PD-L1-PD-1 interactions limit effector regulatory T cell populations at homeostasis and during infection.

Phenotypic and transcriptional profiling of regulatory T (Treg) cells at homeostasis reveals that T cell receptor activation promotes Treg cells with an effector phenotype (eTreg) characterized by the production of interleukin-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eTreg cell activity, whereas during infection with Toxoplasma gondii, early interferon-γ upregulates myeloid cell expression of PD-L1 associated with reduced Treg cell populations. In infected mice, blockade of PD-L1, complete deletion of PD-1 or lineage-specific deletion of PD-1 in Treg cells prevents loss of eTreg cells. These interventions resulted in a reduced ratio of pathogen-specific effector T cells: eTreg cells and increased levels of interleukin-10 that mitigated the development of immunopathology, but which could compromise parasite control. Thus, eTreg cell expression of PD-1 acts as a sensor to rapidly tune the pool of eTreg cells at homeostasis and during inflammatory processes.

Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. METHODS: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. FINDINGS: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. INTERPRETATION: Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. FUNDING: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.

Implementing a cognitive behavioral intervention for patients with head and neck cancer.

PURPOSE: Sequelae of and therapies for head and neck cancers (HNC) are associated with physical and functional impairment as well as increased levels of psychological distress post treatment. Given the impact of HNC and treatment on functioning (i.e., eating and talking), health-related quality of life (HRQOL) is a significant area of survivorship concern within this population. Although prior research indicates that the incidence of anxiety and depression ranges from 15 to 50%, to date, there is a paucity of research on specific psychosocial interventions related to HNC treatment and completed studies have been limited by infrequent use of a randomized design and provision of non-standardized psychosocial interventions. This study aimed to address these gaps and utilize a brief cognitive behavioral intervention (CBI) to improve (1) self-efficacy for coping with cancer, (2) depressive symptoms, (3) other psychological symptoms, and (4) HRQOL among patients with HNC. METHODS: In an effort to conduct a randomized clinical trial of those undergoing treatment for HNC, eighty-eight patients were assigned to receive either a standardized CBI or usual psychological care (N = 47 and 41, respectively) with a 1-year follow-up. The means of all variables for both groups, adjusted for baseline, were visually compared at 3, 6, and 12 months post treatment. RESULTS: As has been a challenge in other longitudinal HNC studies, a high degree of attrition occurred, with a loss of 35 patients from the CBI group and 29 from the usual care group. Despite the high attrition, analysis of existing data indicated that the effect of CBI was discernable among the patients who completed the course of the study. Of the 38 comparisons, 34 showed that the CBI group had the favorable outcome. Important considerations for implementation of a structured psychotherapy intervention during active cancer treatment with multiple barriers including communication challenges and practical limitations were realized. CONCLUSIONS: The impact of HNC treatment can be particularly distressing as it often results in functional impairment and markedly changed activities of daily living among survivors. However, engaging in therapeutic methods to cope and manage distress during treatment can influence QOL and mood into the survivorship phase.

Assignment of the absolute configuration of molecules that are chiral by virtue of deuterium substitution using chiral tag molecular rotational resonance spectroscopy.

Chiral tag molecular rotational resonance (MRR) spectroscopy is used to assign the absolute configuration of molecules that are chiral by virtue of deuterium substitution. Interest in the improved performance of deuterated active pharmaceutical ingredients has led to the development of precision deuteration reactions. These reactions often generate enantioisotopomer reaction products that pose challenges for chiral analysis. Chiral tag rotational spectroscopy uses noncovalent derivatization of the enantioisotopomer to create the diastereomers of the 1:1 molecular complexes of the analyte and a small, chiral molecule. Assignment of the absolute configuration requires high-confidence determinations of the structures of these weakly bound complexes. A general search method, CREST, is used to identify candidate geometries. Subsequent geometry optimization using dispersion corrected density functional theory gives equilibrium geometries with sufficient accuracy to identify the isomers of the chiral tag complexes produced in the pulsed jet expansion used to introduce the sample into the MRR spectrometer. Rotational constant scaling based on the fact that the diastereomers have the same equilibrium geometry gives accurate predictions allowing identification of the homochiral and heterochiral tag complexes and, therefore, assignment of absolute configuration. The method is successfully applied to three oxygenated substrates from enantioselective Cu-catalyzed alkene transfer hydrodeuteration reaction chemistry.

Direct ventriculoatrial shunt in a pediatric patient: case report and technical note.

BACKGROUND /IMPORTANCE: The safety of direct cardiac shunts has been historically described in the pediatric population before the introduction of silastic catheters but are rarely utilized in modern practice. Herein, we describe several technical nuances regarding the placement of a direct ventriculoatrial catheter in a pediatric patient, including the creation of a sternal divot to accommodate for the movement of the catheter during growth. CLINICAL PRESENTATION: We report a complex case of a 2-year-old former premature infant with multiple systemic congenital abnormalities, including tracheal atresia (type 2), complete atrioventricular septal defect status post repair, and shunted hydrocephalus. She developed multiple shunt malfunctions secondary to abdominal malabsorption and shunt infections. CONCLUSION: Multiple options for distal shunt placement, including the atrium via open and endovascular techniques, the abdomen, gallbladder, and pleura, were considered, but the direct cardiac placement was felt to be the safest option given the patient's coexisting conditions. Placement requires a multidisciplinary team. Special consideration should be made for linear growth in children.

Highly selective catalytic transfer hydrodeuteration of cyclic alkenes.

Selective deuterium installation into small molecules is becoming increasingly desirable not only for the elucidation of mechanistic pathways and studying biological processes but also because of deuterium's ability to favorably adjust the pharmacokinetic parameters of bioactive molecules. Fused bicyclic moieties, especially those containing heteroatoms, are prevalent in drug discovery and pharmaceuticals. Herein, we report a copper-catalyzed transfer hydrodeuteration of cyclic and heterocyclic alkenes, which enables the synthesis of chromans, quinolinones, and tetrahydronaphthalenes that are precisely deuterated at the benzylic position. We also demonstrate the ability to place one deuterium atom at the homobenzylic site of these scaffolds with high regioselectivity by swapping transfer reagents for their isotopic analogs. Furthermore, examples of chemoselective transfer hydrogenation and transfer deuteration are disclosed, allowing for the simultaneous incorporation of two vicinal hydrogen or deuterium atoms into a double bond.

Safety and utility of modified ultrafiltration in pediatric cardiac surgery.

INTRODUCTION: Modified ultrafiltration (MUF) is employed at the termination of cardiopulmonary bypass (CPB) in pediatric and neonatal patients undergoing congenital heart surgery to reduce the accumulation of total body water thus increasing the concentration of red blood cells and the other formed elements in the circulation. Modified ultrafiltration has been reported to remove circulating pro-inflammatory mediators that result in systemic inflammatory response syndrome (SIRS) postoperatively. METHODS: Four hundred patients undergoing cardiac surgery requiring cardiopulmonary bypass and weighing less than or equal to 12 kg were retrospectively evaluated for the effectiveness of MUF. After the termination of CPB, blood was withdrawn through the aortic cannula and passed through a hemoconcentrator attached to the blood cardioplegia set and returned to the patient through the venous cannula. The entire CPB circuit volume in addition to the patient's circulating blood volume were concentrated until the hematocrit value displayed on the CDI cuvette within the MUF circuit reached 45% or there was no more volume to safely remove. At the same time a full unit of FFP can be infused as water is being removed, thus maintaining euvolemia. RESULTS: MUF was performed in all 400 patients with no MUF-related complications. Following the conclusion of MUF, anecdotal observations included improved surgical hemostasis, improved hemodynamic parameters, decreased transfusion requirements, and decreased ventilator times. CONCLUSIONS: Complete MUF enables the clinician to safely raise the post-CPB hematocrit to at least 40% while potentially removing mediators that could result in SIRS. In addition a full unit of FFP can be administered while maintaining euvolemia.

A Novel Hierarchical Security Solution for Controller-Area-Network-Based 3D Printing in a Post-Quantum World.

As the popularity of 3D printing or additive manufacturing (AM) continues to increase for use in commercial and defense supply chains, the requirement for reliable, robust protection from adversaries has become more important than ever. Three-dimensional printing security focuses on protecting both the individual Industrial Internet of Things (I-IoT) AM devices and the networks that connect hundreds of these machines together. Additionally, rapid improvements in quantum computing demonstrate a vital need for robust security in a post-quantum future for critical AM manufacturing, especially for applications in, for example, the medical and defense industries. In this paper, we discuss the attack surface of adversarial data manipulation on the physical inter-device communication bus, Controller Area Network (CAN). We propose a novel, hierarchical tree solution for a secure, post-quantum-supported security framework for CAN-based AM devices. Through using subnet hopping between isolated CAN buses, our framework maintains the ability to use legacy or third-party devices in a plug-and-play fashion while securing and minimizing the attack surface of hardware Trojans or other adversaries. The results of the physical implementation of our framework demonstrate 25% and 90% improvement in message costs for authentication compared to existing lightweight and post-quantum CAN security solutions, respectively. Additionally, we performed timing benchmarks on the normal communication (hopping) and authentication schemes of our framework.

Updates in Butterfly Graft Technique.

Nasal obstruction is a significant challenge greatly affecting individual quality of life. It is one of the most common presentations in the otolaryngology clinic, often persisting despite medical and, at times, surgical intervention. The butterfly graft has proven to be a veritable option addressing nasal valve collapse. Herein, we describe our most recent operative technique, highlight its application in ethnic rhinoplasty and revision cases, and discuss incorporation of dorsal preservation techniques in functional rhinoplasty.

Highly Regioselective Copper-Catalyzed Transfer Hydrodeuteration of Unactivated Terminal Alkenes.

Catalytic transfer hydrodeuteration of unactivated alkenes is challenging because of the requirement that chemically similar hydrogen and deuterium undergo selective insertion across a π-bond. We now report a highly regioselective catalytic transfer hydrodeuteration of unactivated terminal alkenes across a variety of heteroatom- or heterocycle-containing substrates. The base-metal-catalyzed reaction is also demonstrated on two complex natural products. Reaction studies indicate modular conditions that can also be extended to perform either an alkene transfer hydrogenation or transfer deuteration.

Lower workforce participation is associated with more severe persisting breathlessness.

BACKGROUND: Not being able to work has negative health, social and financial consequences. Persisting breathlessness is prevalent in working-aged people. Is it associated with lower workforce participation? This study, using the South Australian Health Omnibus, aimed to explore associations between paid workforce participation and persisting breathlessness intensity, and economic impacts on income in people of working age. METHODS: This cross-sectional study conducted face-to-face interviews with a random sample of adults in South Australia (n = 8916). Questions included key demographic data, workforce participation and the presence and intensity of persisting breathlessness. Data from working-aged respondents (20-65 years of age) were standardised to the census for regression analyses. Work was coded to paid full- or part-time work or 'other'. Persisting breathlessness (more than three of the last six months) used the modified Medical Research Council breathlessness scale (aggregated to 0, 1, 2-4). Opportunity cost valuations compared annual income foregone by persisting breathlessness severity. RESULTS: Of people interviewed, 6,608 were working-aged (49.9% male; 67.5% had post-secondary qualifications; 70.9% were in paid full- or part-time work; and 1.7% had mMRC score 2-4). Workforce participation dropped in working aged people with increasing breathlessness: mMRC 0, 70.6%; mMRC 1, 51.7%; mMRC 2-4, 20.3%. In the regression model, people with the most severe breathlessness were much less likely to work (OR 0.14; 95% CI 0.09, 0.22). Annual income foregone by people with persisting breathlessness was AU$10.7 billion (AU$9.1b for full-time and AU$1.6b for part-time work; range AU$5.9b, AU$49.7b). CONCLUSION: Worsening persisting breathlessness is associated with lower workforce participation with direct financial consequences, greatest for older males.

Enantioselective Synthesis of Enantioisotopomers with Quantitative Chiral Analysis by Chiral Tag Rotational Spectroscopy.

Fundamental to the synthesis of enantioenriched chiral molecules is the ability to assign absolute configuration at each stereogenic center, and to determine the enantiomeric excess for each compound. While determination of enantiomeric excess and absolute configuration is often considered routine in many facets of asymmetric synthesis, the same determinations for enantioisotopomers remains a formidable challenge. Here, we report the first highly enantioselective metal-catalyzed synthesis of enantioisotopomers that are chiral by virtue of deuterium substitution along with the first general spectroscopic technique for assignment of the absolute configuration and quantitative determination of the enantiomeric excess of isotopically chiral molecules. Chiral tag rotational spectroscopy uses noncovalent chiral derivatization, which eliminates the possibility of racemization during derivatization, to perform the chiral analysis without the need of reference samples of the enantioisotopomer.

Late-Stage Intermolecular Allylic C-H Amination.

Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [MnIII(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [MnIII(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.

Copper-Catalyzed Transfer Hydrodeuteration of Aryl Alkenes with Quantitative Isotopomer Purity Analysis by Molecular Rotational Resonance Spectroscopy.

A copper-catalyzed alkene transfer hydrodeuteration reaction that selectively incorporates one hydrogen and one deuterium atom across an aryl alkene is described. The transfer hydrodeuteration protocol is selective across a variety of internal and terminal alkenes and is also demonstrated on an alkene-containing complex natural product analog. Beyond using 1H, 2H, and 13C NMR analysis to measure reaction selectivity, six transfer hydrodeuteration products were analyzed by molecular rotational resonance (MRR) spectroscopy. The application of MRR spectroscopy to the analysis of isotopic impurities in deuteration chemistry is further explored through a measurement methodology that is compatible with high-throughput sample analysis. In the first step, the MRR spectroscopy signatures of all isotopic variants accessible in the reaction chemistry are analyzed using a broadband chirped-pulse Fourier transform microwave spectrometer. With the signatures in hand, measurement scripts are created to quantitatively analyze the sample composition using a commercial cavity enhanced MRR spectrometer. The sample consumption is below 10 mg with analysis times on the order of 10 min using this instrument-both representing order-of-magnitude reduction compared to broadband MRR spectroscopy. To date, these measurements represent the most precise spectroscopic determination of selectivity in a transfer hydrodeuteration reaction and confirm that product regioselectivity ratios of >140:1 are achievable under this mild protocol.

The effects of internal jugular vein compression for modulating and preserving white matter following a season of American tackle football: A prospective longitudinal evaluation of differential head impact exposure.

The purpose of this clinical trial was to examine whether internal jugular vein compression (JVC)-using an externally worn neck collar-modulated the relationships between differential head impact exposure levels and pre- to postseason changes in diffusion tensor imaging (DTI)-derived diffusivity and anisotropy metrics of white matter following a season of American tackle football. Male high-school athletes (n = 284) were prospectively assigned to a non-collar group or a collar group. Magnetic resonance imaging data were collected from participants pre- and postseason and head impact exposure was monitored by accelerometers during every practice and game throughout the competitive season. Athletes' accumulated head impact exposure was systematically thresholded based on the frequency of impacts of progressively higher magnitudes (10 g intervals between 20 to 150 g) and modeled with pre- to postseason changes in DTI measures of white matter as a function of JVC neck collar wear. The findings revealed that the JVC neck collar modulated the relationships between greater high-magnitude head impact exposure (110 to 140 g) and longitudinal changes to white matter, with each group showing associations that varied in directionality. Results also revealed that the JVC neck collar group partially preserved longitudinal changes in DTI metrics. Collectively, these data indicate that a JVC neck collar can provide a mechanistic response to the diffusion and anisotropic properties of brain white matter following the highly diverse exposure to repetitive head impacts in American tackle football. Clinicaltrials.gov: NCT# 04068883.

Catalytic Transfer Deuteration and Hydrodeuteration: Emerging Techniques to Selectively Transform Alkenes and Alkynes to Deuterated Alkanes.

Increasing demand for deuterium-labeled organic molecules has spurred a renewed interest in selective methods for deuterium installation. Catalytic transfer deuteration and transfer hydrodeuteration are emerging as powerful techniques for the selective incorporation of deuterium into small molecules. These reactions not only obviate the use of D2 gas and pressurized reaction setups but provide new opportunities for selectively installing deuterium into small molecules. Commercial or readily synthesized deuterium donors are typically employed as easy-to-handle reagents for transfer deuteration and hydrodeuteration reactions. In this minireview, recent advances in the catalytic transfer deuteration and hydrodeuteration of alkenes and alkynes for the selective synthesis of deuterated alkanes will be discussed.

Role of Imaging in Renal Cell Carcinoma: A Multidisciplinary Perspective.

With the expansion in cross-sectional imaging over the past few decades, there has been an increase in the number of incidentally detected renal masses and an increase in the incidence of renal cell carcinomas (RCCs). The complete characterization of an indeterminate renal mass on CT or MR images is challenging, and the authors provide a critical review of the best imaging methods and essential, important, and optional reporting elements used to describe the indeterminate renal mass. While surgical staging remains the standard of care for RCC, the role of renal mass CT or MRI in staging RCC is reviewed, specifically with reference to areas that may be overlooked at imaging such as detection of invasion through the renal capsule or perirenal (Gerota) fascia. Treatment options for localized RCC are expanding, and a multidisciplinary group of experts presents an overview of the role of advanced medical imaging in surgery, percutaneous ablation, transarterial embolization, active surveillance, and stereotactic body radiation therapy. Finally, the arsenal of treatments for advanced renal cancer continues to grow to improve response to therapy while limiting treatment side effects. Imaging findings are important in deciding the best treatment options and to monitor response to therapy. However, evaluating response has increased in complexity. The unique imaging findings associated with antiangiogenic targeted therapy and immunotherapy are discussed. An invited commentary by Remer is available online. Online supplemental material is available for this article. ©RSNA, 2021.

Perceptions and experiences of laws and regulations governing access to opioids in South, Southeast, East and Central Asia: A systematic review, critical interpretative synthesis and development of a conceptual framework.

BACKGROUND: Opioids are essential medicines. Despite international and national laws permitting availability, opioid access remains inadequate, particularly in South, Southeast, East and Central Asia. AIM: To review evidence of perceptions and experiences of regulatory enablers and barriers to opioid access in South, Southeast, East and Central Asia. DESIGN: Systematic review of post-2000 research according to PRISMA guidelines. Data were subjected to critical interpretive synthesis. International, national and sub-national barriers were organised developing a conceptual framework of opioid availability. DATA SOURCES: PsycINFO, Medline, Embase, The Cochrane Library. CINAHL, Complete and ASSIA from 2000 until 20th May 2019. RESULTS: 21/14097 studies included: quantitative n = 15, qualitative n = 3 and mixed-methods n = 3. Four barrier/enabler themes were developed: Legal, regulatory, socio-political; lack of laws explicitly enabling opioid access, restrictive international controls and clinician prescribing concerns. Opioid availability; limited availability, poor policymaker and clinician education regarding opioid benefits, poor continuity of supply. Opioid Accessibility; medicine costs, distance to prescribing centres. Prescribing; extensive bureaucratic barriers, lack of human resources for prescribing. We present a novel framework of a self-perpetuating model of inadequate opioid provision. The Single Convention on Narcotics provides the context of restrictive laws and negative attitudes amongst policymakers. A consequent lack of prescribers and clinicians' negative attitudes at sub-national levels, results in inadequate access to and use of opioids. Data of inadequate consumption informs annual requirement estimates used by the International Narcotics Control Board to determine future opioid availability. CONCLUSIONS: Regulatory and socio-political actions unintentionally limit opioid access. International and national laws explicitly enabling opioid access are required, to assuage concerns, promote training and appropriate prescribing.

Professionals', patients' and families' views on the use of opioids for chronic breathlessness: A systematic review using the framework method and pillar process.

BACKGROUND: In combination with non-pharmacological interventions, opioids may safely reduce chronic breathlessness in patients with severe illness. However, implementation in clinical practice varies. AIM: To synthesise the published literature regarding health professionals', patients' and families' views on the use of opioids for chronic breathlessness, identifying issues which influence implementation in clinical practice. DESIGN: Systematic review and synthesis using the five-stage framework synthesis method. DATA SOURCES: Three electronic databases (MEDLINE, Embase via OVID, ASSIA via Proquest) were searched (March 2020) using a predefined search strategy. Studies were also citation chained from key papers. Papers were screened against a priori eligibility criteria. Data were extracted from included studies using the framework synthesis method. Qualitative and quantitative data were synthesised using the pillar process. Included studies were critically appraised using the Mixed-Methods Appraisal Tool. RESULTS: After de-duplication, 843 papers were identified. Following screening, 22 studies were included. Five themes were developed: (i) clinician/patient characteristics, (ii) education/knowledge/experience, (iii) relationship between clinician/family, (iv) clinician/patient fear of opioids and (v) regulatory issues. CONCLUSIONS: There are significant barriers and enablers to the use of opioids for the symptomatic reduction of chronic breathlessness based on the knowledge, views and attitudes of clinicians, patients and families. Clinicians' interactions with patients and their families strongly influences adherence with opioid treatment regimens for chronic breathlessness. Clinicians', patients' and families' knowledge about the delicate balance between benefits and risks is generally poor. Education for all, but particularly clinicians, is likely to be a necessary (but insufficient) factor for improving implementation in practice.

Challenges Facing Young Scientists in Academia and Industry in the United States from the Lens of a Millennial Academic.

Rising to the challenge: Pictured from left to right: Salma L. Nuñez, Albert Reyes and Lisandra Santiago-Capeles, Ph.D. The challenges that young scientists face in academia and industry in the United States are discussed. Prof. Joseph Clark provides insight about how social media, funding, diversity, natural disasters, COVID-19 and student loan debt are impacting young scientists. A discussion of strategies to meet these challenges and support young scientists are presented.