The feasibility of using mouthpiece ventilation in the intensive care unit for post-extubation breathing support after acute tetraplegia.

STUDY DESIGN: A prospective cohort of patients with acute tetraplegia. OBJECTIVES: This study aimed to determine the feasibility of using mouthpiece ventilation (MPV) in the intensive care unit (ICU) for patients who are extubated after suffering an acute cervical spinal cord injury (CSCI). SETTING: ICU, Princess Alexandra Hospital, Brisbane Australia. METHODS: New admissions to ICU in the 14 months between April 2017 and June 2018 with a CSCI who underwent intubation were assessed for inclusion. MPV was provided to consenting participants (who were deemed likely to be able to maintain ventilation on their own) at the time of extubation and was utilised in addition to standard care while participants were awake. MPV settings, usage, and support hours to educate and facilitate MPV were collected. Feedback from participants and clinical staff was gathered throughout the study. Pre- and post-extubation measures of forced vital capacity (FVC), the frequency of endotracheal suction of sputum, and gas exchange using ventilation-perfusion ratios were recorded along with the incidence of reintubation. RESULTS: Fourteen participated in utilising MPV with 16 episodes of extubation. The average time per participant to have MPV titrated and bedside data collected was 178 minutes. Data from 16 episodes of extubation have been included. Three of the 14 participants failed initial extubation. Feedback from participants and clinicians has been positive and constructive, enabling MPV settings to be adapted to the person with acute CSCI during this pilot study. CONCLUSION: MPV is feasible to use post-extubation for people with CSCI in ICU. Pressure control mode MPV was deemed the most suitable for newly extubated acute CSCI patients. Intensive clinical support is required initially to provide education prior to MPV, and at the time of extubation for both patient and treating clinicians. Both report it to be a useful adjunct to ICU treatment.

The impact of inotersen on Neuropathy Impairment Score in patients with hereditary transthyretin amyloidosis with polyneuropathy.

BACKGROUND: Patients with hereditary transthyretin amyloidosis (ATTRv) frequently experience symptoms of polyneuropathy (PN) that worsen over time and impair daily functioning. Previous analyses supported efficacy of inotersen, an antisense oligonucleotide, to slow neuropathic progression in patients with ATTRv-PN, as indicated by larger mean changes, relative to placebo, in total score and several subscales of the Neuropathy Impairment Score (NIS), and for the subset of NIS items specific to lower limbs (NIS-LL) for the overall study sample. A key objective of the current study was to evaluate efficacy of inotersen for slowing neuropathic progression in NIS/NIS-LL within key clinical subgroups of patients with ATTRv-PN. Additionally, for this study, responder definition (RD) thresholds were estimated for NIS/NIS-LL total and subscale scores, for the purpose of evaluating clinically meaningful benefit of inotersen at the individual patient-level. METHODS: Post hoc analyses used data from the NEURO-TTR phase 3 trial of inotersen in patients with ATTRv-PN (NCT01737398). Treatment differences in mean changes on NIS/NIS-LL total and subscale scores from baseline to week 65 were examined within patient subgroups defined by clinical characteristics. Anchor- and distribution-based approaches estimated RDs for NIS/NIS-LL scores, with responders defined as patients who did not experience clinically meaningful neuropathic progression. Responder analyses compared the proportion of patients classified as responders for each NIS/NIS-LL score between treatment arms. RESULTS: Within each patient subgroup, mean increases in NIS/NIS-LL total and muscle weakness subscales were significantly smaller after 65 weeks of treatment with inotersen compared to placebo. Similar patterns were observed for some, but not all, subgroups on NIS/NIS-LL reflex subscale scores. Recommended RDs were 8.1 points for NIS total and 4.7 points for NIS-LL total. Patients receiving inotersen for 65 weeks were significantly less likely than those receiving placebo to exhibit clinically meaningful increases on NIS/NIS-LL total, muscle weakness, and sensation subscales. CONCLUSIONS: This study supports previous evidence for efficacy of inotersen in this patient population and provides interpretation guidelines for clinically meaningful changes in NIS/NIS-LL scores.

Improving the handover of complex trauma patients by implementing a standardised process.

BACKGROUND: Patient handover continues to be an international health priority in the prevention of patient harm. Transitioning patients from the intensive care unit (ICU) to the ward is complex, particularly for trauma patients, due to the multifaceted aspects of their care requirements as a result of multiple injuries and different speciality teams. OBJECTIVES/AIM: To design, implement, and evaluate the efficacy of a standardised handover process and tool for the transfer of ICU trauma patients. METHODS: A multimethod before/after study design was used. This included observations before and after an implemented transfer process and semistructured interviews with ICU and ward nurses caring for trauma patients. Comparisons were made of data before and after the intervention. RESULTS: Eleven patient handovers were observed, and 21 nurses (11 from the ICU and 10 from the ward) were interviewed. Patients and family members were included during the handover following the intervention (n = 0/10 [0%] vs n = 4/11 [36%]) and the ward nurses were asked if they had any concerns (n = 5/10 [50%] vs n = 10/11 [91%]). Improvements in patient observations handed over were reported following the intervention. However, omissions remained in some key areas including patient introduction, patient identity, fluid balance, and allergies/alerts. Thematic analysis of interviews revealed that the new handover process was perceived advantageous by both ICU and ward nurses because of its structured and comprehensive approach. Identified future improvements included the need for hospital service managers to ensure integration of ICU and ward electronic health record systems. CONCLUSION: Precise, accurate, and complete handover remains a patient safety concern. Improvements were achieved using a standardised process and handover tool for the transfer of complex trauma patients. Further improvements are required to reduce the failure to hand over essential patient information.

Clinical manifestations and healthcare utilization before diagnosis of transthyretin amyloidosis.

Introduction: Initial clinical manifestations of transthyretin amyloidosis (ATTR) are not well understood, making timely diagnosis challenging. Methods: Patients aged ≥68 years newly diagnosed with ATTR were identified using Medicare Research Identifiable Files. Symptom manifestation and healthcare utilization were measured during 3 years pre-diagnosis; demographics and comorbidity index during 1-year pre-diagnosis. Controls (ATTR-free) were matched 1:1 to patients with ATTR based on age, sex and region; same index date and enrollment as match. Results: We identified 552 matched ATTR-control pairs: mean age 78.3 (standard deviation 6.3) and 64.5% male. Among patients with ATTR (vs controls), cardiovascular conditions (92.9 vs 75.9%) and hospitalization (54.0 vs 35.5%) were frequent during 3 years pre-diagnosis. Conclusion: Patients with ATTR have multiple symptoms and hospitalizations pre-diagnosis, recognition of which may facilitate earlier diagnosis and treatment.

Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial.

INTRODUCTION/AIMS: Hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN) progressively affects patients' functionality and compromises health-related quality of life (HRQL). The aim of this study was to quantify the projected long-term treatment effects of inotersen vs placebo on HRQL measures. METHODS: The inotersen phase 2/3 randomized, double-blind, placebo-controlled trial NEURO-TTR (NCT01737398, 65 weeks) and its subsequent open-label extension (OLE; NCT02175004, 104 weeks) included 172 (112 inotersen and 60 placebo) patients. Placebo double-blind period and overall inotersen-inotersen (double-blind/OLE) treatment period (170 weeks) data were used to extrapolate the long-term placebo-placebo effect using mixed-effects models with repeated measures. Changes from baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) and 36-Item Short Form Health Survey version 2 (SF-36v2) in hATTR-PN were estimated. Differences in changes were compared between the inotersen-inotersen and extrapolated placebo-placebo arms. RESULTS: Inotersen-inotersen patients maintained their HRQL with an observed change ranging from 10.3% improvement (Norfolk QoL-DN item "Pain kept you awake at night") to 11.6% deterioration (SF-36v2 Activities of Daily Living subdomain). The extrapolated placebo-placebo results suggest greater deterioration over time compared with inotersen-inotersen treatment on Norfolk QoL-DN total score (23.6; 95% confidence interval [CI], 8.9-38.3; P < .01), Activities of Daily Living (4.6; 95% CI, 2.0-7.3; P < .001), and "Pain kept you awake at night" (1.2; 95% CI, 0.4-1.9; P < .01). Similarly, greater deterioration was expected for the SF-36v2 Physical Component Summary (8.0; 95% CI, 3.2-12.8, P < .01), Bodily Pain (7.8; 95% CI, 2.0-13.5; P < .01), and Physical Functioning (10.6; 95% CI, 5.5-15.6; P < .0001). DISCUSSION: Long-term (>3 years) inotersen treatment was associated with slowing and, in some domains, halting of deterioration in key HRQL outcome measures, particularly physical functioning and pain.

Developing antisense oligonucleotides for a TECPR2 mutation-induced, ultra-rare neurological disorder using patient-derived cellular models.

Mutations in the TECPR2 gene are the cause of an ultra-rare neurological disorder characterized by intellectual disability, impaired speech, motor delay, and hypotonia evolving to spasticity, central sleep apnea, and premature death (SPG49 or HSAN9; OMIM: 615031). Little is known about the biological function of TECPR2, and there are currently no available disease-modifying therapies for this disease. Here we describe implementation of an antisense oligonucleotide (ASO) exon-skipping strategy targeting TECPR2 c.1319delT (p.Leu440Argfs∗19), a pathogenic variant that results in a premature stop codon within TECPR2 exon 8. We used patient-derived fibroblasts and induced pluripotent stem cell (iPSC)-derived neurons homozygous for the p.Leu440Argfs∗19 mutation to model the disease in vitro. Both patient-derived fibroblasts and neurons showed lack of TECPR2 protein expression. We designed and screened ASOs targeting sequences across the TECPR2 exon 8 region to identify molecules that induce exon 8 skipping and thereby remove the premature stop signal. TECPR2 exon 8 skipping restored in-frame expression of a TECPR2 protein variant (TECPR2ΔEx8) containing 1,300 of 1,411 amino acids. Optimization of ASO sequences generated a lead candidate (ASO-005-02) with ∼27 nM potency in patient-derived fibroblasts. To examine potential functional rescue induced by ASO-005-02, we used iPSC-derived neurons to analyze the neuronal localization of TECPR2ΔEx8 and showed that this form of TECPR2 retains the distinct, punctate neuronal expression pattern of full-length TECPR2. Finally, ASO-005-02 had an acceptable tolerability profile in vivo following a single 20-mg intrathecal dose in cynomolgus monkeys, showing some transient non-adverse behavioral effects with no correlating histopathology. Broad distribution of ASO-005-02 and induction of TECPR2 exon 8 skipping was detected in multiple central nervous system (CNS) tissues, supporting the potential utility of this therapeutic strategy for a subset of patients suffering from this rare disease.

Factors associated with increased health-related quality-of-life benefits in hereditary transthyretin amyloidosis polyneuropathy patients treated with inotersen.

INTRODUCTION/AIMS: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a genetic condition associated with significant morbidity and mortality. In this study we aimed to identify patient subgroups exhibiting the greatest health-related quality of life (HRQL) benefit from inotersen treatment. METHODS: We examined data from the inotersen phase 2/3 randomized, controlled trial for ATTRv-PN, NEURO-TTR (NCT01737398, 66 weeks). LASSO regression models predicted changes in Norfolk QoL-DN total score (TQoL, range -4 to 136; higher scores indicate poorer HRQL) from baseline in the inotersen and placebo arm, respectively. Individualized efficacy scores (ES) were calculated as differences between predicted change scores had patients received inotersen vs placebo. Patients were ranked by ES to define the greatest-benefit subpopulation (top 50%). Characteristics of the top 50% and bottom 50% of patients were compared. RESULTS: The overall mean ± standard deviation TQoL change was -0.20 ± 19.13 for inotersen (indicating no change) and 10.77 ± 21.13 for placebo (indicating deterioration). Within the highest-benefit patients, mean TQoL change was -11.03 ± 17.06 (improvement) for inotersen and 11.24 ± 22.97 (deterioration) for placebo (P < .001). Compared with the overall population, patients in the greatest-benefit subpopulation were younger, more likely to have polyneuropathy disability (PND) scores 1 or 2, less likely to have received prior tafamidis or diflunisal treatment, and more likely to have Val30Met mutations and higher (worse) baseline TQoL. CONCLUSIONS: Patients who were younger and/or at earlier polyneuropathy stages experienced greater HRQL benefits from inotersen over 66 weeks. These findings underscore the need for early diagnosis and treatment initiation, especially among more severely affected patients in early stages of ATTRv-PN.

Responder analysis for neuropathic impairment and quality-of-life assessment in patients with hereditary transthyretin amyloidosis with polyneuropathy in the NEURO-TTR study.

OBJECTIVE: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare disease characterized by rapid neuropathic progression. In pivotal studies of gene-silencing treatments, the modified Neuropathy Impairment Score + 7 tests (mNIS + 7) and Norfolk-Quality of Life (QOL)-Diabetic Neuropathy (DN) questionnaire assessed treatment impact on neuropathic progression. Establishing responder definition (RD) thresholds for these measures would enable evaluation of clinically meaningful treatment benefit. METHODS: mNIS + 7 and Norfolk-QOL-DN were administered at baseline and week 65 to 165 adults with ATTRv-PN receiving inotersen (n = 106) or placebo (n = 59) in the NEURO-TTR study. Anchor-based approaches for estimating RD thresholds were used for Norfolk QOL-DN, while distribution-based approaches were used for both measures. Responders were patients with a score change < RD, indicating improvement or stabilization (i.e., no clinically meaningful progression). Odds ratios (ORs) and Fisher's exact tests compared proportions of responders by treatment. RESULTS: The mean RD estimates were 12.2 points and 8.8 points for mNIS + 7 and Norfolk QOL-DN, respectively. The proportions of patients whose change in score indicated improvement or stabilization were statistically significantly larger for inotersen than placebo for all estimated RD thresholds for mNIS + 7 (64-86% responders for inotersen vs. 27-46% for placebo, ORs = 3.8-7.2, ps < 0.001) and Norfolk QOL-DN (66-81% vs. 35-56%, ORs = 2.4-3.6, ps < 0.05). DISCUSSION: Establishing RD thresholds for these instruments enables evaluation of clinically relevant and individual-level treatment benefit on neuropathic progression. Across RDs estimated using multiple methods, a higher proportion of patients receiving inotersen than placebo showed improved or stabilized neuropathic progression at week 65. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01737398; Date of registration: November 29, 2012.

REVOLUTION (Routine EValuatiOn of people LivIng with caNcer)-Protocol for a prospective characterisation study of patients with incurable cancer.

INTRODUCTION: There is a pressing need for a holistic characterisation of people with incurable cancer. In this group, where quality of life and improvement of symptoms are therapeutic priorities, the physical and biochemical manifestations of cancer are often studied separately, giving an incomplete picture. In order to improve care, spur therapeutic innovation, provide meaningful endpoints for trials and set priorities for future research, work must be done to explore how the tumour influences the clinical phenotype. Characterisation of the host-tumour interaction may also provide information regarding prognosis, allowing appropriate planning of investigations, treatment and referral to palliative medicine services. METHODS: Routine EValuatiOn of people LivIng with caNcer (REVOLUTION) is a prospective observational study that aims to characterise people with incurable cancer around five key areas, namely body composition, physical activity, systemic inflammatory response, symptoms, and quality of life by developing a bio-repository. Participants will initially be recruited from a single centre in the UK and will have assessments of body composition (bio-impedance analysis [BIA] and computed tomography [CT]), assessment of physical activity using a physical activity monitor, measurement of simple markers of inflammation and plasma cytokine proteins and three symptom and quality of life questionnaires. DISCUSSION: This study aims to create a comprehensive biochemical and clinical characterisation of people with incurable cancer. Data in this study can be used to give a better understanding of the 'symptom phenotype' and quality of life determinants, development of a profile of the systemic inflammatory response and a detailed characterisation of body composition.

A randomized, feasibility trial of an exercise and nutrition-based rehabilitation programme (ENeRgy) in people with cancer.

BACKGROUND: Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would support an approach that targets these factors. This trial aimed to assess the feasibility of an exercise and nutrition based rehabilitation programme in people with incurable cancer. METHODS: We randomized community dwelling adults with incurable cancer to either a personalized exercise and nutrition based programme (experimental arm) or standard care (control arm) for 8 weeks. Endpoints included feasibility, quality of life, physical activity (step count), and body weight. Qualitative and health economic analyses were also included. RESULTS: Forty-five patients were recruited (23 experimental arm, 22 control arm). There were 26 men (58%), and the median age was 78 years (IQR 69-84). At baseline, the median BMI was 26 kg/m2 (IQR: 22-29), and median weight loss in the previous 6 months was 5% (IQR: -12% to 0%). Adherence to the experimental arm was >80% in 16/21 (76%) patients. There was no statistically significant difference in the following between trial arms: step count - median % change from baseline to endpoint, per trial arm (experimental -18.5% [IQR: -61 to 65], control 5% [IQR: -32 to 50], P = 0.548); weight - median % change from baseline to endpoint, per trial arm (experimental 1%[IQR: -3 to 3], control -0.5% [IQR: -3 to 1], P = 0.184); overall quality of life - median % change from baseline to endpoint, per trial arm (experimental 0% [IQR: -20 to 19], control 0% [IQR: -23 to 33], P = 0.846). Qualitative findings observed themes of capability, opportunity, and motivation amongst patients in the experimental arm. The mean incremental cost of the experimental arm versus control was £-319.51 [CI -7593.53 to 6581.91], suggesting the experimental arm was less costly. CONCLUSIONS: An exercise and nutritional rehabilitation intervention is feasible and has potential benefits for people with incurable cancer. A larger trial is now warranted to test the efficacy of this approach.

Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR.

INTRODUCTION: Patients with hereditary transthyretin amyloidosis associated with polyneuropathy (ATTRv-PN) experience deterioration in health-related quality of life (HRQOL) as the disease progresses. Findings from the randomized placebo-controlled phase III NEURO-TTR study showed treatment benefit of inotersen, an antisense oligonucleotide, for preserving or improving HRQOL after 65 weeks of treatment. The current analysis examines longitudinal trends in specific aspects of HRQOL, including polyneuropathy symptoms, daily activities, and physical, role, and social functioning in patients with ATTRv-PN receiving long-term treatment in a follow-up open-label extension (OLE) study. METHODS: One-hundred thirty-five patients with ATTRv-PN were enrolled in an ongoing 5-year OLE study following completion of NEURO-TTR. Eighty-five patients received continuous weekly treatment with inotersen in both studies (inotersen-inotersen group), while 50 patients switched from placebo to inotersen at OLE study baseline (placebo-inotersen group). Descriptive analyses of changes in domain scores and item responses through week 104 of the OLE study were conducted for measures of neuropathy-related and generic HRQOL: Norfolk QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2), respectively. RESULTS: For both inotersen-inotersen and placebo-inotersen groups, all Norfolk QOL-DN and most SF-36v2 domain scores remained stable from OLE baseline through week 104. Differences in HRQOL between the two groups at OLE baseline were sustained through week 104. Analysis of item responses from NEURO-TTR baseline to OLE study week 104 (170 weeks) for the inotersen-inotersen group found no notable increases in the proportion of patients reporting substantial impairments across a wide variety of symptoms, daily activities, and functioning. CONCLUSION: Long-term treatment with inotersen preserved HRQOL for patients with ATTRv-PN for periods of up to 3 years. The gap in HRQOL between those who had previously received inotersen or placebo in NEURO-TTR did not close by week 104 of the OLE phase, indicating the importance of early treatment for maintaining HRQOL in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT01737398 for NEURO-TTR study; NCT02175004 for OLE study INFOGRAPHIC.

Hereditary transthyretin amyloidosis with polyneuropathy is a rare disease that causes damage to nerves in the limbs, leading to pain, numbness, loss of sensitivity, and muscle weakness, with eventual loss of the ability to walk (i.e., patients require a wheelchair or are bedridden). As the disease progresses, patients' quality of life, including their ability to engage in everyday activities, socialize with others, work, and live independently, continually worsens. In a recent clinical trial (the NEURO-TTR study), patients with this disease randomized to receive the drug inotersen for 66 weeks maintained their quality of life, while patients randomized to receive a placebo showed continued worsening. All patients completing the NEURO-TTR study could participate in an extension study during which all patients knowingly received inotersen for up to 5 years. We examined quality of life in patients through the first 2 years of this extension study. For all patients, regardless of previous treatment (inotersen or placebo), most aspects of quality of life did not change throughout the 2-year extension study, showing that inotersen can preserve quality of life of these patients for up to 2­3 years. However, while quality of life in patients who had received placebo in the NEURO-TTR study did not get worse during the extension study, it also did not improve to match that of patients who received inotersen during the NEURO-TTR study. This finding shows the importance of treating these patients with inotersen as early as possible to preserve their quality of life before it substantially deteriorates.

Rate of neuropathic progression in hereditary transthyretin amyloidosis with polyneuropathy and other peripheral neuropathies: a systematic review and meta-analysis.

BACKGROUND: We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including diabetic peripheral neuropathy (DPN) and Charcot-Marie-Tooth disease (CMT). METHODS: Literature searches identified studies reporting neuropathic progression, measured by Neuropathy Impairment Score (NIS) or NIS-Lower Limbs (NIS-LL). Our study also included unpublished data from a clinical registry of patients who were diagnosed with different peripheral neuropathies and seen at the Oregon Health & Science University (OHSU) during 2016-2020. Meta-analysis and meta-regression models examined and compared annual progression rates, calculated from extracted data, between studies of ATTRv-PN and other peripheral neuropathies. RESULTS: Data were synthesized from 15 studies in which NIS and/or NIS-LL total scores were assessed at least twice, with ≥12 weeks between assessments, among untreated patients with ATTRv-PN or other peripheral neuropathies. Meta-analysis models yielded that the annual progression rate in NIS total scores was significantly different from zero for studies in ATTRv-PN and CMT (11.77 and 1.41; both P < 0.001), but not DPN (- 1.96; P = 0.147). Meta-regression models showed significantly faster annual progression in studies in ATTRv-PN, which statistically exceeded that in other peripheral neuropathies by 12.45 points/year for NIS, and 6.96 for NIS-LL (both P < 0.001). CONCLUSIONS: Peripheral nervous function deteriorates more rapidly in patients with ATTRv-PN than for other peripheral neuropathies. These findings may improve understanding of the natural history of neuropathy in ATTRv-PN, facilitate early diagnosis, and guide the development of assessment tools and therapies specifically targeting neuropathic progression in this debilitating disease.

Relationship between cytokines and symptoms in people with incurable cancer: A systematic review.

BACKGROUND: Development and spread of cancer is linked to the inflammatory response, in which cytokines serve a key role. The inflammatory response may also form the basis for symptoms of cancer. This systematic review examines the relationship between cytokines and symptoms in incurable cancer. METHODS: MEDLINE, EMBASE, Cochrane Library, CINAHL, Web of Science and PsycINFO databases were searched for studies from January 2004 to January 2020. RESULTS: Twenty studies were selected (n = 1806 patients, 119 controls). Symptoms studied included depression, fatigue, pain, and loss of appetite. Nine studies examined patients with a specified tumour type, the remainder included patients with a mix of tumour types. Thirty-one cytokines were examined; multiple associations between cytokines and symptoms were described, supporting the hypothesis that cytokines may have a key role in symptom generation. CONCLUSION: Symptoms of incurable cancer are associated with circulating cytokines. Further study is required to characterise these relationships, and to explore their therapeutic potential.

Handover practices of nurses transferring trauma patients from intensive care units to the ward: A multimethod observational study.

Poor-quality patient handover leads to adverse patient outcomes. Consequently, handover has been identified as a national and international priority for preventing patient harm. Risks are exacerbated during transfers of trauma intensive care unit (ICU) patients to a ward because of the complexity of their injuries coupled with a de-escalation in care and monitoring. This study assessed current handover practices for ICU trauma patients, identifying barriers and facilitators to best practice handover. A multimethod design was used, including naturalistic observations of clinical handover of trauma patients transferred to a ward and semistructured interviews with both the ICU and ward nurses caring for the trauma patient. The study was conducted at an Australian metropolitan public adult teaching hospital ICU. Purposive maximal sampling of patient handover opportunities was sought. Recruitment continued until data saturation was reached using thematic analysis. Ten ICU and ward nurses were recruited, with 10 observations of handover and 20 interviews conducted. Observations of the handovers identified multiple issues, including deficits and discrepancies in the information communicated that could impact patient safety, variable handover processes, and poor patient and family involvement. Interviews elicited two major themes around the handover: practices and processes. Nurses identified that interruptions, time, and workload pressures presented barriers to handover, whilst teamwork, using a structured and systematic approach, preparation time for handover, and communication before transfer facilitated effective handover and transfer. Nurses suggested a structured tool to aid handover. This study identified clinically significant deficits and discrepancies in the information communicated to the ward nurses. Nurses identified that interruptions, time, and workload pressures presented barriers to effective handover. Teamwork where preparation and the handover event are prioritised over other activities is needed. A minimum data set for handover in conjunction with patients and family members is recommended.

Posterior samples of the parameters of binary black holes from Advanced LIGO, Virgo's second observing run.

This paper presents a parameter estimation analysis of the seven binary black hole mergers-GW170104, GW170608, GW170729, GW170809, GW170814, GW170818, and GW170823-detected during the second observing run of the Advanced LIGO and Virgo observatories using the gravitational-wave open data. We describe the methodology for parameter estimation of compact binaries using gravitational-wave data, and we present the posterior distributions of the inferred astrophysical parameters. We release our samples of the posterior probability density function with tutorials on using and replicating our results presented in this paper.

Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation.

Clinical application of siRNA-based therapeutics outside of the liver has been hindered by the inefficient delivery of siRNA effector molecules into extra-hepatic organs and cells of interest. To understand the parameters that enable RNAi activity in vivo, it is necessary to develop a systematic approach to identify which cells within a tissue are permissive to oligonucleotide internalization and activity. In the present study, we evaluate the distribution and activity within the lung of chemically stabilized siRNA to characterize cell-type tropism and structure-activity relationship. We demonstrate intratracheal delivery of fully modified siRNA for RNAi-mediated target knockdown in lung CD11c+ cells (dendritic cells, alveolar macrophages) and alveolar epithelial cells. Finally, we use an allergen-induced model of lung inflammation to demonstrate the capacity of inhaled siRNA to induce target knockdown in dendritic cells and ameliorate lung pathology.

Tidal Deformabilities and Radii of Neutron Stars from the Observation of GW170817.

We use gravitational-wave observations of the binary neutron star merger GW170817 to explore the tidal deformabilities and radii of neutron stars. We perform a Bayesian parameter estimation with the source location and distance informed by electromagnetic observations. We also assume that the two stars have the same equation of state; we demonstrate that, for stars with masses comparable to the component masses of GW170817, this is effectively implemented by assuming that the stars' dimensionless tidal deformabilities are determined by the binary's mass ratio q by Λ_{1}/Λ_{2}=q^{6}. We investigate different choices of prior on the component masses of the neutron stars. We find that the tidal deformability and 90% credible interval is Λ[over ˜]=222_{-138}^{+420} for a uniform component mass prior, Λ[over ˜]=245_{-151}^{+453} for a component mass prior informed by radio observations of Galactic double neutron stars, and Λ[over ˜]=233_{-144}^{+448} for a component mass prior informed by radio pulsars. We find a robust measurement of the common areal radius of the neutron stars across all mass priors of 8.9≤R[over ^]≤13.2 km, with a mean value of ⟨R[over ^]⟩=10.8 km. Our results are the first measurement of tidal deformability with a physical constraint on the star's equation of state and place the first lower bounds on the deformability and areal radii of neutron stars using gravitational waves.

Value of a Second Dose of Epinephrine During Anaphylaxis: A Patient/Caregiver Survey.

BACKGROUND: Anaphylaxis guidelines recommend prescription of more than 1 epinephrine autoinjector (EAI) for patients at risk. A second epinephrine dose is required in 16% to 36% of patients. OBJECTIVE: To evaluate real-world use of EAIs and understand the patients'/caregivers' adherence to guidelines. METHODS: We collected survey responses from US patients and caregivers with an EAI prescription in November 2015. The survey covered several domains relevant to anaphylaxis and EAI use. RESULTS: The survey was completed by 953 respondents (505 patients and 448 caregivers). Most respondents were women (71%). Most of the respondents had previously administered an EAI (75%). The mean age of the respondents was 28 ± 14.0 years. A total of 786 (82%) respondents did not carry 2 EAIs all the time, and the main reason given was to have 1 EAI in another location. Most respondents kept at least 1 EAI at home (84%). The percentages of respondents with more than 1 EAI available at locations surveyed were low (patients: 22% at home, 2% at work; caregivers: 27% at home, 10% at school). During training, most respondents (64%) were instructed to always carry 1 EAI and keep the other in another location. Half of the respondents reported the use of a second epinephrine dose in a previous event. Forty-five percent of the 73 respondents who sought emergency care did so because of the unavailability of a second dose. CONCLUSIONS: Our study suggests poor adherence in patients and caregivers to anaphylaxis guidelines recommending more than 1 EAI available at all times and implies that this can result in adverse outcomes.