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ObjectiveAcute brain injury remains common after extracorporeal cardiopulmonary resuscitation. Using a large international multicenter cohort, we investigated the impact of peri-cannulation arterial oxygen (PaO2) and carbon dioxide (PaCO2) on ABI occurrence.DesignRetrospective cohort study.SettingData in the Extracorporeal Life Support Organization Registry from 2009 to 2020.PatientsAdult patients (≥18 years old) who underwent extracorporeal cardiopulmonary resuscitation.InterventionsNone.Measurements and Main ResultsOf 3,125 patients with extracorporeal cardiopulmonary resuscitation (median age=58, 69% male), 488 (16%) experienced at least one form of acute brain injury, which included ischemic stroke, intracranial hemorrhage, seizures, and brain death. 217 (7%) experienced ischemic stroke and 88 (3%) experienced intracranial hemorrhage. The registry collects two blood gas data pre- (6 hours before) and on- (24 hours after) extracorporeal membrane oxygenation (ECMO) cannulation. Blood gas parameters were classified as: hypoxia (2 levels were not significantly associated with composite ABI or mortality, though mild hypercarbia pre- and on-ECMO were protective of ischemic stroke and intracranial hemorrhage, respectively.ConclusionsEarly severe hyperoxia (≥300mmHg) on ECMO was a significant risk factor for acute brain injury and mortality for patients undergoing extracorporeal cardiopulmonary resuscitation. Careful consideration should be given in early oxygen delivery in ECPR patients who are at risk of reperfusion injury.

Objective: Despite the common occurrence of extracorporeal membrane oxygenation (ECMO)–associated acute ischemic stroke (AIS) and intracranial hemorrhage (ICH), there are little data to guide optimal anticoagulation management. We sought to describe antithrombotic therapy management after stroke and outcomes. Methods: A retrospective analysis was conducted of venoarterial (VA) and venovenous (VV) ECMO patients treated at a tertiary care center from June 2016 to February 2021. Patients with image-confirmed diagnosis of AIS or ICH while receiving ECMO were included for study with data collected regarding anticoagulation management and clinical outcomes. Results: Overall, 216 patients (153 VA-ECMO, 63 VV-ECMO) were included in this study. Of the 153 patients on VA-ECMO, 13 (8.4%) had AIS and 6 (3.9%) had ICH. Of the 63 patients on VV-ECMO, none had AIS and 5 (7.9%) had ICH. One patient (9%) received anticoagulation reversal after ICH. Anticoagulation was discontinued and later resumed in all 5 ICH survivors (median cessation time, 30 h) and 1 of 2 (50%) AIS survivors (median cessation time, 96 h). While off anticoagulation, 2 of 11 patients (18%) had thromboembolic events and none had new AIS. Upon resumption, there were no cases of hemorrhagic transformation of AIS or ICH expansion. There was no difference in in-hospital mortality between patients with ICH and those without in both the VA-ECMO and VV-ECMO cohorts nor between VA-ECMO patients with AIS and those without. Conclusions: Early cessation and judicious resumption of anticoagulation appeared feasible in the cohort of patients with ECMO-associated AIS and ICH.

Extracorporeal membrane oxygenation (ECMO) carries a high morbidity of acute brain injury (ABI) with resultant mortality increase. Transcranial Doppler (TCD) allows real-time characterization of regional cerebral hemodynamics, but limited data exist on the interpretation of microembolic signals (MES) in ECMO.This prospective cohort study was conducted at a single tertiary care center, November 2017 through February 2022, and included all adult patients receiving venoarterial (VA) and venovenous (VV) ECMO undergoing TCD examinations, which all included MES monitoring.Of 145 patients on ECMO who underwent at least 1 TCD examination, 100 (68.9%) patients on VA-ECMO received 187 examinations whereas 45 (31.1%) patients on VV-ECMO received 65 examinations (TCD analysis in a large cohort of patients on ECMO demonstrates a significant number of MES, especially in patients on VA-ECMO with intra-aortic balloon pump, and/or left ventricular assist device. However, clinical associations and significance of TCD MES remain unresolved and warrant further correlation with systematic imaging and long-term neurologic follow-up.

Supplementary Methods and Supplementary Figure Legends

Supplementary Tables. Supplementary Table S1. Summary of cell lines used. Supplementary Table S2. Summary of Repeat-Dose Toxicity Study with LY2875358

Purpose: MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms.Experimental Design/Results: Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody.Conclusions: LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies. Clin Cancer Res; 20(23); 6059–70. ©2014 AACR.

Background Antibodies targeting envelope glycoproteins have been shown in some instances to enhance infection by subverting Fc receptor and complement function, or by directly inducing fusion with cellular membranes. The potential for antibody dependent enhancement (ADE) of infection raises concern that passive immunization with a therapeutic anti-viral antibody could increase risk of disease. As part of the nonclinical package characterizing the risk profile of the SARS-CoV-2 neutralizing monoclonal antibody bamlanivimab, studies were conducted to evaluate the potential for ADE of infection in vitro and in a non-human primate model of COVID-19. Methods In vitro assays were performed in primary human macrophage, Raji, or THP-1 cells exposed to SARS-CoV-2 in the presence of bamlanivimab ranging from approximately IC50 to more than 100-fold above or below the IC50. Samples were evaluated for demonstration of productive viral infection. Bamlanivimab binding to C1q and FcR were quantified, and activity was studied by cell-based assays. In vivo studies were performed in African green monkeys (AGM) infected with SARS-CoV-2 virus following sub-saturating or saturating doses of bamlanivimab or IgG control. Viral loads, clinical pathology, and histology endpoints were assessed to determine if bamlanivimab enhanced SARS-CoV-2 replication or clinical illness. Mixed model repeated measures were used to evaluate virology statistics. Results Bamlanivimab did not increase viral RNA production in FcγR-expressing cell lines, despite demonstration of effector function. No significant differences were found among the AGM groups in terms of weight, temperature, or food intake. Treatment with bamlanivimab reduced viral loads in nasal and oral swabs and BAL fluid relative to control groups. Viral antigen was not detected in lung tissue from animals treated with the highest dose of bamlanivimab. Microscopic findings along with decreases in viral loads in bamlanivimab-treated animals indicated that ADE of disease was not observed in this study. Conclusions Sub-saturating doses of bamlanivimab treatment do not induce ADE of SARSCoV2 infection in either in vitro or an AGM model of infection. Findings suggest that high affinity monoclonal antibodies pose a low risk of mediating ADE in patients and further supports their safety profile as a treatment of COVID-19 disease.

Therapeutics for patients hospitalized with coronavirus disease 2019 (COVID-19) are urgently needed during the pandemic. Bamlanivimab is a potent neutralizing monoclonal antibody that blocks severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) attachment and entry into human cells, which could potentially lead to therapeutic benefit. J2W-MC-PYAA was a randomized, double-blind, sponsor unblinded, placebo-controlled, single ascending dose first-in-human trial (NCT04411628) in hospitalized patients with COVID-19. A total of 24 patients received either placebo or a single dose of bamlanivimab (700 mg, 2,800 mg, or 7,000 mg). The primary objective was assessment of safety and tolerability, including adverse events and serious adverse events, with secondary objectives of pharmacokinetic (PK) and pharmacodynamic analyses. Treatment-emergent adverse event (TEAE) rates were identical in the placebo and pooled bamlanivimab groups (66.7%). There were no apparent dose-related increases in the number or severity of TEAEs. There were no serious adverse events or deaths during the study, and no discontinuations due to adverse events. PKs of bamlanivimab is linear and exposure increased proportionally with dose following single i.v. administration. The half-life was ~ 17 days. These results demonstrate the favorable safety profile of bamlanivimab, and provided the initial critical evaluation of safety, tolerability, and PKs in support of the development of bamlanivimab in several ongoing clinical trials.

The immunogenicity of biotherapeutics presents a major challenge during the clinical development of new protein drugs including monoclonal antibodies. To address this, multiple humanization and de-immunization techniques that employ in silico algorithms and in vitro test systems have been proposed and implemented. However, the success of these approaches has been variable and to date, the ability of these techniques to predict immunogenicity has not been systematically tested in humans or other primates. This study tested whether antibody humanization and de-immunization strategies reduce the risk of anti-drug antibody (ADA) development using cynomolgus macaque as a surrogate for human. First human-cyno chimeric antibodies were constructed by grafting the variable domains of the adalimumab and golimumab monoclonal antibodies onto cynomolgus macaque IgG1 and Igκ constant domains followed by framework germlining to cyno to reduce the xenogenic content. Next, B and T cell epitopes and aggregation-prone regions were identified using common in silico methods to select domains with an ADA risk for additional modification. The resultant engineered antibodies had a comparable affinity for TNFα, demonstrated similar biophysical properties, and exhibited significantly reduced ADA levels in cynomolgus macaque compared with the parental antibodies, with a corresponding improvement in the pharmacokinetic profile. Notably, plasma concentrations of the engineered antibodies were quantifiable through 504 hours (chimeric) and 840 hours (germlined/de-immunized), compared with only 336 hours (adalimumab) or 336-672 hours (golimumab). The results point to the significant value in the investment in these engineering strategies as an important guide for monoclonal antibody optimization that can contribute to improved clinical outcomes.

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies., Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb293

Background Individuals with advanced Parkinson’s Disease (PD) and Parkinson-related disorders (PRD) are frequently referred for home allied therapies and nursing care, yet home healthcare professionals have limited training in PD/PRD. While recognizing the need for such care, patients and families report home healthcare professionals are unfamiliar with these conditions, which may be driven by neurophobia and may contribute to suboptimal care and early termination of services. We sought to determine the feasibility and effects of a virtual, multimodal educational intervention on PD knowledge, confidence, and empathy among home health professionals. Methods Home health nurses, occupational therapists, physical therapists and physical therapy assistants, and speech-language pathologists participated in a daylong, virtual symposium on advanced PD/PRD, combining focused lectures, discipline-specific breakout sessions, immersive virtual reality vignettes, and interactive panels with both patients and families, and movement disorders and home healthcare experts. Participants completed online pre- and post-symposium surveys including: demographics; PD/PRD knowledge (0–10 points possible); empathy (Interpersonal Reactivity Index); and 10-point scales of confidence with and attitudes towards individuals with PD/PRD, respectively. Pre-post intervention changes and effect sizes were evaluated with paired t-tests and Cohen’s d. We performed qualitative analyses of post-symposium free-text feedback using a grounded theory approach to identify participants’ intentions to change their practice. Results Participants had a mean improvement of 3.1 points on the PD/PRD knowledge test (p p = 0.0003, d = .36), and no change in empathy. The interactive, virtual format was rated as effective by 95%. Common themes regarding symposium-motivated practice change included: interdisciplinary collaboration; greater involvement and weighting of the patient and caregiver voice in care plans; attention to visit scheduling in relation to patient function; recognition and practical management of the causes of sudden change in PD/PRD, including infections and orthostatic hypotension. Conclusions A virtual, multimodal, brief educational pilot intervention improved PD/PRD-specific knowledge and confidence among home healthcare nurses and allied health professionals. Future studies are necessary to test the short- and long-term effects of this intervention more broadly and to investigate the impact of this education on patient and caregiver outcomes.

Immunogenicity of biomolecules is one of the largest concerns in biological therapeutic drug development. Adverse immune responses as a result of immunogenicity to biotherapeutics range from mild hypersensitivity reactions to potentially life-threatening anaphylactic reactions and can negatively impact human health and drug efficacy. Numerous confounding patient-, product- or treatment-related factors can influence the development of an immune reaction against therapeutic proteins. The goal of this study was to investigate the relationship between pre-existing drug reactivity (PE-ADA), individual immunogenetics (MHC class II haplotypes), and development of treatment-induced antidrug antibodies (TE-ADA) in cynomolgus macaque. PE-ADA refers to the presence of antibodies immunoreactive against the biotherapeutic in treatment-naïve individuals. We observed that PE-ADA frequency against four different bispecific antibodies in naïve cynomolgus macaque is similar to that reported in humans. Additionally, we report a trend towards an increased incidence of TE-ADA development in macaques with high PE-ADA levels. In order to explore the relationship between MHC class II alleles and risk of ADA development, we obtained full-length MHC class II sequences from 60 cynomolgus macaques in our colony. We identified a total of 248 DR, DP, and DQ alleles and 236 unique haplotypes in our cohort indicating a genetically complex set of animals potentially reflective of the human population. Based on our observations, we propose the evaluation of the magnitude/frequency of pre-existing reactivity and consideration of MHC class II genetics as additional useful tools to understand the immunogenic potential of biotherapeutics.

Over 50 years’ experience at the Children’s Court Clinic of Victoria informs this valedictory account of its director. Changes over time to the model of service at the Clinic are detailed; an independent practitioner model (psychologist/psychiatrist) with oversight now endures, while the Clinic works exclusively for the Court. Clinic operations, clinicians, clients, reputation, the nature of referrals and the need for kindness in report writing are discussed. An integral theme is the politics of the child protection field, which can affect the Clinic, and lately – through new child law – has also affected the powers of the Court and the lives of children on care applications (and the purview of the Clinic’s protection assessments). New child protection legislation is discussed along with its impacts on the care of a growing number of children, signalling the need to revisit the legislation, promote better engagement of families and greatly increase coordinated expert services to them.

295 Background: Patients with advanced cancer often experience frequent and prolonged hospitalizations, and the transition from hospital to home represents a critical period for these individuals, as they prefer to maximize time at home and avoid readmissions. We sought to demonstrate the feasibility and acceptability of a Supportive Oncology Care at Home intervention to address the post-discharge needs of recently hospitalized patients with advanced cancer. Methods: We conducted a single-arm pilot trial at Massachusetts General Hospital (MGH). We enrolled English-speaking adults with advanced solid tumors experiencing their second or later unplanned hospitalization, who were being discharged home without hospice services and residing within a 50 mile radius of MGH. The three-week intervention consisted of: 1) hospital in the home care model for proactive symptom assessment and management, including clinician visits to assess patients, draw labs, administer intravenous medications and hydration, and ensure optimal symptom management; 2) remote monitoring of daily patient-reported symptoms, vital signs, and body weight; and 3) structured communication with the oncology team. The primary endpoint of the study was feasibility, defined as ≥60% of approached and eligible patients enrolling and ≥60% of participants completing daily symptom assessments. After intervention completion, patients rated the helpfulness and convenience of the intervention and symptom monitoring technology. Results: From 12/2021-6/2022, we enrolled 40 out of 66 approached patients (60.6% enrollment rate). Enrolled patients (median age = 58.5 years, 50% female, 75% white, 68% married, 50% gastrointestinal cancers) completed 93.8% of daily symptom assessments. 12 patients (30%) did not complete the intervention due to withdrawal (5), hospice transfer (4), or death (3). Among enrolled patients, 20.0% were enrolled in hospice and 15.4% died at 30 days after hospital discharge. In exit interviews, 100% and 75% rated the intervention and symptom monitoring as helpful, respectively. 83% of patients found the in-home monitoring technology convenient. Conclusions: We found that a three-week Supportive Oncology Care at Home intervention is a feasible approach to providing post-discharge care for high acuity, seriously ill hospitalized patients with advanced cancer. These patients also found the intervention highly acceptable. Future studies will test the efficacy of the intervention for reducing hospital readmissions, improving symptom management and quality of life, and increasing days spent at home near the end of life. Clinical trial information: NCT04637035.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a public health threat for which preventive and therapeutic agents are urgently needed. Neutralizing antibodies are a key class of therapeutics that may bridge widespread vaccination campaigns and offer a treatment solution in populations less responsive to vaccination. Here, we report that high-throughput microfluidic screening of antigen-specific B cells led to the identification of LY-CoV555 (also known as bamlanivimab), a potent anti-spike neutralizing antibody from a hospitalized, convalescent patient with coronavirus disease 2019 (COVID-19). Biochemical, structural, and functional characterization of LY-CoV555 revealed high-affinity binding to the receptor-binding domain, angiotensin-converting enzyme 2 binding inhibition, and potent neutralizing activity. A pharmacokinetic study of LY-CoV555 conducted in cynomolgus monkeys demonstrated a mean half-life of 13 days and a clearance of 0.22 ml hour-1 kg-1, consistent with a typical human therapeutic antibody. In a rhesus macaque challenge model, prophylactic doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract in samples collected through study day 6 after viral inoculation. This antibody has entered clinical testing and is being evaluated across a spectrum of COVID-19 indications, including prevention and treatment.

LY-CoV555, a SARS-CoV-2 spike protein–specific antibody, neutralizes SARS-CoV-2 and protects the airways of nonhuman primates against infection., A monoclonal for SARS-CoV-2 Among the most promising therapeutic options for individuals with coronavirus disease 2019 (COVID-19) are monoclonal antibodies (mAbs). In this study, Jones et al. identified, characterized, and tested one such mAb, LY-CoV555, in vitro and in vivo. They found that LY-CoV555 bound to the severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) spike protein and prevented its interaction with angiotensin-converting enzyme 2. Prophylactic treatment with LY-CoV555 protected the upper and lower respiratory tracts of nonhuman primates from becoming infected with SARS-CoV-2. Together, these data support the clinical use of LY-CoV555 for treating patients with COVID-19., Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a public health threat for which preventive and therapeutic agents are urgently needed. Neutralizing antibodies are a key class of therapeutics that may bridge widespread vaccination campaigns and offer a treatment solution in populations less responsive to vaccination. Here, we report that high-throughput microfluidic screening of antigen-specific B cells led to the identification of LY-CoV555 (also known as bamlanivimab), a potent anti-spike neutralizing antibody from a hospitalized, convalescent patient with coronavirus disease 2019 (COVID-19). Biochemical, structural, and functional characterization of LY-CoV555 revealed high-affinity binding to the receptor-binding domain, angiotensin-converting enzyme 2 binding inhibition, and potent neutralizing activity. A pharmacokinetic study of LY-CoV555 conducted in cynomolgus monkeys demonstrated a mean half-life of 13 days and a clearance of 0.22 ml hour−1 kg−1, consistent with a typical human therapeutic antibody. In a rhesus macaque challenge model, prophylactic doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract in samples collected through study day 6 after viral inoculation. This antibody has entered clinical testing and is being evaluated across a spectrum of COVID-19 indications, including prevention and treatment.

6558 Background: Patients with pancreatic cancer receiving chemotherapy often experience substantial symptoms and high healthcare utilization. We sought to determine the feasibility of delivering a Supportive Oncology Care at Home intervention designed to address the needs of patients receiving treatment for pancreatic cancer. Methods: We prospectively enrolled patients with pancreatic cancer who were participating in a parent trial of neoadjuvant FOLFIRINOX and residing in-state, within 50 miles of our hospital. Patients received the Supportive Oncology Care at Home intervention during neoadjuvant treatment (i.e., up to 4 months). The intervention entailed: 1) remote monitoring of daily patient-reported symptoms, daily vital signs, and weekly body weight; 2) a hospital in the home care model for symptom assessment and management; and 3) structured communication with the oncology team. We defined the intervention as feasible if ≥60% of patients enrolled in the study and ≥60% completed the daily assessments within the first two weeks of enrollment. We tracked numbers of phone calls, emails, and home visits generated by the intervention. We conducted exit interviews with patients, caregivers, and oncology clinicians to assess the acceptability of the intervention. In addition, we compared rates of treatment delays, urgent clinic visits, emergency room (ER) visits, and hospitalizations among those who did (n = 20) and did not (n = 24) receive Supportive Oncology Care at Home from the parent trial. Results: From 1/2019-9/2020, we enrolled 80.8% (21/26) of potentially eligible patients. One patient became ineligible following consent due to moving out-of-state, resulting in 20 participants (median age = 67 years [range 55-77]; 60.0% female). Within the first two weeks of enrollment, 65.0% completed all the daily assessments, with participants reporting 96.1% of daily symptoms, 96.1% of daily vital signs, and 92.5% of weekly body weights. Each participant generated an average of 2.22 phone calls (range 0.62-3.77), 2.96 emails (range 1.50-5.88), and 0.15 home visits (range 0-0.69) per week. During exit interviews, > 80% of patients, caregivers, and clinicians found the intervention to be helpful and convenient, and they reported high satisfaction with the communication among patients, clinicians, and the hospital in the home team. Patients receiving the intervention had lower rates of treatment delays (55.0% v 75.0%), urgent clinic visits (10.0% v 25.0%), ER visits or hospitalizations (45.0% v 62.5%), as well as a lower proportion of days spent in urgent clinic, ER, or hospital (2.7% v 7.8%), compared with those not receiving the intervention who were in the same parent trial. Conclusions: These findings demonstrate the feasibility and acceptability of a Supportive Oncology Care at Home intervention. Future work will investigate the efficacy of this intervention for decreasing healthcare use and improving patient outcomes. Clinical trial information: NCT03798769.

We report a rare case of extradural arteriovenous (AV) fistula of the right vertebral artery and vein following cervical spinal fusion. A 68-year-old female patient presented with complaints of a persistent buzzing sound in her right ear for 4 months that began following cervical spinal fusion surgery via an anterior approach. A right-sided bruit was noted and the patient was referred for a carotid duplex study. A carotid duplex was performed on a Philips IU22 using a 9-3 linear array transducer. The exam revealed a high-velocity vertebral artery waveform with spectral broadening and venous component suggestive of an AV fistula. Magnetic resonance angiography (MRA) of the neck confirmed a right extradural AV fistula at the level of C4 between the right vertebral artery and vein. The patient subsequently underwent angiography and coil embolization of the right vertebral artery. Postembolization angiography revealed resolution of the AV fistula and occlusion/near occlusion of the vertebral artery distal to the embolization. While vascular injuries are a known complication of spinal surgery using the anterior approach, it is rare for them to present as a late finding. Duplex evaluations of the carotid arteries for patients’ subjective noise complaints often do not reveal significant pathology; though in cases involving a history of prior surgical intervention, ultrasound may be useful in identifying iatrogenic vascular injury.

To explore student nurses' and nurse mentors' perceptions and experiences of raising concerns on clinical placement and the influence (if any) of their relationship on this process. A secondary aim is to consider the above, from a regulatory perspective in light of current literature and policy developments.Raising concerns whilst on clinical placement has been shown to be challenging for student nurses internationally. Registered nurses in the UK (in this case called "nurse mentors") facilitate learning and assessment in practice. However, limited research exists on the influence of the relationship between the nurse mentor and student nurse on the raising concerns process.A qualitative approach was used to undertake secondary thematic analysis of interview data. The primary data set was generated during a PhD study, focusing on the mentor-student dynamic and the possible influence of this relationship on students' raising concerns.30 individual semi-structured interviews were subjected to concurrent and thematic analysis. Interviews were undertaken with student nurses (n = 16) and nurse mentors (n = 14) between April 2016-January 2018. The COREQ 32-item checklist was used during the preparation of this article.The following three interrelated analytical themes were generated from the data, "developing a mentor-student relationship," "keeping your mentor sweet" and "the mentor role in the raising concerns process."Our analysis of participants' experiences and perceptions offers an original contribution to understanding the factors associated with student nurses raising concerns in practice. Student nurses and most mentors believed that students should be encouraged and supported to raise concerns, but students' decisions were strongly influenced by their perceptions of the immediate interpersonal and educational context. Similar barriers to raising concerns have been shown to exist regardless of geographical boundaries, therefore the findings of this study are nationally and internationally relevant. Relevance to clinical practice This study provides new insight into the role of the nurse mentor in supporting students who raise concerns on clinical placements. The majority of the mentor participants believed that students should be encouraged and supported to speak up if they witness poor care or unprofessional behaviour. Focusing on the compexities around raising concerns in mentorship training and updates would rovide a forum for open discussion amongst mentors and educators.

OBJECTIVES: To examine elevated neonatal inflammatory and neurotrophic proteins from children born extremely preterm in relation to later childhood brain Magnetic Resonance Imaging volumes and cognition. STUDY DESIGN: We measured circulating inflammation-related proteins and neurotrophic proteins on postnatal days 1, 7, and 14 in 166 children at 10 years of age (73 males; 93 females). Top quartile levels on ≥2 days for ≥3 inflammation-related proteins and for ≥4 neurotrophic proteins defined exposure. We examined associations among protein levels, brain Magnetic Resonance Imaging volumes, and cognition with multiple linear and logistic regressions. RESULTS: Analyses were adjusted for gestational age at birth and sex. Children with ≥3 elevated inflammation-related proteins had smaller grey matter, brain stem/cerebellar, and total brain volumes than those without elevated inflammation-related proteins, adjusted for neurotrophic proteins. When adjusted for inflammation-related proteins, children with ≥4 neurotrophic proteins, compared with children with no neurotrophic proteins, had larger grey matter and total brain volumes. Higher grey matter, white matter, and cerebellum and brainstem volumes were significantly correlated with higher IQ. Grey and white matter volumes were correlated with each other (r = −0.18; P = .021), and cerebellum and brainstem was highly correlated with grey matter (r = 0.55; P < .001) and white matter (r = 0.29; P < .001). Adjusting for other brain compartments, cerebellum and brainstem was associated with IQ (P = .016), but the association with white matter was marginally significant (P = .051). Grey matter was not associated with IQ. After adjusting for brain volumes, elevated inflammation-related proteins remained significantly associated with a lower IQ, and elevated neurotrophic proteins remained associated with a higher IQ. CONCLUSIONS: Newborn inflammatory and neurotrophin protein levels are associated with later brain volumes and cognition, but their effects on cognition are not entirely explained by altered brain volumes.

Background:Many neurodegenerative diseases are caused by nucleotide repeat expansions, but most expansions, like theC9orf72‘GGGGCC’ (G4C2) repeat that causes approximately 5-7% of all amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases, are too long to sequence using short-read sequencing technologies. It is unclear whether long-read sequencing technologies can traverse these long, challenging repeat expansions. Here, we demonstrate that two long-read sequencing technologies, Pacific Biosciences’ (PacBio) and Oxford Nanopore Technologies’ (ONT), can sequence through disease-causing repeats cloned into plasmids, including the FTD/ALS-causing G4C2repeat expansion. We also report the first long-read sequencing data characterizing theC9orf72G4C2repeat expansion at the nucleotide level in two symptomatic expansion carriers using PacBio whole-genome sequencing and a no-amplification (No-Amp) targeted approach based on CRISPR/Cas9.Results:Both the PacBio and ONT platforms successfully sequenced through the repeat expansions in plasmids. Throughput on the MinlON was a challenge for whole-genome sequencing; we were unable to attain reads covering the humanC9orf72repeat expansion using 15 flow cells. We obtained 8x coverage across theC9orf72locus using the PacBio Sequel, accurately reporting the unexpanded allele at eight repeats, and reading through the entire expansion with 1324 repeats (7941 nucleotides). Using the No-Amp targeted approach, we attained >800x coverage and were able to identify the unexpanded allele, closely estimate expansion size, and assess nucleotide content in a single experiment. We estimate the individual’s repeat region was >99% G4C2content, though we cannot rule out small interruptions.Conclusions:Our findings indicate that long-read sequencing is well suited to characterizing known repeat expansions, and for discovering new disease-causing, disease-modifying, or risk-modifying repeat expansions that have gone undetected with conventional short-read sequencing. The PacBio No-Amp targeted approach may have future potential in clinical and genetic counseling environments. Larger and deeper long-read sequencing studies inC9orf72expansion carriers will be important to determine heterogeneity and whether the repeats are interrupted by non-G4C2content, potentially mitigating or modifying disease course or age of onset, as interruptions are known to do in other repeat-expansion disorders. These results have broad implications across all diseases where the genetic etiology remains unclear.

Insulin lispro 200 U/mL (IL200) is a new strength formulation of insulin lispro (Humalog®, IL100), developed as an option for diabetic patients on higher daily mealtime insulin doses. This phase 1, open‐label, 2‐sequence, 4‐period crossover, randomized, 8‐hour euglycemic clamp study aimed to demonstrate the bioequivalence of IL200 and IL100 after subcutaneous administration of 20 U (U) to healthy subjects (n = 38). Pharmacokinetic (PK) and pharmacodynamic (PD) responses were similar in both formulations. All 90%CIs for the ratios of area under the concentration‐versus‐time curve from time zero to the time of the last measurable concentration (AUC0–tlast) and maximum observed drug concentration (Cmax), as well as the total glucose infused throughout the clamp (Gtot) and the maximum glucose infusion rate (Rmax), were contained within 0.80 and 1.25. Time of maximum observed drug concentration (tmax) was similar between formulations, with a median difference of 15 minutes and a 95%CI of the difference that included zero. Inter‐ and intrasubject variability estimates were similar for both formulations. Both formulations were well tolerated. IL200 was bioequivalent to IL100 after subcutaneous administration of 20‐U single doses, and PD responses were comparable between formulation strengths.

Basal insulin peglispro (BIL) comprises insulin lispro covalently bound to a 20-kDa polyethylene glycol (PEG) at lysine B28. The biologic fate of BIL and unconjugated PEG were examined in rats given a single 0.5-mg/kg i.v. or 2-mg/kg s.c. dose of BIL with (14)C label in 20-kDa PEG or (125)I label in lispro. Unconjugated (14)C-labeled 20-kDa PEG was dosed at 10 mg/kg i.v. or s.c. Blood, urine, and feces were collected up to 336 hours after dosing. Radioactivity was measured by scintillation spectrometry, and BIL was quantitated by enzyme-linked immunosorbent assay. Area under the curve and half-life for immunoreactive BIL were lower than those for both (14)C and (125)I after subcutaneous and intravenous administration. The half-lives of (14)C after BIL and PEG dosing were similar. The clearance of immunoreactive BIL was 2.4-fold faster than that of (14)C and 1.6-fold faster than (125)I. After a subcutaneous dose of BIL, immunoreactive BIL accounted for 31% of the circulating (125)I and 16% of the circulating (14)C, indicating extensive catabolism of BIL. Subcutaneous bioavailability of BIL was 23%-29%; bioavailability for unconjugated PEG was 78%. For unconjugated PEG, most of the (14)C dose was recovered in urine. For BIL, ≥86% of (125)I was eliminated in urine and (14)C was eliminated about equally in urine and feces. The major (14)C-labeled catabolism product of BIL in urine was 20-kDa PEG with lysine attached. The attachment of 20-kDa PEG to lispro in BIL led to a different elimination pathway for PEG compared with unconjugated 20-kDa PEG.

Background: An 8-mm needle length is commonly used for insulin injections; however, recent recommendations suggest shorter needles may help patients avoid intramuscular injections and reduce pain, while maintaining adequate glucose control. The goal of these analyses was to compare the pharmacokinetics (PK) and glucodynamics (GD) of insulin lispro after a 5-mm or an 8-mm injection depth administration in 2 populations: normal weight (study 1) or obese (study 2). Methods: In both open-label, randomized, 2-period crossover euglycemic clamp studies, subjects received single 0.25 U/kg insulin lispro doses on 2 occasions (at 5-mm and 8-mm injection depths); samples for PK and GD analyses were collected up to 6 hours postdose. Noncompartmental PK parameters AUC0-tlast, AUC0-∞, Cmax and GD parameters Gtot, Rmax, tRmax were log-transformed prior to analysis using a mixed effects model. Results: There were no apparent differences between PK profiles at the 5-mm or 8-mm injection depth in either study, demonstrated by the ratios of geometric means of AUC0-tlast, AUC0-∞, and Cmax being close to 1, with 90% confidence intervals (CI) within (0.80, 1.25). There were no apparent differences between GD profiles at either injection depth with the ratios of Gtot and Rmax near unity and 90% CIs that included 1. In both studies, the tRmax values were similar between injection depths, with a small median of pairwise differences and a 90% CI that included zero. Conclusions: Injection depths in the 5-8 mm range did not affect the PK or GD of insulin lispro in normal weight or obese subjects.

Background Childhood overnutrition is a serious public health problem, with consequences that extend into adulthood. The aim of this study was to determine the prevalence and determinants of overweight and obesity among school-age children in two urban settings in Ghana. Methods This cross-sectional study involved 3089 children (9–15 years) recruited between December 2009 and February 2012 in Accra and Kumasi, Ghana. Socio-demographic, dietary, and physical activity data were collected using pretested questionnaires. BMI-for-age z-scores were used to categorize anthropometric data of the children as thin, normal, or overweight/obese. Determinants of overweight were examined using multiple logistic regressions. Results Seventeen percent of children were overweight or obese. Children who reported lower participation (< 3 times/week) in sports activity were 44% more likely to be overweight or obese (AOR = 1.44; 95% CI: 1.07, 1.94). Maternal tertiary education (AOR = 1.91, 95% CI: 1.07, 3.42), higher household socioeconomic status (AOR = 1.56, 95% CI: 1.18, 2.06), and attending private school (AOR = 1.74, 95% CI: 1.31, 2.32) were also associated with elevated risk of overweight and obesity. Conclusions Physical inactivity is a modifiable independent determinant of overweight or obesity among Ghanaian school-aged children. Promoting and supporting a physically active lifestyle in this population is likely to reduce risk of childhood overnutrition.

Background The incidence of attention deficit hyperactivity disorder is higher among children born very preterm than among children who are mature at birth. Methods We studied 583 ten-year-old children who were born before 28 weeks of gestation whose IQ was above 84 and had a parent-completed Child Symptom Inventory-4, which allowed classification of the child as having or not having symptoms of attention deficit hyperactivity disorder. For 422 children, we also had a teacher report, and for 583 children, we also had a parent report of whether or not a physician made an attention deficit hyperactivity disorder diagnosis. Results The risk profile of screening positive for attention deficit hyperactivity disorder based on a parent's report differed from the risk profile based on the teacher's report, whereas the risk profile according to a physician and according to any two observers closely resembled the parent-reported profile. Among the statistically significant risk factors were young maternal age (parent, physician, and two observers), maternal obesity (parent, physician, and two observers), maternal smoking (parent, physician, and two observers), magnesium given at delivery for seizure prophylaxis (parent and two observers), recovery of Mycoplasma sp. from the placenta (teacher and two observers), low gestational age (parent and two observers), low birth weight (teacher and physician), singleton (parent, physician, and two observers), male (parent, teacher, physician, and two observers), mechanical ventilation on postnatal day seven (physician), receipt of a sedative (parent and two observers), retinopathy of prematurity (parent), necrotizing enterocolitis (physician), antibiotic receipt (physician and two observers), and ventriculomegaly on brain scan (parent and two observers). Conclusions The multiplicity of risk factors identified can be subsumed as components of four broad themes: low socioeconomic state, immaturity or vulnerability, inflammation, and epigenetic phenomena.

The association of hand preference (left, mixed, and right) with cognitive, academic, motor, and behavioral function was evaluated in 864 extremely preterm children at 10 years of age. Left-handed and right-handed children performed similarly but mixed-handed children had greater odds of functional deficits across domains than right-handed children.

Purpose: MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms. Experimental Design/Results: Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody. Conclusions: LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies. Clin Cancer Res; 20(23); 6059–70. ©2014 AACR.