birth and adverse neonatal outcome. The neutrophil-lymphocyte ratio (NLR) can identify various inflammatory disorders, however its utility in HCA is not clear. Our goal was to examine NLR values and HCA diagnoses in at-risk pregnancies and neonates., Study Design: We retrospectively analyzed the EHR of mothers and preterm (<33 wk GA) neonates with or without HCA (identified by placental histology). The NLR was calculated from complete blood counts in laboring women and in their neonates (0-24 h of life)., Result: In 712 consecutive gestations, 50.8% had HCA (26.5% fetal HCA). The neonatal NLR (0-12 h, 13-24 h) predicted fetal HCA better than chance alone (p = 0.01 and 0.002, respectively)., Conclusion: Early NLR elevation in preterm neonates is consistent with a diagnosis of fetal HCA. The NLR may identify preterm neonates at risk for HCA-related complications.

Objective: The purpose of this study was to evaluate the use of a respiratory protocol for the interhospital transport of infants with respiratory distress on bubble continuous positive airway pressure (bCPAP) and provide information on the safety of bCPAP during transport via ground and helicopter., Methods: We evaluated a retrospective cohort study of neonates (gestational age 22-41 weeks) transported to our level 4 neonatal intensive care unit (NICU) before (n = 529) and after implementing (n = 540) protocols for increasing bCPAP and intubation criteria. Infants were evaluated for intubation before transport, the safety of transport, and the need for intubation shortly after arrival in the NICU., Results: After initiating the protocols, less infants received mechanical ventilation, and more infants received bCPAP for transport via ground and helicopter. Upon arrival to the NICU, infants using the protocols had lower fraction of inspired oxygen and higher continuous positive airway pressures, and similar numbers required intubations in the first 12 hours. There were no differences in the rate of pneumothoraces., Conclusions: bCPAP can be used on both ground and helicopter transport of very small infants. Respiratory protocols decreased mechanical ventilation during transport without increasing the need for intubation within 12 hours of arrival., (Copyright © 2020 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade., Competing Interests: Declaration of Interests K.W.W. serves on the scientific advisory board of TCR2 Therapeutics, T-Scan Therapeutics, and Nextechinvest and receives sponsored research funding from Novartis. He is a scientific co-founder of Immunitas Therapeutics. M.D. receives research funding from Novartis and is on the Scientific Advisory Board for Neoleukin Therapeutics. S.K.D. receives research funding from Novartis, Bristol-Myers Squibb, and Eli Lilly. F.S.H. receives research funding from Bristol-Myers Squibb and Novartis; he also consults for Merck, EMD Serono, Novartis, Takeda, Genentech/Roche, Compass Therapeutics, Apricity, Aduro, Sanofi, Pionyr, 7 Hills Pharma, Verastem, Torque, Rheos Kairos, Psioxus Therapeutics, Amgen, and Pieris Pharmaceutical. O.R. receives research support from Merck and is a speaker for activities supported by educational grants from BMS and Merck. He is a consultant for Merck, Celgene, Five Prime, GSK, GFK, Bayer, Roche/Genentech, Puretech, Imvax, and Sobi. In addition, he has patent “Methods of using pembrolizumab and trebananib” pending. J.A.N. has a provisional patent application for spatial quantification of immune cell infiltration in the tumor microenvironment. R.J.S. has received research funding from Merck and Amgen., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In preterm infants on moderately high ventilator support, the addition of budesonide to surfactant lowered bronchopulmonary dysplasia (BPD) rates by 20% without increased morbidity or mortality. The aim of this cohort comparison was to determine the safety and efficacy of the combination in infants with milder respiratory distress syndrome (RDS)., Methods: In August 2016 we began administering budesonide (0.25 mg/kg) mixed with surfactant (Survanta 4 mL/kg) to all infants ≤ 1250 g who failed CPAP and required intubation. Infants were compared to a historical cohort (2013-2016) who received surfactant alone., Results: BPD or death did not change between the historical surfactant cohort (71%, n = 294) and the budesonide cohort (69%, n = 173). Budesonide was associated with a decrease in the need for continued mechanical ventilation, severe BPD type II or death (19-12%), grade III BPD or death (31-21%), and the median gestational age at discharge was 1 week earlier. Histologic chorioamnionitis was associated with decreased budesonide effects. Secondary morbidities (NEC, IVH, ROP, Sepsis) were similar., Conclusion: Overall BPD rates remained unchanged with the addition of budesonide. Budesonide was associated with decreased severity of BPD, decreased mechanical ventilation use, earlier discharge, and similar short-term outcomes.

In the remember/know paradigm, a "know" response can be defined to participants as a high-confidence state of certainty or as a low-confidence state based on a feeling of familiarity. To examine the effects of definition on use of responses, in two experiments, definitions of "remember" and "guess" were kept constant, but definitions of "know" and/or "familiar" were systematically varied to emphasize (a) a subjective experience of high confidence without recollection, (b) a feeling of familiarity, (c) both of these subjective experiences combined within one response option, or (d) both of these experiences as separate response options. The confidence expressed in "know" and/or "familiar" definitions affected how participants used response options. Importantly, this included use of the "remember" response, which tended to be used more frequently when the nonrecollection-based middle response option emphasized a feeling of familiarity rather than an experience of "just knowing." The influence of the definitions on response patterns was greater for items that had undergone deep rather than shallow processing, and was greater when deep-encoded and shallow-encoded items were mixed, rather than blocked, at test. Our findings fit with previous research suggesting that the mnemonic traces underlying subjective judgments are continuous and that the remember/know paradigm is not a pure measure of underlying processes. Findings also emphasize the importance of researchers publishing the exact definitions they have used to enable accurate comparisons across studies.

Ubiquitylation, the posttranslational linkage of ubiquitin moieties to lysines in target proteins, helps regulate a myriad of biological processes. Ubiquitin, and sometimes ubiquitin-homology domains, are recognized by ubiquitin-binding domains, including CUE domains. CUE domains are thus generally thought to function by mediating interactions with ubiquitylated proteins. The chromatin remodeler, SMARCAD1, interacts with KAP1, a transcriptional corepressor. The SMARCAD1-KAP1 interaction is direct and involves the first SMARCAD1 CUE domain (CUE1) and the RBCC domain of KAP1. Here, we present a structural model of the KAP1 RBCC-SMARCAD1 CUE1 complex based on X-ray crystallography. Remarkably, CUE1, a canonical CUE domain, recognizes a cluster of exposed hydrophobic and surrounding charged/amphipathic residues on KAP1, which are presented in the context of a coiled-coil domain, not in a structure resembling ubiquitin. Together, these data suggest that CUE domains may have a wider function than simply recognizing ubiquitin and the ubiquitin-fold., (Copyright © 2019 Francis Crick Institute. Published by Elsevier Ltd.. All rights reserved.)

Previous work supports an age-specific impairment for recognition memory of pairs of words and other stimuli. The present study tested the generalization of an associative deficit across word, name, and nonword stimulus types in younger and older adults. Participants completed associative and item memory tests in one of three stimulus conditions and made metacognitive ratings of perceptions of self-efficacy, task success ("postdictions"), strategy success, task effort, difficulty, fatigue, and stamina. Surprisingly, no support was found for an age-related associative deficit on any of the stimulus types. We analyzed our data further using a multilayer perceptron artificial neural network. The network was trained to classify individuals as younger or older and its hidden unit activities were examined to identify data patterns that distinguished younger from older participants. Analysis of hidden unit activities revealed that the network was able to correctly classify by identifying three different clusters of participants, with two qualitatively different groups of older individuals. One cluster of older individuals found the tasks to be relatively easy, they believed they had performed well, and their beliefs were accurate. The other cluster of older individuals found the tasks to be difficult, believed they were performing relatively poorly, yet their beliefs did not map accurately onto their performance. Crucially, data from the associative task were more useful for neural networks to discriminate between younger and older adults than data from the item task. This work underscores the importance of considering both individual and age differences as well as metacognitive responses in the context of associative memory paradigms., Competing Interests: The authors have declared that no competing interests exist.

Independent recollection-familiarity (RF) ratings are sometimes collected to measure subjective experiences of recollection and familiarity during recognition. Although the RF ratings task purports to measure the degree to which each recognition state is experienced, the rating scale has been worded in terms of confidence rather than amount. Given prior evidence that wording influences recognition and remember/know judgments, we compared RF rating scales worded in terms of amount versus confidence across 2 groups. A robust levels-of-processing effect occurred on both recollection and familiarity ratings, and its magnitude was similar across scale wording. Scale wording did not influence recognition, and, most importantly, it had little influence on ratings of recollection and familiarity. These findings suggest that participants may use confidence to rate amount, or vice versa. Regardless, researchers should align their task instructions and scale wording, and should publish them. Such alignment and transparency is crucial for interpreting measures of the memory states that arise during recognition memory. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Introduction: Bubble continuous positive airway pressure (bCPAP) generates a variable pressure due to bubble size and frequency, and these pressure oscillations may contribute to lung recruitment and gas exchange. Single-outlet bCPAP devices generate larger pressure fluctuation than bCPAP devices with diffusers, but clinical efficacy is unclear. Our hypothesis was that a single-outlet bCPAP device (B&B Bubbler©) would decrease extubation failure and improve oxygenation compared with a bCPAP device with a diffuser (BabiPlus©)., Methods: Bench testing of bCPAP devices with the RAM© cannula determined pressure averages, fluctuations, and CPAP transmission at prongs. The B&B Bubbler© and the BabiPlus© devices were compared for oxygenation and bCPAP failure within 72 h of extubation in a randomized trial in infants less than 1,250 g (n = 43). Additionally, a cohort study with infants extubated to BabiPlus© (n = 128), B&B Bubbler© (n = 119), and noninvasive positive pressure ventilation (NIPPV) (n = 107) were compared., Results: Small differences in pressure fluctuations between bCPAP devices are attenuated by the RAM© cannula. Pressures at RAM© prongs are 62% of set pressure. The bCPAP extubation failure rate (35%) and oxygenation were similar between the bCPAP devices. bCPAP success was associated with lower FiO2 at extubation and decreased need for additional FiO2 in both groups. In the setting of the RAM© cannula, there were no differences in extubation failure rate for infants extubated to bCPAP or NIPPV., Conclusions: There were no clinical differences at extubation between the B&B Bubbler© and BabiPlus© devices. Oxygenation may predict bCPAP failure. The use of the RAM© cannula as a bCPAP interface should be more closely examined., (© 2018 S. Karger AG, Basel.)

We investigate whether patents on human genes have affected follow-on scientific research and product development. Using administrative data on successful and unsuccessful patent applications submitted to the US Patent and Trademark Office, we link the exact gene sequences claimed in each application with data measuring follow-on scientific research and commercial investments. Using these data, we document novel evidence of selection into patenting: patented genes appear more valuable--prior to being patented--than non-patented genes. This evidence of selection motivates two quasi-experimental approaches, both of which suggest that on average gene patents have had no quantitatively important effect on follow-on innovation.

The clinical utility of next-generation sequencing (NGS) for a diverse range of targets is expanding, increasing the need for multiplexed analysis of both DNA and RNA. However, translation into daily use requires a rigorous and comprehensive validation strategy. The aim of this clinical validation was to assess the performance of the Ion Torrent Personal Genome Machine (IonPGM ™ ) and validate the Oncomine ™ Focus DNA and RNA Fusion panels for clinical application in solid tumour testing of formalin-fixed, paraffin-embedded (FFPE) tissue. Using a mixture of routine FFPE and reference material across a variety of tissue and specimen types, we sequenced 86 and 31 samples on the Oncomine ™ Focus DNA and RNA Fusion assays, respectively. This validation considered a number of parameters including the clinical robustness of the bioinformatics pipeline for variant detection and interpretation. The Oncomine ™ Focus DNA assay had a sample and variant-based sensitivity of 99.1 and 97.1%, respectively, and an assay specificity of 100%. The Oncomine ™ Focus Fusion panel had a good sensitivity and specificity based upon the samples assessed, however requires further validation to confirm findings due to limited sample numbers. We observed a good sequencing performance based upon amplicon, gene (hotspot variants within gene) and sample specific analysis with 92% of clinical samples obtaining an average amplicon coverage above 500X. Detection of some indels was challenging for the routine IonReporter ™ workflow; however, the addition of NextGENe® software improved indel identification demonstrating the importance of both bench and bioinformatic validation. With an increasing number of clinically actionable targets requiring a variety of methodologies, NGS provides a cost-effective and time-saving methodology to assess multiple targets across different modalities. We suggest the use of multiple analysis software to ensure identification of clinically applicable variants.

Objective: The aim of this study was to explore the relationships between nurse-reported health-promoting behaviors (HPBs), job stress, and job satisfaction in a hospital setting., Background: Job stress and satisfaction are key components of the nursing work environment; however, evidence of the relationship between HPB and job stress and satisfaction is lacking., Methods: A cross-sectional, 144-item survey was administered to nurses working in an acute care, community hospital in the southeastern United States., Results: Higher levels of HPB were associated with lower job stress and higher job satisfaction. Total HPB was associated with the competence subscale of job stress. Lower job stress was significantly associated with HPB subscales: spiritual growth, interpersonal relations, and stress management., Conclusions: Nursing organizations can implement interventions that support HPB for nurses to reduce job stress and improve satisfaction.

The excited state relaxation dynamics of adenosine and adenosine monophosphate were studied at multiple excitation energies using femtosecond time-resolved photoelectron spectroscopy in a liquid water microjet. At pump energies of 4.69-4.97 eV, the lowest ππ * excited state, S 1 , was accessed and its decay dynamics were probed via ionization at 6.20 eV. By reversing the role of the pump and probe lasers, a higher-lying ππ * state was excited at 6.20 eV and its time-evolving photoelectron spectrum was monitored at probe energies of 4.69-4.97 eV. The S 1 ππ * excited state was found to decay with a lifetime ranging from ∼210 to 250 fs in adenosine and ∼220 to 250 fs in adenosine monophosphate. This lifetime drops with increasing pump photon energy. Signal from the higher-lying ππ * excited state decayed on a time scale of ∼320 fs and was measureable only in adenosine monophosphate.

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism.

The excited state relaxation dynamics of the solvated electron in H2O and D2O are investigated using time-resolved photoelectron spectroscopy in a liquid microjet. The data show that the initial excited state decays on a time scale of 75 ± 12 fs in H2O and 102 ± 8 fs in D2O, followed by slower relaxation on time scales of 400 ± 70 fs and 390 ± 70 fs that are isotopically invariant within the precision of our measurements. Based on the time evolution of the transient signals, the faster and slower time constants are assigned to p → s internal conversion (IC) of the hydrated electron and relaxation on the ground electronic state, respectively. This assignment is consistent with the non-adiabatic mechanism for relaxation of the hydrated electron and yields an isotope effect of 1.4 ± 0.2 for IC of the hydrated electron.

A well-developed theoretical literature - dating back at least to Nordhaus (1969) - has analyzed optimal patent policy design. We re-present the core trade-off of the Nordhaus model and highlight an empirical question which emerges from the Nordhaus framework as a key input into optimal patent policy design: namely, what is the elasticity of R&D investment with respect to the patent term? We then review the - surprisingly small - body of empirical evidence that has been developed on this question over the nearly half century since the publication of Nordhaus's book.

Objective: 10% of all hip fractures are occult on plain radiography, requiring further investigation to ascertain the diagnosis. MRI is presently the gold standard investigation, but frequently has disadvantages of time delay, resulting in increased hospital stay and mortality. Our aim was to establish whether multidetector CT (MDCT) is an appropriate first-line investigation of occult femoral neck (NOF) fractures., Methods: From 2013, we elected to use MDCT as the first-line investigation in patients believed to have an NOF fracture with negative plain films. These were reported by consultant musculoskeletal radiologists. We retrospectively analysed the data of consecutive patients presenting to the University Hospital of Wales, over 30 months with a clinical suspicion of a hip fracture., Results: 1443 patients were admitted during the study period. 209 (14.5%) patients had negative plain films requiring further investigation to exclude an NOF fracture, of which 199 patients had a CT. 93 patients had no fracture and 20 patients had isolated greater trochanter fractures. None of these patients progressed to develop an intracapsular femoral neck fracture at 4-month follow-up, although one patient sustained an extracapsular fracture following a high-energy fall whilst admitted. 26 femoral neck fractures were diagnosed on CT, whilst the remaining 60 patients were diagnosed with other pelvic ring fractures., Conclusion: When interpreted by experienced radiologists, MDCT has both sensitivity and specificity of 100%., Advances in Knowledge: We recommend the use of MDCT as a safe and appropriate first-line investigation for NOF fractures.