Understanding the language barriers to translating informed consent documents for maternal health trials in Zambia: a qualitative study.

OBJECTIVE: Providing comprehensible information is essential to the process of valid informed consent. Recruitment materials designed by sponsoring institutions in English-speaking, high-income countries are commonly translated for use in global health studies in other countries; however, key concepts are often missed, misunderstood or 'lost in translation'. The aim of this study was to explore the language barriers to informed consent, focusing on the challenges of translating recruitment materials for maternal health studies into Zambian languages. DESIGN: We used a qualitative approach, which incorporated a multistakeholder workshop (11 participants), in-depth interviews with researchers and translators (8 participants) and two community-based focus groups with volunteers from community advisory boards (20 participants). Content analysis was used to identify terms commonly occurring in recruitment materials prior to the workshop. The framework analysis approach was used to analyse interview data, and a simple inductive thematic analysis approach was used to analyse focus group data. SETTING: The study was based in Lusaka, Zambia. RESULTS: The workshop highlighted difficulties in translating research terms and pregnancy-specific terms, as well as widespread concern that current templates are too long, use overly formal language and are designed with little input from local teams. Framework analysis of in-depth interviews identified barriers to participant understanding relating to design and development of recruitment materials, language, local context and communication styles. Focus group participants confirmed these findings and suggested potential solutions to ensure the language and content of recruitment materials can be better understood. CONCLUSION: Our findings demonstrate that the way in which recruitment materials are currently designed, translated and disseminated may not enable potential trial participants to fully understand the information provided. Instead of using overly complex institutional templates, recruitment materials should be created through an iterative and interactive process that provides truly comprehensible information in a format appropriate for its intended participants.

Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks' gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. METHODS: In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks' gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. FINDINGS: Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference -3·39%, 90% CI -8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. INTERPRETATION: Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks' gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. FUNDING: UK Medical Research Council and Indian Department of Biotechnology.

Social and biologic determinants in lung transplant allocation.

PURPOSE OF REVIEW: Lung transplant is a life-saving intervention for many with end-stage lung disease. As usable donor lungs are a limited resource and the risk of death on the waitlist is not uniform among candidates, organ allocation must consider many variables in order to be equitable. RECENT FINDINGS: The lung allocation score (LAS) system, implemented in 2005, accounted for disease severity, risk of death without transplant, and 1-year survival estimates; however, recipient size, allosensitization, and blood type, biologic features that influence donor pool for a given recipient, do not impact allocation priority. Additionally, social determinants such as geography, socioeconomic status, race, and ethnicity can impact the likelihood of receiving a transplant. This has resulted in certain groups being transplanted at lower rates and at higher risk of dying on the waitlist. In order to address these disparities, lung organ allocation in the United States transitioned to a continuous distribution system using the composite allocation score (CAS) on 9 March 2023. SUMMARY: In this article, we will review some of the data demonstrating the impact that biologic and social determinants have had on lung allocation in order to provide background as to why these have been incorporated into the CAS.

Addressing sex-based disparities in solid organ transplantation in the United States - a conference report.

Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.

Planned delivery for pre-eclampsia between 34 and 37 weeks of gestation: the PHOENIX RCT.

BACKGROUND: In women with late preterm pre-eclampsia (i.e. at 34+0 to 36+6 weeks' gestation), the optimal delivery time is unclear because limitation of maternal-fetal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether or not planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of perinatal or infant outcomes, compared with expectant management, in women with late preterm pre-eclampsia. METHODS: We undertook an individually randomised, triple non-masked controlled trial in 46 maternity units across England and Wales, with an embedded health economic evaluation, comparing planned delivery and expectant management (usual care) in women with late preterm pre-eclampsia. The co-primary maternal outcome was a maternal morbidity composite or recorded systolic blood pressure of ≥ 160 mmHg (superiority hypothesis). The co-primary short-term perinatal outcome was a composite of perinatal deaths or neonatal unit admission (non-inferiority hypothesis). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The primary 2-year infant neurodevelopmental outcome was measured using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. The planned sample size of the trial was 900 women; the trial is now completed. We undertook two linked substudies. RESULTS: Between 29 September 2014 and 10 December 2018, 901 women were recruited; 450 women [448 women (two withdrew consent) and 471 infants] were allocated to planned delivery and 451 women (451 women and 475 infants) were allocated to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group [289 (65%) women] than in the expectant management group [338 (75%) women] (adjusted relative risk 0.86, 95% confidence interval 0.79 to 0.94; p = 0.0005). The incidence of the co-primary perinatal outcome was significantly higher in the planned delivery group [196 (42%) infants] than in the expectant management group [159 (34%) infants] (adjusted relative risk 1.26, 95% confidence interval 1.08 to 1.47; p = 0.0034), but indicators of neonatal morbidity were similar in both groups. At 2-year follow-up, the mean PARCA-R scores were 89.5 points (standard deviation 18.2 points) for the planned delivery group (290 infants) and 91.9 points (standard deviation 18.4 points) for the expectant management group (256 infants), both within the normal developmental range (adjusted mean difference -2.4 points, 95% confidence interval -5.4 to 0.5 points; non-inferiority p = 0.147). Planned delivery was significantly cost-saving (-£2711, 95% confidence interval -£4840 to -£637) compared with expectant management. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. CONCLUSION: In women with late preterm pre-eclampsia, planned delivery reduces short-term maternal morbidity compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater short-term neonatal morbidity (such as need for respiratory support). At 2-year follow-up, around 60% of parents reported follow-up scores. Average infant development was within the normal range for both groups; the small between-group mean difference in PARCA-R scores is unlikely to be clinically important. Planned delivery was significantly cost-saving to the health service. These findings should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on timing of delivery. LIMITATIONS: Limitations of the trial include the challenges of finding a perinatal outcome that adequately represented the potential risks of both groups and a maternal outcome that reflects the multiorgan manifestations of pre-eclampsia. The incidences of maternal and perinatal primary outcomes were higher than anticipated on the basis of previous studies, but this did not limit interpretation of the analysis. The trial was limited by a higher loss to follow-up rate than expected, meaning that the extent and direction of bias in outcomes (between responders and non-responders) is uncertain. A longer follow-up period (e.g. up to 5 years) would have enabled us to provide further evidence on long-term infant outcomes, but this runs the risk of greater attrition and increased expense. FUTURE WORK: We identified a number of further questions that could be prioritised through a formal scoping process, including uncertainties around disease-modifying interventions, prognostic factors, longer-term follow-up, the perspectives of women and their families, meta-analysis with other studies, effect of a similar intervention in other health-care settings, and clinical effectiveness and cost-effectiveness of other related policies around neonatal unit admission in late preterm birth. TRIAL REGISTRATION: The trial was prospectively registered as ISRCTN01879376. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.

Disseminated tuberculosis in a lung transplant recipient presenting as tenosynovitis, subcutaneous nodules, and liver abscesses.

Tuberculosis is of particular concern in lung transplant recipients. We present the case of a patient who received a double lung transplant from a deceased donor from Mexico and developed disseminated tuberculosis 60 days post-transplant manifested as tenosynovitis, liver abscesses, and subcutaneous nodules with no definitive lung allograft involvement. The recipient did not have evidence of tuberculosis on explanted lungs, had a negative interferon gamma release assay pre-transplant, and did not have risk factors for this infection. Mycobacterium tuberculosis should remain in the differential diagnosis of early post-transplant infections with atypical presentations, evidence of dissemination, or lack of improvement with appropriate antimicrobial coverage, even in the absence of typical lung findings.

Cost-Utility Analysis of Planned Early Delivery or Expectant Management for Late Preterm Pre-eclampsia (PHOENIX).

AIM: There is currently limited evidence on the costs associated with late preterm pre-eclampsia beyond antenatal care and post-natal discharge from hospital. The aim of this analysis is to evaluate the 24-month cost-utility of planned delivery for women with late preterm pre-eclampsia at 34+0-36+6 weeks' gestation compared to expectant management from an English National Health Service perspective using participant-level data from the PHOENIX trial. METHODS: Women between 34+0 and 36+6 weeks' gestation in 46 maternity units in England and Wales were individually randomised to planned delivery or expectant management. Resource use was collected from hospital records between randomisation and primary hospital discharge following birth. Women were followed up at 6 months and 24 months following birth and self-reported resource use for themselves and their infant(s) covering the previous 6 months. Women completed the EQ-5D 5L at randomisation and follow-up. RESULTS: A total of 450 women were randomised to planned delivery, 451 to expectant management: 187 and 170 women, respectively, had complete data at 24 months. Planned delivery resulted in a significantly lower mean cost per woman and infant(s) over 24 months (- £2711, 95% confidence interval (CI) - 4840 to - 637), with a mean incremental difference in QALYs of 0.019 (95% CI - 0.039 to 0.063). Short-term and 24-month infant costs were not significantly different between the intervention arms. There is a 99% probability that planned delivery is cost-effective at all thresholds below £37,000 per QALY gained. CONCLUSION: There is a high probability that planned delivery is cost-effective compared to expectant management. These results need to be considered alongside clinical outcomes and in the wider context of maternity care. TRIAL REGISTRATION: ISRCTN registry ISRCTN01879376. Registered 25 November 2013.

Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection.

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.

Planned delivery or expectant management in preeclampsia: an individual participant data meta-analysis.

OBJECTIVE: Pregnancy hypertension is a leading cause of maternal and perinatal mortality and morbidity. Between 34+0 and 36+6 weeks gestation, it is uncertain whether planned delivery could reduce maternal complications without serious neonatal consequences. In this individual participant data meta-analysis, we aimed to compare planned delivery to expectant management, focusing specifically on women with preeclampsia. DATA SOURCES: We performed an electronic database search using a prespecified search strategy, including trials published between January 1, 2000 and December 18, 2021. We sought individual participant-level data from all eligible trials. STUDY ELIGIBILITY CRITERIA: We included women with singleton or multifetal pregnancies with preeclampsia from 34 weeks gestation onward. METHODS: The primary maternal outcome was a composite of maternal mortality or morbidity. The primary perinatal outcome was a composite of perinatal mortality or morbidity. We analyzed all the available data for each prespecified outcome on an intention-to-treat basis. For primary individual patient data analyses, we used a 1-stage fixed effects model. RESULTS: We included 1790 participants from 6 trials in our analysis. Planned delivery from 34 weeks gestation onward significantly reduced the risk of maternal morbidity (2.6% vs 4.4%; adjusted risk ratio, 0.59; 95% confidence interval, 0.36-0.98) compared with expectant management. The primary composite perinatal outcome was increased by planned delivery (20.9% vs 17.1%; adjusted risk ratio, 1.22; 95% confidence interval, 1.01-1.47), driven by short-term neonatal respiratory morbidity. However, infants in the expectant management group were more likely to be born small for gestational age (7.8% vs 10.6%; risk ratio, 0.74; 95% confidence interval, 0.55-0.99). CONCLUSION: Planned early delivery in women with late preterm preeclampsia provides clear maternal benefits and may reduce the risk of the infant being born small for gestational age, with a possible increase in short-term neonatal respiratory morbidity. The potential benefits and risks of prolonging a pregnancy complicated by preeclampsia should be discussed with women as part of a shared decision-making process.

Two-year follow-up of infant and maternal outcomes after planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): A randomised controlled trial.

OBJECTIVE: We evaluated the best time to initiate delivery in late preterm pre-eclampsia in order to optimise long-term infant and maternal outcomes. DESIGN: Parallel-group, non-masked, randomised controlled trial. SETTING: Forty-six maternity units in the UK. POPULATION: Women with pre-eclampsia between 34+0 and 36+6  weeks of gestation, without severe disease, were randomised to planned delivery or expectant management. MAIN OUTCOME MEASURES: Infant neurodevelopmental outcome at 2 years of age, using the Parent Report of Children's Abilities - Revised (PARCA-R) composite score. RESULTS: Between 29 September 2014 and 10 December 2018, 901 women were enrolled in the trial, with 450 women allocated to planned delivery and 451 women allocated to expectant management. At the 2-year follow-up, the intention-to-treat analysis population included 276 women (290 infants) allocated to planned delivery and 251 women (256 infants) allocated to expectant management. The mean composite standardised PARCA-R scores were 89.5 (SD 18.2) in the planned delivery group and 91.9 (SD 18.4) in the expectant management group, with an adjusted mean difference of -2.4 points (95% CI -5.4 to 0.5 points). CONCLUSIONS: In infants of women with late preterm pre-eclampsia, the average neurodevelopmental assessment at 2 years lies within the normal range, regardless of whether planned delivery or expectant management was pursued. With the lower than anticipated follow-up rate there was limited power to demonstrate that these scores did not differ, but the small between-group difference in PARCA-R scores is unlikely to be clinically important.

Rapid deployment of a virtual simulation curriculum to prepare for critical care triage during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic in Ontario, Canada, an Emergency Standard of Care for Major Surge was created to establish a uniform process for the "triage" of finite critical care resources. This proposed departure from usual clinical care highlighted the need for an educational tool to prepare physicians for making and communicating difficult triage decisions. We created a just-in-time, virtual, simulation-based curriculum and evaluated its impact for our group of academic Emergency Physicians. METHODS: Our curriculum was developed and evaluated following Stufflebeam's Context-Input-Process-Product model. Our virtual simulation sessions, delivered online using Microsoft Teams, addressed a range of clinical scenarios involving decisions about critical care prioritization (i.e., Triage). Simulation participants completed a pre-course multiple-choice knowledge test and rating scales pertaining to their attitudes about using the Emergency Standard of Care protocol before and 2-4 weeks after participating. Qualitative feedback about the curriculum was solicited through surveys. RESULTS: Nine virtual simulation sessions were delivered over 3 weeks, reaching a total of 47 attending emergency physicians (74% of our active department members). Overall, our intervention led to a 36% (95% CI 22.9-48.3%) improvement in participants' self-rated comfort and attitudes in navigating triage decisions and communicating with patients at the end of life. Scores on the knowledge test improved by 13% (95% CI 0.4-25.6%). 95% of participants provided highly favorable ratings of the course content and similarly indicated that the session was likely or very likely to change their practice. The curriculum has since been adopted at multiple sites around the province. CONCLUSION: Our novel virtual simulation curriculum facilitated rapid dissemination of the Emergency Standard of Care for Major Surge to our group of Emergency Physicians despite COVID-19-related constraints on gathering. The active learning afforded by this method improved physician confidence and knowledge with these difficult protocols.

RéSUMé: CONTEXTE: Au cours de la pandémie de COVID-19 en Ontario, au Canada, une norme de soins d'urgence pour les poussées majeures a été créée afin d'établir un processus uniforme pour le " triage " des ressources limitées en soins intensifs. Cette proposition d'écart par rapport aux soins cliniques habituels a mis en évidence la nécessité d'un outil éducatif pour préparer les médecins à prendre et à communiquer des décisions de triage difficiles. Nous avons créé un programme d'études virtuel, juste à temps, basé sur la simulation et avons évalué son impact sur notre groupe de médecins urgentistes universitaires. MéTHODES: Notre programme d'études a été développé et évalué selon le modèle Contexte-Intrant-Processus-Produit de Stufflebeam. Nos sessions de simulation virtuelle, réalisées en ligne à l'aide de Microsoft Teams, ont abordé une série de scénarios cliniques impliquant des décisions sur la priorisation des soins intensifs (c.-à-d. le triage). Les participants à la simulation ont rempli un test de connaissances à choix multiples avant le cours et des échelles d'évaluation concernant leurs attitudes à l'égard de l'utilisation du protocole de soins d'urgence standard avant et deux à quatre semaines après leur participation. Des commentaires qualitatifs sur le programme ont été sollicités par le biais d'enquêtes. RéSULTATS: Neuf sessions de simulation virtuelle ont été dispensées sur trois semaines, touchant au total 47 médecins urgentistes titulaires (74 % des membres actifs de notre service). Dans l'ensemble, notre intervention a conduit à une amélioration de 36 % (IC 95 % 22,9-48,3 %) de l'auto-évaluation du confort et des attitudes des participants en matière de décisions de triage et de communication avec les patients en fin de vie. Les scores au test de connaissances se sont améliorés de 13% (IC 95% 0,4-25,6%). 95 % des participants ont donné une évaluation très favorable du contenu du cours et ont également indiqué que la session était susceptible ou très susceptible de modifier leur pratique. Le programme d'études a depuis été adopté à plusieurs endroits dans la province. CONCLUSION: Notre nouveau programme de simulation virtuelle a facilité la diffusion rapide des normes de soins d'urgence en cas de crise majeure à notre groupe d'urgentistes, malgré les contraintes de rassemblement liées au COVID-19. L'apprentissage actif que permet cette méthode a amélioré la confiance et les connaissances des médecins concernant ces protocoles difficiles.

Perioperative anidulafungin combined with triazole prophylaxis for the prevention of early invasive candidiasis in lung transplant recipients.

BACKGROUND: Invasive candidiasis (IC) is a substantial cause of morbidity and mortality among lung transplant recipients (LTRs). Postoperative factors include prolonged hospital stay, central lines, delayed chest closure, and dehiscence increase IC risk. Correspondingly, current guidelines propose targeted IC coverage early posttransplant with fluconazole or an echinocandin. METHODS: This retrospective analysis was performed on LTRs from January 2016 to January 2020 and evaluated effectiveness of a recent protocol utilizing perioperative anidulafungin for early IC prevention in addition to long-term triazole antifungal prophylaxis. Prior to this protocol, patients were primarily established on itraconazole prophylaxis alone. The primary endpoint was proven or probable IC within 90 days after transplant. Multivariable logistic regression modeling was used to assess risk factors for invasive fungal infection (IFI). RESULTS: Among 144 LTRs, there was a numerically lower incidence of IC in the protocol group, although not statistically significant (6% vs. 13%, p = 0.16). Incidence of proven or probable IFI was 7.5% in the protocol cohort and 19.5% in the pre-protocol cohort (p = 0.038). In multivariable analysis, when controlling for lung allocation score (OR 1.04, 95% CI 1.01-1.08), donor perioperative culture with fungal growth (OR 2.92, 95% CI 1.02-8.92), and dehiscence (OR 3.54, 95% CI 1.14-10.85), protocol cohort was not significantly associated with IFI (OR 0.41, 95% CI 0.12-1.23). CONCLUSIONS: To our knowledge, this is the first study investigating combination triazole/echinocandin use in the early post-lung transplant period. These findings demonstrate that in-hospital anidulafungin offers unclear benefit for early IC prevention when used in combination with triazole prophylaxis.

Planned early delivery for late preterm pre-eclampsia in a low- and middle-income setting: a feasibility study.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity globally. Planned delivery between 34+0 and 36+6 weeks may reduce adverse pregnancy outcomes but is yet to be evaluated in a low and middle-income setting. Prior to designing a randomised controlled trial to evaluate this in India and Zambia, we carried out a 6-month feasibility study in order to better understand the proposed trial environment and guide development of our intervention. METHODS: We used mixed methods to understand the disease burden and current management of pre-eclampsia at our proposed trial sites and explore the acceptability of the intervention. We undertook a case notes review of women with pre-eclampsia who delivered at the proposed trial sites over a 3-month period, alongside facilitating focus group discussions with women and partners and conducting semi-structured interviews with healthcare providers. Descriptive statistics were used to analyse audit data. A thematic framework analysis was used for qualitative data. RESULTS: Case notes data (n = 326) showed that in our settings, 19.5% (n = 44) of women with pre-eclampsia delivering beyond 34 weeks experienced an adverse outcome. In women delivering between 34+0 and 36+6 weeks, there were similar numbers of antenatal stillbirths [n = 3 (3.3%)] and neonatal deaths [n = 3 (3.4%)]; median infant birthweight was 2.2 kg and 1.9 kg in Zambia and India respectively. Lived experience of women and healthcare providers was an important facilitator to the proposed intervention, highlighting the serious consequences of pre-eclampsia. A preference for spontaneous labour and limited neonatal resources were identified as potential barriers. CONCLUSIONS: This study demonstrated a clear need to evaluate the intervention and highlighted several challenges relating to trial context that enabled us to adapt our protocol and design an acceptable intervention. Our study demonstrates the importance of assessing feasibility when developing complex interventions, particularly in a low-resource setting. Additionally, it provides a unique insight into the management of pre-eclampsia at our trial settings and an understanding of the knowledge, attitudes and beliefs underpinning the acceptability of planned early delivery.

Pre-eclampsia is a complication of pregnancy and is one of the major causes of pregnancy-related death and serious illness for women and babies around the world. Most of these deaths occur in lower income countries in Africa and Asia. Signs of pre-eclampsia include high blood pressure and protein in the urine. It is unpredictable and may affect different organs within the woman, leading to seizures, stroke and even death if not well managed. It can also affect the baby's growth and in severe cases lead to stillbirth. We know that birth of the baby (and placenta) is the only cure for pre-eclampsia. Currently, it is recommended by the World Health Organisation that all women with pre-eclampsia are offered planned early birth once they reach 37 weeks of pregnancy, unless they develop severe complications needing intervention sooner than this. However, research from higher income countries has shown that planned early birth from 34 weeks of pregnancy may reduce serious complications in the woman, without causing harm to the baby. We are designing a clinical trial to find out whether, in women with pre-eclampsia between 34 and 37 weeks of pregnancy, it is better to offer planned early birth or to offer close monitoring until either they reach 37 weeks, or a complication develops requiring emergency intervention. Before designing this trial, we carried out a study in order to establish whether the main trial would be possible, and acceptable to the local community, at our potential trial sites in India and Zambia.

Absence of monitoring in withdrawal of clinically-assisted nutrition and hydration (CANH) and other treatments: a cause for concern?

Since 2018, there has been no requirement to bring decisions about the withdrawal of clinically-assisted nutrition and hydration (CANH) in patients with persistent disorders of consciousness before the courts, providing that the requirements of the Mental Capacity Act 2005 (MCA) are fulfilled. Subsequent British Medical Association and Royal College of Physicians guidance on CANH withdrawal recommended standards of record keeping and internal and external audit to ensure local decision making was compliant with the MCA to safeguard patients. The scope of the guidance also included patients with stroke and neurodegenerative disorders.Freedom of Information requests made 2 years after the introduction of this guidance have shown that none of the NHS trusts or clinical commissioning groups who responded were undertaking any systematic monitoring of these decisions. Neither is the Care Quality Commission reviewing these decisions, as there is 'no statutory requirement' to do so. It appears there is a lack of organised scrutiny of these highly complex life-ending treatment decisions. This omission must surely be a cause for concern.

The clock is ticking: using in situ simulation to improve time to blood administration for bleeding trauma patients.

INTRODUCTION: Massive hemorrhage protocols are widely used to facilitate the administration of blood components to bleeding trauma patients. Delays in this process are associated with worse patient outcomes. We used in situ simulation as a novel and iterative quality improvement technique to reduce the mean time between massive hemorrhage protocol activation and blood administration during actual trauma resuscitations. METHODS: We completed monthly, risk-informed unannounced in situ trauma simulations at a Canadian Level 1 trauma centre. We identified three major latent safety threats: (1) massive hemorrhage protocol activation; (2) transport of blood components; and (3) situational awareness of team members. Process improvements for each latent safety threats were tested and implemented during subsequent in situ simulation sessions. We evaluated the effect of this simulation-based intervention on the care of patients before, during and after the intervention. Demographic, clinical and massive hemorrhage protocol data were collected. The primary outcome was mean time between massive hemorrhage protocol activation and blood administration during actual trauma resuscitations as analyzed using a two-sample t test. RESULTS: Each group was similar in demographic and injury characteristics. The time from massive hemorrhage protocol activation to blood administration decreased from 11.6 min pre-intervention to 9.1 min post-intervention. This represented a significant reduction (2.5 min, 95% confidence interval, 0.03-5.08) following the in situ simulation-based quality improvement intervention. CONCLUSIONS: A comprehensive, in situ simulation-based quality improvement project was associated with a significant reduction in the mean time between massive hemorrhage protocol activation and blood administration among injured patients. In situ simulation represents a novel approach to the identification and mitigation of latent safety threats during massive hemorrhage protocol activation.

RéSUMé: INTRODUCTION: Les protocoles d'hémorragie massive sont largement utilisés pour faciliter l'administration de composants sanguins aux patients souffrant de traumatismes hémorragiques. Les retards dans ce processus sont associés à de pires résultats pour les patients. Nous avons utilisé la simulation in situ comme une technique novatrice et itérative d'amélioration de la qualité pour réduire le temps moyen entre l'activation du protocole d'hémorragie massive et l'administration de sang lors des réanimations de traumatismes réels. LES MéTHODES: Nous avons effectué des simulations mensuelles de traumatismes in situ, sans préavis et en tenant compte des risques, dans un centre de traumatologie de niveau 1 au Canada. Nous avons identifié trois grandes menaces latentes pour la sécurité : 1) l'activation du protocole d'hémorragie massive ; 2) le transport de composants sanguins ; et 3) la connaissance de la situation des membres de l'équipe. Des améliorations de processus pour chaque menace latente à la sécurité ont été testées et mises en œuvre lors de séances de simulation in situ subséquentes. Nous avons évalué l'effet de cette intervention basée sur la simulation sur la prise en charge des patients avant, pendant et après l'intervention. Des données démographiques, cliniques et de protocole d'hémorragie massive ont été recueillies. Le critère de jugement principal était le temps moyen entre l'activation du protocole d'hémorragie massive et l'administration de sang pendant les réanimations traumatiques réelles, tel qu'analysé à l'aide d'un test t à deux échantillons. RéSULTATS: Chaque groupe était similaire en termes de caractéristiques démographiques et de blessures. Le temps entre l'activation du protocole d'hémorragie massive et l'administration de sang est passé de 11,6 minutes avant l'intervention à 9,1 minutes après l'intervention. Cela a représenté une réduction significative (2,5 minutes, intervalle de confiance de 95%, 0,03 à 5,08) suite à l'intervention d'amélioration de la qualité basée sur la simulation in situ. CONCLUSIONS: Un projet exhaustif d'amélioration de la qualité basé sur une simulation in situ a été associé à une réduction significative du temps moyen entre l'activation du protocole d'hémorragie massive et l'administration de sang chez les patients blessés. La simulation in situ représente une nouvelle approche pour l'identification et l'atténuation des menaces latentes pour la sécurité lors de l'activation du protocole d'hémorragie massive.

Planned early delivery versus expectant management to reduce adverse pregnancy outcomes in pre-eclampsia in a low- and middle-income setting: study protocol for a randomised controlled trial (CRADLE-4 Trial).

BACKGROUND: Pre-eclampsia is a pregnancy complication characterised by high blood pressure and multi-organ dysfunction in the mother. It is a leading contributor to maternal and perinatal mortality, with 99% of these deaths occurring in low- and middle-income countries (LMIC). Whilst clear guidelines exist for management of early-onset (< 34 weeks) and term (≥ 37 weeks) disease, the optimal timing of delivery in pre-eclampsia between 34+ 0 and 36+ 6 weeks is less clear. In a high-income setting, delivery may improve maternal outcomes without detriment to the baby, but this intervention is yet to be evaluated in LMIC. METHODS: The CRADLE-4 Trial is a non-masked, randomised controlled trial comparing planned early delivery (initiation of delivery within 48 h of randomisation) with routine care (expectant management) in women with pre-eclampsia between 34+ 0 and 36+ 6 weeks' gestation in India and Zambia. The primary objective is to establish whether a policy of planned early delivery can reduce adverse maternal outcomes, without increasing severe neonatal morbidity. DISCUSSION: The World Health Organization recommends delivery for all women with pre-eclampsia from 37 weeks onwards, based on evidence showing clear maternal benefit without increased neonatal risk. Before 34 weeks, watchful waiting is preferred, with delivery recommended only when there is severe maternal or fetal compromise, due to the neonatal risks associated with early preterm delivery. Currently, there is a lack of guidance for clinicians managing women with pre-eclampsia between 34+ 0 and 36+ 6 weeks. Early delivery benefits the mother but may increase the need for neonatal unit admission in the infant (albeit without serious morbidity at this gestation). On the other hand, waiting to deliver may increase the risk of stillbirth, fetal growth restriction and hypoxic brain injury in the neonate as a result of severe maternal complications. This is especially true for LMIC where there is a higher prevalence of adverse events. The balance of risks and benefits therefore needs to be carefully assessed before making firm recommendations. This is the first trial evaluating the optimal timing of delivery in pre-eclampsia in LMIC, where resources and disease burden are considerably different. TRIAL REGISTRATION: ISRCTN 10672137 . Registered on 28 November 2019.

Split-Bolus, Single-Acquisition, Dual-Phase Abdominopelvic CT Angiography for the Evaluation of Lung Transplant Candidates: Image Quality and Resource Utilization.

OBJECTIVE. The purpose of this study was to assess the image quality and resource utilization of single-injection, split-bolus, dual-enhancement abdominopelvic CT angiography (hereafter referred to as dual-enhancement CTA) performed for combined vascular and solid organ assessment compared with those of single-injection, single-enhancement abdominopelvic CT angiography (hereafter referred to as single-enhancement CTA) for vascular assessment in combination with additional examinations (CT, MRI, and US) performed to assess for malignancy in lung transplant candidates. MATERIALS AND METHODS. We retrospectively reviewed 100 patients who underwent abdominopelvic CTA examinations before lung transplant. Cohort A (n = 50) underwent dual-enhancement CTA and cohort B (n = 50) underwent single-enhancement CTA. Contrast opacification of the vasculature was assessed along the abdominal aorta through the right femoral artery. Solid organ enhancement was assessed in the right lobe of the liver and the right renal cortex. Measurements of mean radiation dose, contrast exposure, and cost of the studies (in U.S. dollars) were compared. RESULTS. Mean (± SD) vascular enhancement on dual-enhancement CTA and single-enhancement CTA was 334.2 ± 26.5 HU (coefficient of variation, 8.3%) and 340.0 ± 21.6 HU (coefficient of variation, 6.5%) (p = 0.23), respectively. For dual-enhancement CTA and single-enhancement CTA, mean liver enhancement was 125.8 ± 30.5 HU and 60.4 ± 6.9 HU (p < 0.01), respectively, whereas mean renal cortical enhancement was 260.3 ± 62.2 HU and 133.4 ± 38.6 HU (p < 0.01), respectively. The mean IV contrast volume was 150 mL for dual-enhancement CTA and 75 mL for single-enhancement CTA. Cohort A underwent six additional imaging studies (one of which was a CT colonography study with an effective dose of 19.0 mSv) at a total cost of $9840 per patient. Cohort B underwent 44 additional imaging studies (mean effective dose, 12.7 ± 6.5 mSv) at a total cost of $12,846 per patient (resulting in a 30.6% reduction in cost for dual-enhancement CTA studies; p < 0.0001). CONCLUSION. Dual-enhancement abdominopelvic CTA allows combined vascular and abdominopelvic solid organ assessment with improved image quality and a lower cost compared with traditional imaging pathways.

The Stronger Downregulation of in vitro and in vivo Innate Antiviral Responses by a Very Virulent Strain of Infectious Bursal Disease Virus (IBDV), Compared to a Classical Strain, Is Mediated, in Part, by the VP4 Protein.

IBDV is economically important to the poultry industry. Very virulent (vv) strains cause higher mortality rates than other strains for reasons that remain poorly understood. In order to provide more information on IBDV disease outcome, groups of chickens (n = 18) were inoculated with the vv strain, UK661, or the classical strain, F52/70. Birds infected with UK661 had a lower survival rate (50%) compared to F52/70 (80%). There was no difference in peak viral replication in the bursa of Fabricius (BF), but the expression of chicken IFNα, IFNß, MX1, and IL-8 was significantly lower in the BF of birds infected with UK661 compared to F52/70 (p < 0.05) as quantified by RTqPCR, and this trend was also observed in DT40 cells infected with UK661 or F52/70 (p < 0.05). The induction of expression of type I IFN in DF-1 cells stimulated with polyI:C (measured by an IFN-ß luciferase reporter assay) was significantly reduced in cells expressing ectopic VP4 from UK661 (p < 0.05), but was higher in cells expressing ectopic VP4 from F52/70. Cells infected with a chimeric recombinant IBDV carrying the UK661-VP4 gene in the background of PBG98, an attenuated vaccine strain that induces high levels of innate responses (PBG98-VP4UK661) also showed a reduced level of IFNα and IL-8 compared to cells infected with a chimeric virus carrying the F52/70-VP4 gene (PBG98-VP4F52/70) (p < 0.01), and birds infected with PBG98-VP4UK661 also had a reduced expression of IFNα in the BF compared to birds infected with PBG98-VP4F52/70 (p < 0.05). Taken together, these data demonstrate that UK661 induced the expression of lower levels of anti-viral type I IFN and proinflammatory genes than the classical strain in vitro and in vivo and this was, in part, due to strain-dependent differences in the VP4 protein.

Discrete Virus Factories Form in the Cytoplasm of Cells Coinfected with Two Replication-Competent Tagged Reporter Birnaviruses That Subsequently Coalesce over Time.

The Birnaviridae family, responsible for major economic losses to poultry and aquaculture, is composed of nonenveloped viruses with a segmented double-stranded RNA (dsRNA) genome that replicate in discrete cytoplasmic virus factories (VFs). Reassortment is common; however, the underlying mechanism remains unknown given that VFs may act as a barrier to genome mixing. In order to provide new information on VF trafficking during dsRNA virus coinfection, we rescued two recombinant infectious bursal disease viruses (IBDVs) of strain PBG98 containing either a split GFP11 or a tetracysteine (TC) tag fused to the VP1 polymerase (PBG98-VP1-GFP11 and PBG98-VP1-TC). DF-1 cells transfected with GFP1-10 prior to PBG98-VP1-GFP11 infection or stained with a biarsenical derivative of the red fluorophore resorufin (ReAsH) following PBG98-VP1-TC infection, had green or red foci in the cytoplasm, respectively, that colocalized with VP3 and dsRNA, consistent with VFs. The average number of VFs decreased from a mean of 60 to 5 per cell between 10 and 24 h postinfection (hpi) (P < 0.0001), while the average area increased from 1.24 to 45.01 µm2 (P < 0.0001), and live cell imaging revealed that the VFs were highly dynamic structures that coalesced in the cytoplasm. Small VFs moved faster than large (average 0.57 µm/s at 16 hpi compared to 0.22 µm/s at 22 hpi), and VF coalescence was dependent on an intact microtubule network and actin cytoskeleton. During coinfection with PBG98-VP1-GFP11 and PBG98-VP1-TC viruses, discrete VFs initially formed from each input virus that subsequently coalesced 10 to 16 hpi, and we speculate that Birnaviridae reassortment requires VF coalescence.IMPORTANCE Reassortment is common in viruses with segmented double-stranded RNA (dsRNA) genomes. However, these viruses typically replicate within discrete cytoplasmic virus factories (VFs) that may represent a barrier to genome mixing. We generated the first replication competent tagged reporter birnaviruses, infectious bursal disease viruses (IBDVs) containing a split GFP11 or tetracysteine (TC) tag and used the viruses to track the location and movement of IBDV VFs, in order to better understand the intracellular dynamics of VFs during a coinfection. Discrete VFs initially formed from each virus that subsequently coalesced from 10 h postinfection. We hypothesize that VF coalescence is required for the reassortment of the Birnaviridae This study provides new information that adds to our understanding of dsRNA virus VF trafficking.

Depression, Immunosuppressant Levels, and Clinical Outcomes in Postlung Transplant Recipients.

OBJECTIVE: Posttransplant depression has been linked to increased risk for adverse outcomes in lung transplant patients. Maintaining target serum immunosuppressant levels is also essential for optimal lung transplant clinical outcome and may be a crucial predictor of outcomes. Because depression could affect medication nonadherence, resulting in out-of-range immunosuppressant levels, we examined the relationship between posttransplant depression, immunosuppressant medication trough level variability, indexed by out-of-range values on clinical outcomes and coefficient of variability, and clinical outcomes. METHOD: A consecutive series of 236 lung transplant recipients completed the Center for Epidemiological Studies-Depression two-month posttransplant. Immunosuppressant trough levels (i.e., tacrolimus or cyclosporine) within the range of individualized immunosuppressant targets were obtained at three-, six-, nine-month follow-up clinic visits. Clinical outcomes including hospitalizations and mortality were obtained from medical records. RESULTS: Fourteen percent of patients were classified as depressed (Center for Epidemiological Studies-Depression ≥16), 144 (61%) of patients had at least 25% out-of-range immunosuppressant values, and the average coefficient of variability was 36%. Over a median of 2.6 years (interquartile range = 1.2), 32 participants died (14%) and 144 (61%) had at least one unplanned, transplant-related hospitalization. Both depression (hazard ratio = 1.45 (1.19, 1.76), p < . 01) and immunosuppressant variation (immunosuppressant out-of-range: hazard ratio = 1.41 (1.10, 1.81), p < .01) independently predicted more frequent hospitalizations and higher mortality. CONCLUSIONS: Early posttransplant depression was associated with significantly worse clinical outcomes. While immunosuppressant level variability is also related to adverse outcomes, such variability does not account for increased risk observed with depression.