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California is increasingly investing in policies and programs that promote soil stewardship on natural and working lands as a way to help achieve multiple goals, including improved forage production and climate change mitigation. To inform the growing expectations for rangeland management activities to promote such services, we conducted an evidence synthesis assessing how four commonly suggested practices (silvopasture, prescribed grazing, compost application and riparian restoration) affect a suite of soil properties and plant-related metrics throughout the state. We extracted data on soil properties that are potentially responsive to management and relevant to soil health. We also extracted data on aboveground forage production, forage nitrogen content and herbaceous species richness. Our search resulted in 399 individual soil observations and 64 individual plant observations. We found that the presence of oaks had the largest effects on soil properties, with soil organic carbon, microbial biomass and other measures of soil fertility increasing beneath oak canopies. The presence of grazing increased compaction and total nitrogen, and decreased pH. Compost applications did not significantly affect any of the measured soil properties, but did boost forage production. Due to a lack of published data, we were unable to characterize the influence of rangeland riparian restoration on any of the soil or plant metrics in our review.

The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on phase 1 clinical trial (NCT03294954) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine interleukin 15 (GD2-CAR.15). This patient was the first to be treated on dose level (DL) 5 and the first patient whose product was restimulated with K562-derived artificial antigen-presenting cells (aAPCs) instead of autologous peripheral blood mononuclear cells (PBMCs). 12 previously treated patients on DLs 1 through 4 did not experience significant toxicity. Our root-cause analysis revealed no genetic alterations of known clinical significance and excluded the possibility of clonal expansion due to insertional retroviral mutagenesis. We report that the use of aAPCs instead of PBMCs for CAR-NKT restimulation contributed to a hyperproliferative state associated with distinct gene expression that possibly led to explosive lymphocyte expansion and uncontrolled toxicity in the patient. These findings warrant the implementation of measures to control immune cell activation during manufacture of cell therapy products, especially those armed with transgenic cytokines.

Background: In recent years human resource management (HRM) has been seen as an important factor in the successful realisation of organisational change programmes. The UK NHS is undergoing substantial organisational change and there is a need to establish which human resource (HR) initiatives may be most effective. Objectives: To assess the results from a wide-ranging series of systematic reviews of the evidence on HRM and performance. The first part assesses evidence on use of HRM in the UK and fidelity of practice implemented. The second part considers evidence for the impact of HRM practices on intermediate outcomes, which can impact on final outcomes, such as organisational performance or patient care. Data sources: The following databases were searched: Applied Social Sciences Index and Abstracts (ASSIA), British Nursing Index (BNI), Business Source Premier, Campbell Collaboration, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Database of Abstracts of Reviews of Effectiveness (DARE), DH-Data, EMBASE, Health Management Information Consortium (HMIC), International Bibliography of the Social Sciences (IBSS), King’s Fund database, MEDLINE, NHS Economic Evaluation Database (NHS EED), National Research Register (NRR), PREMEDLINE, PsycINFO, ReFeR, Social Sciences Citation Index (SSCI) and Science Citation Index (SCI). The searches were conducted in May/June 2006. Review methods: Broad categories of HRM interventions and intermediate outcomes were generated: 10 HRM categories and 12 intermediate outcome categories. Seven patient final outcomes were derived from the NHS Performance Indicators and the NHS Improvement Plan. The quality criteria used to select papers incorporated a longitudinal study design filter to provide evidence of the causal direction of relationships between HRM and relevant outcomes. Single HRM practices were considered. Within the health-specific literature, focus was on the impact of HRM on patient outcomes. Information is presented on the reliability of measures in each of the intermediate outcome areas. Results: Work design practices that enhance employee autonomy and control influenced a number of outcomes and there was consistent evidence for the positive impact of increased job control on employee outcomes, such as job satisfaction, absence and health. For employee participation, the small number of studies reviewed supported the involvement of employees in design/implementation of changes that affect their work. In health literature in particular, employee involvement through quality improvement teams resulted in improved patient outcomes. Findings were positive for the impact of training on the intended outcomes of the initiatives. Support for the impact of performance management practices was apparent, in particular feedback on performance outcomes and the use of participative goal setting. Strong associations were found among all intermediate outcomes, and the relationship between most intermediate behaviours and outcomes were significant. Limitations: Limited evidence was available on the use of HRM and on the implementation of policy. Also, the specific practices studied within each HRM category differ so there was little evidence to show whether similar practices have the same effects in health and non-health settings. Conclusions: Some potentially effective practices for both health and non-health areas were identified, and HRM methods could be used to support change processes within the NHS; the findings relating to work organisation are particularly promising with regard to changes in methods of service delivery. Using training to support the implementation of change is highlighted. However, future multilevel studies that embrace the individual, team and organisational level are needed. Studies should look into interventions aimed at improving HR outcomes and performance, and allow for pre- and post-intervention measurement of practices and outcomes.

Abstract Background Audit and feedback is widely used in healthcare improvement, with evidence of modest yet potentially important effects upon professional practice. There are approximately 60 national clinical audit programmes in the UK. These programmes often develop and adapt new ways of delivering feedback to optimise impacts on clinical practice. Two such programmes, the National Diabetes Audit (NDA) and the Trauma Audit Research Network (TARN), recently introduced changes to their delivery of feedback. We assessed the extent to which the design of these audit programmes and their recent changes were consistent with best practice according to the Clinical Performance Feedback Intervention Theory (CP-FIT). This comprehensive framework specifies how variables related to the feedback itself, the recipient, and the context operate via explanatory mechanisms to influence feedback success. Methods We interviewed 19 individuals with interests in audit and feedback, including researchers, audit managers, healthcare staff, and patient and public representatives. This range of expert perspectives enabled a detailed exploration of feedback from the audit programmes. We structured interviews around the CP-FIT feedback cycle and its component processes (e.g. Data collection and analysis, Interaction). Our rapid analytic approach explored the extent to which both audits applied features consistent with CP-FIT. Results Changes introduced by the audit programmes were consistent with CP-FIT. Specifically, the NDA’s increased frequency of feedback augmented existing strengths, such as automated processes (CP-FIT component: Data collection and analysis) and being a credible source of feedback (Acceptance). TARN’s new analytic tool allowed greater interactivity, enabling recipients to interrogate their data (Verification; Acceptance). We also identified scope for improvement in feedback cycles, such as targeting of feedback recipients (Interaction) and feedback complexity (Perception) for the NDA and specifying recommendations (Intention) and demonstrating impact (Clinical performance improvement) for TARN. Conclusions The changes made by the two audit programmes appear consistent with suggested best practice, making clinical improvement more likely. However, observed weaknesses in the feedback cycle may limit the benefits of these changes. Applying CP-FIT via a rapid analysis approach helps identify strengths and remediable weaknesses in the design of audit programmes that can be shared with them in a timely manner.

Abstract Background Kra monkeys (Macaca fascicularis), a natural host of Plasmodium knowlesi, control parasitaemia caused by this parasite species and escape death without treatment. Knowledge of the disease progression and resilience in kra monkeys will aid the effective use of this species to study mechanisms of resilience to malaria. This longitudinal study aimed to define clinical, physiological and pathological changes in kra monkeys infected with P. knowlesi, which could explain their resilient phenotype. Methods Kra monkeys (n = 15, male, young adults) were infected intravenously with cryopreserved P. knowlesi sporozoites and the resulting parasitaemias were monitored daily. Complete blood counts, reticulocyte counts, blood chemistry and physiological telemetry data (n = 7) were acquired as described prior to infection to establish baseline values and then daily after inoculation for up to 50 days. Bone marrow aspirates, plasma samples, and 22 tissue samples were collected at specific time points to evaluate longitudinal clinical, physiological and pathological effects of P. knowlesi infections during acute and chronic infections. Results As expected, the kra monkeys controlled acute infections and remained with low-level, persistent parasitaemias without anti-malarial intervention. Unexpectedly, early in the infection, fevers developed, which ultimately returned to baseline, as well as mild to moderate thrombocytopenia, and moderate to severe anaemia. Mathematical modelling and the reticulocyte production index indicated that the anaemia was largely due to the removal of uninfected erythrocytes and not impaired production of erythrocytes. Mild tissue damage was observed, and tissue parasite load was associated with tissue damage even though parasite accumulation in the tissues was generally low. Conclusions Kra monkeys experimentally infected with P. knowlesi sporozoites presented with multiple clinical signs of malaria that varied in severity among individuals. Overall, the animals shared common mechanisms of resilience characterized by controlling parasitaemia 3–5 days after patency, and controlling fever, coupled with physiological and bone marrow responses to compensate for anaemia. Together, these responses likely minimized tissue damage while supporting the establishment of chronic infections, which may be important for transmission in natural endemic settings. These results provide new foundational insights into malaria pathogenesis and resilience in kra monkeys, which may improve understanding of human infections.

Abstract Background A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD). Methods After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema). Results Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin–eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control. Conclusions These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Background This study aimed to analyse the degree of relative variation in specialty‐specific competencies required for certification of completion of training (CCT) by the UK Joint Committee on Surgical Training. Methods Regulatory body guidance relating to operative and non‐operative surgical skill competencies required for CCT were analysed and compared. Results Wide interspecialty variation was demonstrated in the required minimum number of logbook cases (median 1201 (range 60–2100)), indexed operations (13 (5–55)), procedure‐based assessments (18 (7–60)), publications (2 (0–4)), communications to learned associations (0 (0–6)) and audits (4 (1–6)). Mandatory courses across multiple specialties included: Training the Trainers (10 of 10 specialties), Advanced Trauma Life Support (6 of 10), Good Clinical Practice (9 of 10) and Research Methodologies (8 of 10), although no common accord was evident. Discussion Certification guidelines for completion of surgical training were inconsistent, with metrics related to minimum operative caseload and academic reach having wide variation.

Abstract Background First-episode psychosis (FEP) may lead to a progressive, potentially disabling and lifelong chronic illness; however, evidence suggests that the illness course can be improved if appropriate treatments are given at the early stages. Nonetheless, the efficacy of antipsychotic medications is suboptimal, particularly for negative and cognitive symptoms, and more efficacious and benign treatments are needed. Previous studies have shown that the antioxidant amino acid N-acetylcysteine (NAC) reduces negative symptoms and improves functioning in chronic schizophrenia and bipolar disorder. Research is scarce as to whether NAC is beneficial earlier in the course of illness. The primary aim of this study is to determine the efficacy of treatment with adjunctive NAC (2 g/day for 26 weeks) compared with placebo to improve psychiatric symptoms in young people experiencing FEP. Secondary aims are to explore the neurobiological mechanisms underpinning NAC and how they relate to various clinical and functional outcomes at 26- and 52-week follow-ups. Methods/design ENACT is a 26-week, randomised controlled trial of adjunctive NAC versus placebo, with a 26-week non-treatment follow-up period, for FEP. We will be recruiting 162 young people aged 15–25 years who have recently presented to, and are being treated at, the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. The primary outcome is the Total Score on the Positive and Negative Syndrome Scale which will be administered at baseline, and weeks 4, 8, 12, 26 (primary endpoint), and 52 (end of study). Secondary outcomes include: symptomatology, functioning, quality of life, neurocognition, blood-derived measures of: inflammation, oxidative and nitrosative stress, and magnetic resonance spectroscopy measures of glutathione concentration. Discussion Targeted drug development for FEP to date has generally not involved the exploration of neuroprotective agents. This study has the potential to offer a new, safe, and efficacious treatment for people with FEP, leading to better treatment outcomes. Additionally, the neuroprotective dimension of this study may lead to a better long-term prognosis for people with FEP. It has the potential to uncover a novel treatment that targets the neurobiological mechanisms of FEP and, if successful, will be a major advance for psychiatry. Trial registration Australian New Zealand Clinical Trials Registry, ID: ACTRN12618000413224. Registered on 21 March 2018.

Abstract Background Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. Methods Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered “feasible” if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. Results Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16–53) off therapy. No patients developed RECIST PD while off therapy. Conclusions This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. Trial registration NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331).

All human cells are coated by a surface layer of proteoglycans, glycosaminoglycans (GAGs) and plasma proteins, called the glycocalyx. The glycocalyx transmits shear stress to the cytoskeleton of endothelial cells, maintains a selective permeability barrier, and modulates adhesion of blood leukocytes and platelets. Major components of the glycocalyx, including syndecans, heparan sulfate, and hyaluronan, are shed from the endothelial surface layer during conditions including ischaemia and hypoxia, sepsis, atherosclerosis, diabetes, renal disease, and some viral infections. Studying mechanisms of glycocalyx damage in vivo can be challenging due to the complexity of immuno-inflammatory responses which are inextricably involved. Previously, both static as well as perfused in vitro models have studied the glycocalyx, and have reported either imaging data, assessment of barrier function, or interactions of blood components with the endothelial monolayer. To date, no model has simultaneously incorporated all these features at once, however such a model would arguably enhance the study of vasculopathic processes. This review compiles a series of current in vitro models described in the literature that have targeted the glycocalyx layer, their limitations, and potential opportunities for further developments in this field.

Abstract The lack of iron‐reducing capability in some red soils poses an issue for determining the suitability for on‐site wastewater treatment systems (OSWWTS). The Arkansas Department of Health allows for placement of OSWWTS in certain red‐clay soils that have the potential for iron reduction and do not show expansiveness upon wetting, but only in the Ozark Highlands (Major Land Resource Area [MLRA] 116A), which is referred to as the red‐soil exception. The objectives of this study were (a) to confirm the nonexpansiveness and iron reducibility of select soils in the Ozark Highlands that meet the criteria for the red‐soil exception, and (b) to compare the expansiveness and iron reducibility of the residual or colluvial red‐clay soils of the Ozark Highlands with those in four other MLRA region groupings in Arkansas. Fresh and archived soils were used to create a 51‐sample dataset from the 38‐ to 50‐cm soil depth interval for analyses. The alluvial soils of the Red and Arkansas River valleys had a mean coefficient of linear extensibility (COLE) of 0.116 mm mm–1, whereas the residual or colluvial soils from the other MLRA regions evaluated had lower (P

Abstract To mitigate the loss of tallgrass prairies through fragmentation and conversion to other land uses, prairie restoration efforts have been undertaken to reclaim areas that have been previously used for agricultural production. Earthworms are a key component of the soil ecology of natural, undisturbed ecosystems. However, limited research exists on earthworm populations in prairie restorations and how earthworm densities may change over time. The objectives of this study were (a) to evaluate earthworm densities in the upper 20 cm of soil over time (i.e., May 2007 and May 2019) in a native prairie and chronosequence of three prairie restorations (i.e., established in 1979, 2000, and 2002), and (b) to identify relationships between earthworm (i.e., juvenile, adult, and total) density and soil physical and chemical properties. Juvenile (P = .03) earthworm density decreased 25 and 35% and total (P = .03) earthworm density decreased by 33 and 42% in the 2000 and 2002 restorations, respectively, from May 2007 to May 2019. Adult earthworm density did not change over time (P > .05) in any prairie ecosystem. Combined across prairie sites, adult earthworm density was positively correlated (P

Advanced-stage cutaneous T-cell lymphoma (CTCL) is usually a fatal malignancy despite optimal use of currently available treatments. In this preclinical study of novel CTCL therapy, we performed in vitro and ex vivo experiments to determine the efficacy of combination treatment with a panel of BET bromodomain inhibitors (BETi) (JQ1, OTX015, CPI-0610, I-BET762) and HDAC inhibitors (HDACi) (SAHA/Vorinostat, Romidepsin). BETi/HDACi combinations were synergistic (combination index

Abstract Background Nivolumab is approved for the treatment of refractory metastatic renal cell carcinoma. Patterns and predictors of progressive disease (PD) on nivolumab, and outcomes in such patients are lacking. Methods A retrospective analysis of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) who received nivolumab at Cleveland Clinic (2015–2017) was performed. PD was defined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or clinical progression as per treating physician. Univariate analyses (UVA) and multivariate analyses (MVA) were used to identify clinical and laboratory markers as potential predictors of progression-free survival (PFS). Results Ninety patients with mean age of 65, 74% men, and 83% good or intermediate International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group were included. Median number of prior systemic treatments was 2 (range, 1–6). Median overall survival (OS) and PFS were 15.8 and 4.4 months, respectively. Fifty-seven patients (63%) had PD and 44% of patients with radiographic PD had new organ sites of metastases with brain (8/23, 35%) being the most common. Twelve patients received treatment beyond progression (TBP), and among 6 patients with available data, 3 (50%) had any tumor shrinkage (2 pts. with 17% shrinkage, one pt. with 29% shrinkage). Of 57 patients with PD, 28 patients (49%) were able to initiate subsequent treatment, mainly with axitinib and cabozantinib, while 40% of patients were transitioned to hospice after PD. In MVA, a higher baseline Neutrophil-to-Lymphocyte ratio (NLR) (HR, 1.86; 95% CI, 1.05–3.29; p = 0.033) was associated with an increased risk of progression, whereas higher (> 0.1 k/uL) baseline eosinophil count was associated with a lower risk of progression (HR, 0.54; 95% CI, 0.30–0.98; p = 0.042). Conclusion Brain was the most common site of PD in patients treated with nivolumab, and only half of patients progressing on nivolumab were able to initiate subsequent treatment. The risk of PD increased with a higher baseline NLR and reduced with a higher baseline eosinophil count.

Enabling concurrent, high throughput analysis of single nano particles would greatly increase the capacity to study size, composition and inter and intra particle population variance. Here, the authors present a comprehensive platform for single particle automated Raman trapping analysis without any target modification.

Abstract Background Individuals with an extremely rare inherited condition, termed Congenital Insensitivity to Pain (CIP), do not feel pain in response to noxious stimuli. Variants in SCN9A, encoding the transmembrane voltage-gated sodium channel Nav1.7, have previously been reported in subjects with CIP accompanied by anosmia, which are typically transmitted in a recessive pattern. Functional characterisations of some of these SCN9A mutations show that they result in complete loss-of-function of Nav1.7. Methods In a consanguineous family we performed whole exome sequencing of three members who have a diagnosis of CIP and one unaffected family member. The functional effects of the segregating variant in SCN9A were determined using patch clamp electrophysiology in human embryonic kidney (HEK) 293 cells transfected with the variant. Results We found that each CIP subject was homozygous for a putatively nonsense variant, R1488*, in SCN9A. This variant was reported elsewhere in a subject with CIP, though the functional effect was not determined. Using electrophysiology, we confirm that this variant results in a complete loss-of-function of Nav1.7. Conclusions We confirm through electrophysiological analysis that this R1488* variant in SCN9A results in complete loss-of-function of Nav1.7, which is consistent with reports on other variants in this gene in subjects with CIP.