Anticipated impacts of voluntary assisted dying legislation on nursing practice

Background: The Voluntary Assisted Dying Act 2017 passed into law in Victoria, Australia, on the 29 November 2017. Internationally, nurses have been shown to be intimately involved in patient care throughout the voluntary assisted dying process. However, there is a paucity of research exploring Australian nurses’ perspectives on voluntary assisted dying and, in particular, how Victorian nurses anticipate the implementation of this ethically controversial legislation will impact their professional lives. Objectives: To explore Victorian nurses’ expectations of the ethical and practical impacts the voluntary assisted dying legislation will have on their professional lives. Research design: This qualitative study analysed nurses’ free text responses collected as part of a larger mixed methods online survey investigating staff views on the Voluntary Assisted Dying Act. Data were collected during the period between the passing of the voluntary assisted dying legislation and the start date and were analysed using inductive content analysis. Participants and research context: Free text survey responses were analysed from 1873 nurses employed across seven Victorian health services located in both metropolitan and regional areas of the state. Ethical considerations: The study obtained research ethics approval and all participants were informed of the voluntary and anonymous nature of their participation. Findings: This study identified three broad areas of Victorian nurses’ professional lives that they expected to be impacted by the implementation of voluntary assisted dying: professional identity, career development and workplace relationships. Conclusion: Participants anticipate diverse and nursing-specific impacts of the implementation of voluntary assisted dying in Victoria. Their insights can inform health services in jurisdictions considering or already implementing voluntary assisted dying, to develop policies, procedures and staff training programmes that safeguard the well-being and legal rights of their nursing staff

Informed consent in palliative care clinical trials: challenging but possible

Obtaining informed consent is a key protection that should be afforded universally to people using health services and the basis around which any participation in clinical trials is built. Randomized controlled effectiveness studies are necessary to answer key questions in hospice and palliative care, in order to help systematically improve the quality of care. In order to be properly generalizable, such trials need to have broad inclusion criteria to reflect the population most likely to be affected by the condition. The inclusion of patients who are seriously ill, and therefore potentially vulnerable, requires careful exploration of ethical and legal principles that underpin informed consent. Specific challenges in obtaining informed consent for randomised clinical trials (RCTs) in clinically unstable populations such as hospice and palliative care include higher rates of people with impaired cognitive capacity as well as interventional studies in clinical situations which may present as a sudden change in condition. None of these challenges is unique to hospice and palliative care research, but the combination and frequency with which they are encountered require systematic and considered solutions. This article outlines five different ethically valid consent approaches and discusses their applicability to hospice and palliative care research trials. These include: consent by the patient (at the time of enrolment, in advance of the study, or delayed until after the study has commenced); a proxy (or legally authorised representative); or a consent waiver. Increased use of the less traditional modes of informed consent may lead to greater participation rates in hospice and palliative care trials, thereby improving the evidence base more rapidly in part by better reflecting the population served and hence improving generalizability

First-Year Medical Student Feedback Regarding the Addition of Online Learning Modules to the Curriculum

Introduction: The first year of the medical student curriculum at the John A. Burns School of Medicine consists of four blocks. The first block–MD1: Health and Illness–is a 9-week introduction to Problem-Based Learning (PBL) and foundational sciences. In response to the COVID-19 pandemic, MD1 introduced online modules (pre-recorded lectures assigned outside of scheduled lecture times) for fall 2020. While student ratings of MD1 were mostly favorable, students expressed specific concerns regarding online modules in MD1 mid-course evaluations. Comments included, “we feel overwhelmed by the length and content in addition to the scheduled lectures we already have” and “we were not huge fans of the online modules”. Additionally, “Q&A and review sessions” corresponding with each online module were scheduled in the second half of MD1 to provide dedicated time for students to meet with instructors. The formats of these sessions were left to the discretion of the instructor, resulting in high variability. Students were surveyed to elaborate their thoughts towards online modules and review sessions. Although this project was done in the context of MD1 online modules, we hope to extend the recommendations to all lectures in the pre-clerkship units. Objectives: The purpose of this study was to identify strengths, areas of improvement, and suggestions regarding online modules assigned in MD1. Methods: A quality improvement online survey was administered in October 2020 to 77 students in the JABSOM Class of 2024. Quantitative and qualitative questions were newly developed based on feedback from the MD1 mid-course evaluations and addressed areas including preferred presentation style, lecture reviews, effective characteristics, and overall sentiment of the online modules. Patterns among the qualitative responses were identified by the authors to recognize student preferences. Results: The survey was completed by 63 (81.8%) students. Of note, 100% of enrolled students earned passing scores on MD1 end-course exams. Students rated their overall feelings about the online modules 5.9±1.5 out of 10. The majority (55.6%) of students preferred practice questions provided and discussed in pre-recorded lectures. Student comments suggested the most effective review session formats were based on instructors’ practice questions or overviews of key lecture slides. Respondents also reported the most effective lectures had exam-like practice questions with explanations and direct connections to MD1 PBL cases. Additionally, respondents recommended scheduling in specific time blocks to watch pre-recorded lectures during school day hours, to more closely mimic live, in-person lectures. Discussion: The prevalence of online learning in medical school curricula has increased, perhaps due to the COVID-19 pandemic. We surveyed the JABSOM Class of 2024 about their MD1 online learning experience and consolidated feedback to the following recommendations. (1) Regarding content, we recommend lecturers (a) relate the material to PBL cases and (b) discuss clinical examples. (2) Regarding practice questions, we recommend lecturers prepare and discuss practice questions during their lectures. (3) Regarding review sessions, we recommend lecturers prepare a summary of both (a) testable, key concepts and (b) additional practice questions. We propose these changes and practices can lead to improved learner satisfaction while maintaining the high standard of learner performance outcomes that faculty and students share. Target Audience: Students and educators, JABSOM Office of Medical Educatio

Clinicopathological Findings, Treatment and Outcome in 60 cats with Feline Gastrointestinal Eosinophilic Sclerosing Fibroplasia

Background – Feline gastrointestinal eosinophilic sclerosing fibroplasia (FGESF) presents as mass(es) associated with the gastrointestinal tract, mesentery, and abdominal lymph nodes.Hypothesis/Objectives – To report the clinicopathological findings, treatment, and outcome of cats with FGESF.Animals – Sixty client-owned cats diagnosed with FGESF. Methods – Retrospective review of medical records of cats with histopathologically confirmed FGESF. Results – The median age was 5.4 years (interquartile range [IQR] 3.3-8.9.); 30% were Domestic Shorthairs and 12% were Domestic Longhair cats, with the most prevalent pedigree breeds being Ragdolls (25%), Exotic Shorthair (10%) and Persian (8%) cats. The median duration of clinical signs was 90 days (IQR 17.5-247.0); the most common clinical signs were weight loss (60%), hyporexia/anorexia (55%), chronic vomiting (37%), lethargy (35%) and chronic diarrhea (27%). Masses were located in the small intestine (32%), stomach (27%), ileocolic junction (15%), colon (10%), lymph node (8%) and mesentery (8%) and 15% of cats had more than one mass. Eosinophilia was present in 50% and hypoalbuminemia in 28% of cats. The mass was removed surgically in 37% of cases. Most cats (98%) were treated with corticosteroids and 1 cat with antibiotics alone. The survival was not statistically different between cats treated with surgical resection and cats treated with medical therapy alone, 88% of the cats still alive at the time of writing. Conclusions and clinical importance – FGESF is an important differential diagnosis for abdominal masses in cats, and has a much better prognosis than previously reported. <br/

Off-label prescribing in palliative care – a cross-sectional national survey of Palliative Medicine doctors

Background: Regulatory bodies including the European Medicines Agency register medications (formulation, route of administration) for specific clinical indications. Once registered, prescription is at clinicians’ discretion. Off-label use is beyond the registered use. While off-label prescribing may, at times, be appropriate, efficacy and toxicity data are often lacking. Aim: The aim of this study was to document off-label use policies (including disclosure and consent) in Australian palliative care units and current practices by palliative care clinicians. Design: A national, cross-sectional survey was conducted online following an invitation letter. The survey asked clinicians their most frequent off-label medication/indication dyads and unit policies. Dyads were classified into unregistered, off-label and on-label, and for the latter, whether medications were nationally subsidised. Setting/participants: All Australian palliative medicine Fellows and advanced trainees. Results: Overall, 105 clinicians responded (53% response rate). The majority did not have policies on off-label medications, and documented consent rarely. In all, 236 medication/indication dyads for 36 medications were noted: 45 dyads (19%) were for two unregistered medications, 118 dyads (50%) were for 26 off-label medications and 73 dyads (31%) were for 12 on-label medications. Conclusions: Off-label prescribing with its clinical, legal and ethical implications is common yet poorly recognised by clinicians. A distinction needs to be made between where quality evidence exists but registration has not been updated by the pharmaceutical sponsor and the evidence has not been generated. Further research is required to quantify any iatrogenic harm from off-label prescribing in palliative care

An Assessment of Potential Exposure and Risk from Estrogens in Drinking Water

BACKGROUND. Detection of estrogens in the environment has raised concerns in recent years because of their potential to affect both wildlife and humans. OBJECTIVES. We compared exposures to prescribed and naturally occurring estrogens in drinking water to exposures to naturally occurring background levels of estrogens in the diet of children and adults and to four independently derived acceptable daily intakes (ADIs) to determine whether drinking water intakes are larger or smaller than dietary intake or ADIs. METHODS. We used the Pharmaceutical Assessment and Transport Evaluation (PhATE) model to predict concentrations of estrogens potentially present in drinking water. Predicted drinking water concentrations were combined with default water intake rates to estimate drinking water exposures. Predicted drinking water intakes were compared to dietary intakes and also to ADIs. We present comparisons for individual estrogens as well as combined estrogens. RESULTS. In the analysis we estimated that a child's exposures to individual prescribed estrogens in drinking water are 730-480,000 times lower (depending upon estrogen type) than exposure to background levels of naturally occurring estrogens in milk. A child's exposure to total estrogens in drinking water (prescribed and naturally occurring) is about 150 times lower than exposure from milk. Adult margins of exposure (MOEs) based on total dietary exposure are about 2 times smaller than those for children. Margins of safety (MOSs) for an adult's exposure to total prescribed estrogens in drinking water vary from about 135 to > 17,000, depending on ADI. MOSs for exposure to total estrogens in drinking water are about 2 times lower than MOSs for prescribed estrogens. Depending on the ADI that is used, MOSs for young children range from 28 to 5,120 for total estrogens (including both prescribed and naturally occurring sources) in drinking water. CONCLUSIONS. The consistently large MOEs and MOSs strongly suggest that prescribed and total estrogens that may potentially be present in drinking water in the United States are not causing adverse effects in U.S. residents, including sensitive subpopulations.Johnson & Johnson Pharmaceutical Research and Development, LLC; Pfizer Inc.; Wyeth Inc

Trypanosoma brucei BRCA2 acts in a life cycle-specific genome stability process and dictates BRC repeat number-dependent RAD51 subnuclear dynamics

Trypanosoma brucei survives in mammals through antigenic variation, which is driven by RAD51-directed homologous recombination of Variant Surface Glycoproteins (VSG) genes, most of which reside in a subtelomeric repository of &gt;1000 silent genes. A key regulator of RAD51 is BRCA2, which in T. brucei contains a dramatic expansion of a motif that mediates interaction with RAD51, termed the BRC repeats. BRCA2 mutants were made in both tsetse fly-derived and mammal-derived T. brucei, and we show that BRCA2 loss has less impact on the health of the former. In addition, we find that genome instability, a hallmark of BRCA2 loss in other organisms, is only seen in mammal-derived T. brucei. By generating cells expressing BRCA2 variants with altered BRC repeat numbers, we show that the BRC repeat expansion is crucial for RAD51 subnuclear dynamics after DNA damage. Finally, we document surprisingly limited co-localization of BRCA2 and RAD51 in the T. brucei nucleus, and we show that BRCA2 mutants display aberrant cell division, revealing a function distinct from BRC-mediated RAD51 interaction. We propose that BRCA2 acts to maintain the huge VSG repository of T. brucei, and this function has necessitated the evolution of extensive RAD51 interaction via the BRC repeats, allowing re-localization of the recombinase to general genome damage when needed

Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation

Aim To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation. Methods We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay. Results At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3. Conclusion Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors

No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes