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The short meditation, A discourse of life and death was translated by Mary (Sidney) Herbert, Countess of Pembroke in 1590 from Excellent discours de la vie et de la mort by Philippe de Mornay, seigneur du Plessis-Marly. This article presents the publishing history of Herbert’s translation and how it was adapted twice in the seventeenth century. First, it is found as an incomplete manuscript by ‘T. H. Gent.’ (BL MS Sloane 1037). The manuscript has the correct licence to print, but the wrong author, and was used as setting copy in the print shop of George Eld and Miles Flesher in early 1624. All copies of that edition are now lost. In 1697 Herbert’s translation was revised again as the ‘contemplations’ of Sir John Fenwick before his execution for treason.

This study explored mediating pathways, moderating factors, and moderated mediation effects of a web-based, cognitive behavioral therapy (CBT) intervention for chronic pain patients with aberrant drug-related behavior (ADRB). In a 2-arm RCT, patients with chronic pain who screened positive for ADRB received treatment-as-usual (TAU, n = 55) or TAU plus a 12-week, web-based CBT intervention (n = 55). Assessments were conducted at weeks 4, 8, and 12, and at 1- and 3-months post intervention. Web-CBT significantly reduced pain catastrophizing, which, in turn, reduced pain interference and pain severity via a pathway of pain catastrophizing. Web-CBT also significantly reduced ADRB both directly and indirectly by reducing pain catastrophizing. For pain interference and pain severity, web-CBT was more effective than TAU for younger patients (≤ age 50). For pain severity, web-CBT was more effective for both younger patients (≤ age 50), and those with a lifetime substance use disorder. Findings suggest that web-CBT's positive impact on pain outcomes and ADRB are mediated by its effect on pain catastrophizing, and its treatment effects may be most robust for younger patients and those with histories of substance dependence.

Agricultural data are crucial to many aspects of production, commerce, and research involved in feeding the global community. However, in most agricultural research disciplines standard best practices for data management and publication do not exist. Here we propose a set of best practices in the areas of peer review, minimal dataset development, data repositories, citizen science initiatives, and support for best data management. We illustrate some of these best practices with a case study in dairy agroecosystems research. While many common, and increasingly disparate data management and publication practices are entrenched in agricultural disciplines, opportunities are readily available for promoting and adopting best practices that better enable and enhance data-intensive agricultural research and production. National Institute of Food and AgricultureUnited States Department of Agriculture (USDA)National Institute of Food and Agriculture [2018-67023-27843]; Agricultural Research ServiceUnited States Department of Agriculture (USDA)USDA Agricultural Research Service [8042-31000-001-00-D, 8260-88888-001-00-D] Published version National Institute of Food and Agriculture, Grant/Award Number: 2018-67023-27843; Agricultural Research Service, Grant/Award Numbers: 8042-31000-001-00-D, 8260-88888-001-00-D

Objectives: Lurasidone is a new second generation (atypical) antipsychotic agent with unique receptor affinity and side-effect profiles, but limited literature is available on its use in adolescent populations. Contrasting with research treatment trials which typically recruit patients by stringent selection criteria, this case series examined the effects and tolerability of using lurasidone in adolescents within real-life clinical settings in treating complex cases who had not responded to other therapy options. Methods: We conducted a retrospective case-note audit of 6 adolescents aged 14 to 17 years old attending community child and adolescent mental health services (CAMHS) who were prescribed lurasidone. Results: Lurasidone had been prescribed for a range of “hard-to-manage” conditions with complex comorbidities, in adolescents in relation to specific use of lurasidone on the basis of clinical and pharmacological indications after exhausting more conventional treatment options. Case-note review suggested response to lurasidone was clinically positive in 3 cases, equivocal/marginal in 2 cases, and ineffective in 1 case. There were no cases of poor tolerance or adverse effects. Notably, positive responses for depressive and irritable mood symptoms were specifically recorded by prescribing clinicians, indicative of benefits on symptom improvement. No lurasidone attributed weight gain, galactorrhoea, metabolic abnormalities, sexual dysfunction or intolerance were reported. Pro-cognitive effects were not detected; but our findings were constrained by the non-systematic and incomplete information ascertainment, typical in retrospective case-note review. Conclusion: This case series provides preliminary data supporting lurasidone’s potential use in adolescents of complex clinical needs (but without a clinical diagnosis of bipolar disorder) within real-life clinical settings. Lurasidone appears to show a weight-sparing effect, in addition to improving mood symptoms in some cases. Lurasidone deserves further study for its use in the adolescent population (outside the remit of FDA) given its potential more favorable risk-benefit profile in young people. The favorable tolerability appear to be borne out by the pharmacodynamic predictions in our complex patients who would be excluded in formal clinical trial studies.

Background Firefighters have increased cancer incidence and mortality rates compared to the general population, and are exposed to multiple products of combustion including known and suspected carcinogens. Objective The study objective was to quantify fire response exposures by role and self-reported exposure risks. Methods Urinary hydroxylated metabolites of polycyclic aromatic hydrocarbons (PAH-OHs) were measured at baseline and 2–4 h after structural fires and post-fire surveys were collected. Results Baseline urine samples were collected from 242 firefighters. Of these, 141 responded to at least one of 15 structural fires and provided a post-fire urine. Compared with baseline measurements, the mean fold change of post-fire urinary PAH-OHs increased similarly across roles, including captains (2.05 (95% CI 1.59–2.65)), engineers (2.10 (95% CI 1.47–3.05)), firefighters (2.83 (95% CI 2.14–3.71)), and paramedics (1.84 (95% CI 1.33–2.60)). Interior responses, smoke odor on skin, and lack of recent laundering or changing of hoods were significantly associated with increased post-fire urinary PAH-OHs. Significance Ambient smoke from the fire represents an exposure hazard for all individuals on the fireground; engineers and paramedics in particular may not be aware of the extent of their exposure. Post-fire surveys identified specific risks associated with increased exposure.

Background Dysregulated microRNA (miRNA) expression could provide a mechanism linking firefighter exposure to increased cancer risk. Objective To determine if changes in longitudinal miRNA expression in firefighters are associated with occupational exposures. Methods Whole blood MiRNA was evaluated in 52 new recruits prior to live-fire training and 20–37 months later. Linear mixed effects models adjusted for age, ethnicity, BMI, and batch effects were used to determine associations separately for all fires and structure fires only between employment duration, cumulative fire-hours and fire-runs, and time since most recent fire with (1) nine a priori and (2) the full array of 799 miRNAs. Results For multivariable models including all fires, two a priori miRNAs were associated with employment duration and four with time since most recent fire. For multivariable models restricted to structure fires, three a priori miRNAs were associated with employment duration and one with fire-runs. Additional miRNAs from the full array were associated with employment duration for all fires and/or structure fires. In general, tumor suppressive miRNAs decreased and oncogenic miRNAs increased with exposure. Significance Changes in miRNAs may serve as biomarkers of exposure effects and a mechanism for increased cancer risk in firefighters.

A patient with severe mitral regurgitation and chronic systolic heart failure taking inotropic support at home presents for transcatheter edge-to-edge mitral valve repair, complicated by torrential mitral regurgitation from damaged mitral leaflets requiring escalating mechanical circulatory support and ultimately expedited orthotopic heart transplantation. (Level of Difficulty: Intermediate.), Graphical abstract

The purpose of this study was to evaluate the rate of return to play (RTP) in patients who underwent Type V superior labrum anterior–posterior (SLAP) repair compared to patients who underwent isolated Bankart repair in the setting of traumatic anterior shoulder instability. A retrospective review of patients who underwent arthroscopic Bankart repair and SLAP repair by a single surgeon between 2012 and 2017 was performed. Additionally, these were pair-matched in a 1:2 ratio for age, sex, sport and level of pre-operative play, with those undergoing isolated arthroscopic Bankart repair alone as a control group. RTP, level of RTP and the timing of RTP were assessed. The study included a total of 96 patients, with 32 in the study group and 64 in the control group, and a mean follow-up of 59 months. Overall, there was no significant difference in the overall rate of return to play (26/32 (81.3%) vs 56/64 (87.5%), n.s), but there was a significantly higher rate of RTP at the same/higher level in the control group (14/32 (43.6%) vs 43/64 (67.2%), p = 0.0463). There was no significant difference in timing of RTP between the groups (n.s). There was no significant difference in recurrent instability (6/32 (18.8%) vs 5/64 (7.8%), n.s) but there was a significant difference in revision rates (5/32 (15.6%) vs. 2/64 (3.1%), p = 0.0392) between the Type V SLAP repair group and the control group. Following arthroscopic repair, patients with Type V SLAP tears had a similar overall rate of RTP when compared directly to a control group of patients who underwent arthroscopic Bankart repair alone. However, those who underwent Type V SLAP repair reported significantly lower rates of RTP at the same or higher level compared to the control group. III.

PURPOSE OF REVIEW: Cross-discipline fitness, or CrossFit, has exploded in popularity during the last two decades. During this time, there have been a high volume of patients presenting to clinicians with a wide range of associated injuries. Given the high intensity, high repetition, and competitive nature of CrossFit training and competition, athletes are vulnerable to injury, particularly upper extremity injury. The rate of injury to the shoulder, elbow, and wrist in CrossFit is higher when compared to traditional weight-training and more comparable to elite-level gymnastics and Olympic-style lifting. Due to the growing popularity of CrossFit-style exercise and the relatively high rate of injury among its participants, clinicians are likely to encounter these athletes. The purpose of this review is to familiarize clinicians with CrossFit and the associated injuries they will likely encounter. RECENT FINDINGS: The medical literature focusing on CrossFit has demonstrated exponential growth, with the first article published in 2012 and 59 articles published in 2020. Although the body of literature is growing, there are no high-level studies focusing on CrossFit. The literature mainly consists of level IV and V studies, primarily consisting of case reports and case series. Recent studies have proven that CrossFit athletes are vulnerable to high rates of upper extremity injury and a few studies have identified risk factors for injury. Future high-level research is required to study modifiable risk factors, diagnostic criteria, and treatment options for these high-risk athletes in order to improve the safety of their sport. SUMMARY: The CrossFit body of research is limited to level IV and V studies; however, the literature is clear, CrossFit athletes face a high rate of upper extremity injury. For this reason, clinicians must be familiar with CrossFit and its associated pathology. The goal of this review is to familiarize clinicians with CrossFit and the associated pathologies they will likely encounter.

BackgroundOpioid-related deaths continue to rise. Psychological trauma is commonly comorbid with Opioid Use Disorder (OUD). Adverse childhood experiences can disrupt the development of emotion regulation, increasing risk of substance use. Self-compassion may reduce OUD risk and outcomes by facilitating emotion regulation, decreasing the toxicity of shame, and reducing internalized stigma that can hinder recovery. Mindfulness practice enhances self-compassion.MethodsThis study is part of a pilot (N = 18) of the Mindful Recovery OUD Care Continuum (M-ROCC) during buprenorphine office-based opioid treatment (OBOT). The present study was conducted to gain a deeper understanding of the intervention’s effects on self-compassion development, and to explore differential changes in self-compassion during the intervention among participants with varying intensity of trauma exposure measured by high levels of childhood adversity (defined by 4+ adverse childhood experiences (ACEs) at baseline). We conducted secondary analyses of a subset of qualitative interview data (N = 11 unique participants) collected for the pilot study (weeks 4 and 24, 14 total interviews) to elaborate upon changes in Self-Compassion Scale (SCS-SF) scores.ResultsIn the primary pilot study, participants’ mean SCS-SF scores shifted significantly from baseline to week 24, β = 0.22, p = 0.028. This change is elaborated upon through interviews. Despite pervasive challenges to becoming more self-compassionate (e.g., trauma histories and substance use), participants reported increased compassionate self-responding and decreased uncompassionate self-responding. Mindfulness training was identified as the primary mechanism underlying the shift. Kindness to self and others and—to a lesser extent an increased sense of common humanity—were also identified as key to overall self-compassion. Compared to those in the lower ACEs group, participants in the higher ACEs group tended to have lower baseline self-compassion scores (d = 1.09, p = 0.055).ConclusionM-ROCC may increase self-compassion among patients with OUD during OBOT by increasing compassionate, and decreasing uncompassionate, self-responding. Patients with OUD with greater childhood adversity tended to have lower levels of self-compassion, which improved with M-ROCC. Future trials with larger samples are needed to confirm these potential outcomes, mechanisms, and differential impacts between ACEs subgroups.

Lower back pain is a considerable medical problem that will impact 80% of the U.S. population at some point in their life. For the most severe cases, surgical repair is necessary and is associated with costs upwards of $10.2 billion annually in the United States. To alleviate back pain, spine fusions are a common treatment in which two or more vertebrae are biologically fused together often through the use of a graft material. Unfortunately, iliac crest bone autograft, the current gold standard graft material, can yield insufficient fusion and is associated with considerable donor site morbidity and pain as well as limited supply. Therefore, new materials need to be developed in order to better coordinate healing and new bone growth in the affected area to reduce unnecessary patient burden. In order to address this issue, the incorporation of allograft and one of two types of cellulose (i.e., 0CNCs and CNFs) into a dual-crosslinked chitosan hydrogel loaded with bioactive calcium phosphate was investigated. Hydrogels were then tested for both their material and biological properties. Specifically, hydrogel swelling ratio, mass loss, ion release profile, compressive strength, in vitro biocompatibility and osteoinduction as well as in vivo biocompatibility, and effectiveness in a spine fusion model were determined. Cellulose and allograft incorporation significantly improved hydrogel compressive strength and biocompatibility and CNFs were found to be a significantly more biocompatible form of cellulose than 0CNCs. Additionally, through the controlled delivery of osteoinductive simple signaling molecules (i.e., calcium and phosphate ions), DCF-loaded CNF/Chitosan hydrogels were able to induce osteoblast-like activity in murine mesenchymal stem cells. When evaluated in vivo, these hydrogels were found to be non-toxic though the subacute phase (14 days). A 6-week rabbit spine fusion found these materials to achieve near complete fusion when assessed radiographically. This research provides considerable support for the utility of our novel material for spine fusion procedures as well as other future bone applications.

Heterozygous, missense mutations in α- or β-tubulin genes are associated with a wide range of human brain malformations, known as tubulinopathies. We seek to understand whether a mutation’s impact at the molecular and cellular levels scale with the severity of brain malformation. Here, we focus on two mutations at the valine 409 residue of TUBA1A, V409I, and V409A, identified in patients with pachygyria or lissencephaly, respectively. We find that ectopic expression of TUBA1A-V409I/A mutants disrupt neuronal migration in mice and promote excessive neurite branching and a decrease in the number of neurite retraction events in primary rat neuronal cultures. These neuronal phenotypes are accompanied by increased microtubule acetylation and polymerization rates. To determine the molecular mechanisms, we modeled the V409I/A mutants in budding yeast and found that they promote intrinsically faster microtubule polymerization rates in cells and in reconstitution experiments with purified tubulin. In addition, V409I/A mutants decrease the recruitment of XMAP215/Stu2 to plus ends in budding yeast and ablate tubulin binding to TOG (tumor overexpressed gene) domains. In each assay tested, the TUBA1A-V409I mutant exhibits an intermediate phenotype between wild type and the more severe TUBA1A-V409A, reflecting the severity observed in brain malformations. Together, our data support a model in which the V409I/A mutations disrupt microtubule regulation typically conferred by XMAP215 proteins during neuronal morphogenesis and migration, and this impact on tubulin activity at the molecular level scales with the impact at the cellular and tissue levels.

Background: Coronary angiography to identify coronary artery disease has been foundational to distinguish the cause of dilated cardiomyopathy (DCM), including the assignment of idiopathic or ischemic cardiomyopathy. Late gadolinium enhancement (LGE) with cardiovascular magnetic resonance (CMR) has emerged as an approach to identify myocardial scar and identify etiology. Methods: The DCM Precision Medicine Study included patients with left ventricular dilation and dysfunction attributed to idiopathic DCM, after expert clinical review excluded ischemic or other cardiomyopathies. Ischemic cardiomyopathy was defined as coronary artery disease with >50% narrowing at angiography of ≥1 epicardial coronary artery. CMR was not required for study inclusion, but in a post hoc analysis of available CMR reports, patterns of LGE were classified as (1) no LGE, (2) ischemic-pattern LGE: subendocardial/transmural, (3) nonischemic LGE: midmyocardial/epicardial. Results: Of 1204 idiopathic DCM patients evaluated, 396 (32.9%) had a prior CMR study; of these, 327 (82.6% of 396) had LGE imaging (mean age 46 years; 53.2% male; 55.4% White); 178 of the 327 (54.4%) exhibited LGE, and 156 of the 178 had LGE consistent with idiopathic DCM. The remaining 22 had transmural or subendocardial LGE. Of these 22, coronary angiography was normal (13), showed luminal irregularities (3), a distant thrombus (1), coronary artery disease with Conclusions: Of 327 probands enrolled in the DCM Precision Medicine Study cohort who had LGE-CMR data available, an ischemic-pattern of LGE was identified in 22 (6.7%), all of whom had idiopathic DCM as adjudicated by expert clinical review. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632.

Cancer remains the second leading cause of death in the US, accounting for 25% of all deaths nationwide. Immunotherapy techniques bolster the immune cells’ ability to target malignant cancer cells and have brought immense improvements in the field of cancer treatments. One important inhibitory protein in T cells, programmed cell death protein 1 (PD-1), has become an invaluable target for cancer immunotherapy. While anti-PD-1 antibody therapy is extremely successful in some patients, in others it fails or even causes further complications, including cancer hyper-progression and immune-related adverse events. Along with countless translational studies of the PD-1 signaling pathway, there are currently close to 5,000 clinical trials for antibodies against PD-1 and its ligand, PD-L1, around 80% of which investigate combinations with other therapies. Nevertheless, more work is needed to better understand the PD-1 signaling pathway and to facilitate new and improved evidence-based combination strategies. In this work, we consolidate recent discoveries of PD-1 signaling mediators and their therapeutic potential in combination with anti-PD-1/PD-L1 agents. We focus on the phosphatases SHP2 and PTPN2; the kinases ITK, VRK2, GSK-3, and CDK4/6; and the signaling adaptor protein PAG. We discuss their biology both in cancer cells and T cells, with a focus on their role in relation to PD-1 to determine their potential in therapeutic combinations. The literature discussed here was obtained from a search of the published literature and ClinicalTrials.gov with the following key terms: checkpoint inhibition, cancer immunotherapy, PD-1, PD-L1, SHP2, PTPN2, ITK, VRK2, CDK4/6, GSK-3, and PAG. Together, we find that all of these proteins are logical and promising targets for combination therapy, and that with a deeper mechanistic understanding they have potential to improve the response rate and decrease adverse events when thoughtfully used in combination with checkpoint inhibitors.

Bacterial pathogen identification, which is critical for human health, has historically relied on culturing organisms from clinical specimens. More recently, the application of machine learning (ML) to whole-genome sequences (WGSs) has facilitated pathogen identification. However, relying solely on genetic information to identify emerging or new pathogens is fundamentally constrained, especially if novel virulence factors exist. In addition, even WGSs with ML pipelines are unable to discern phenotypes associated with cryptic genetic loci linked to virulence. Here, we set out to determine if ML using phenotypic hallmarks of pathogenesis could assess potential pathogenic threat without using any sequence-based analysis. This approach successfully classified potential pathogenetic threat associated with previously machine-observed and unobserved bacteria with 99% and 85% accuracy, respectively. This work establishes a phenotype-based pipeline for potential pathogenic threat assessment, which we term PathEngine, and offers strategies for the identification of bacterial pathogens.

Background Patients receiving oral anticoagulation who experience a traumatic intracranial hemorrhage (ICH) should receive anticoagulation reversal. Four factor prothrombin complex concentrate (4FPCC) is indicated for reversal of warfarin, and is frequently used for reversal of direct-acting oral anticoagulants (DOACs). The purpose of this study is to compare the safety and efficacy of 4FPCC reversal for traumatic ICH in DOAC- and warfarin-anticoagulated patients. Methods This was a single-center, retrospective review of adult patients with traumatic ICH who received 4FPCC for reversal of anticoagulation between April 2013 and August 2018. The ICH volume on the pre- and post-reversal head CT scans was measured. The primary endpoint was the incidence of expansion of ICH volume of blood using pre-and post-4FPCC imaging. Results A total of 102 patients meeting inclusion criteria were identified with 75 patients in the warfarin group and 27 patients in the DOAC group. There were no significant differences in baseline characteristics between the groups except DOAC patients had larger ICH volumes at baseline as compared to warfarin patients (23.4 mm3 vs 3.7 mm3, p = 0.0001). There was neither a statistical difference in change in ICH volume pre-and post-4FPCC administration, nor in the rate of >20% ICH expansion between the warfarin and DOAC groups. There was no difference in the rate of adverse events compared between groups. Conclusion There was no difference in the either the change in ICH volume or the rate of >20% ICH expansion in patients receiving 4FPCC for reversal DOAC versus warfarin anticoagulation. Rates of complications were low in both groups.