External validation of the computer aided risk scoring system in predicting in-hospital mortality following emergency medical admissions.

BACKGROUND: Clinical prediction models have the potential to improve the quality of care and enhance patient safety outcomes. A Computer-aided Risk Scoring system (CARSS) was previously developed to predict in-hospital mortality following emergency admissions based on routinely collected blood tests and vitals. We aimed to externally validate the CARSS model. METHODS: In this retrospective external validation study, we considered all adult (≥18 years) emergency medical admissions discharged between 11/11/2020 and 11/11/2022 from The Rotherham Foundation Trust (TRFT), UK. We assessed the predictive performance of the CARSS model based on its discriminative (c-statistic) and calibration characteristics (calibration slope and calibration plots). RESULTS: Out of 32,774 admissions, 20,422 (62.3 %) admissions were included. The TRFT sample had similar demographic characteristics to the development sample but had higher mortality (6.1 % versus 5.7 %). The CARSS model demonstrated good discrimination (c-statistic 0.87 [95 % CI 0.86-0.88]) and good calibration to the TRFT dataset (slope = 1.03 [95 % CI 0.98-1.08] intercept = 0 [95 % CI -0.06-0.07]) after re-calibrating for differences in baseline mortality (intercept = 0.96 [95 % CI 0.90-1.03] before re-calibration). CONCLUSION: In summary, the CARSS model is externally validated after correcting the baseline risk of death between development and validation datasets. External validation of the CARSS model showed that it under-predicted in-hospital mortality. Re-calibration of this model showed adequate performance in the TRFT dataset.

Quantifying the carbon footprint of clinical trials: guidance development and case studies.

BACKGROUND: The urgency of the climate crisis requires attention from biomedical research, not least clinical trials which can involve significant greenhouse gas emissions. The Low Carbon Clinical Trials Working Group set out a strategy to reduce the emissions of clinical trials, starting with the development of a method to measure their carbon footprint (CO2e). METHODS: As a first step, we developed a process map defining clinical trial core activities. Corresponding emission factors were sourced to convert activity data into greenhouse gas emissions. The subsequent method was applied to two Cancer Research UK (CRUK)-funded trials (the international randomised sarcoma trial CASPS (ISRCTN63733470) and the UK cohort-based breast cancer trial PRIMETIME (ISRCTN41579286)). A guidance document defining the scope, method and assumptions was written to allow application to any publicly funded/investigator initiated clinical trial. RESULTS: Trial specific activities over and above routine care were grouped into 10 modules covering trial set up, conduct and closure. We identified emission factors for all trial activities within both trials and used them to estimate their total carbon footprint. The carbon footprint of CASPS, an international phase 2 trial of an investigational medicinal product with 47 participants, was 72 tonnes CO2e, largely attributable to clinical trials unit emissions and staff travel. PRIMETIME, a UK-based phase 3 non-investigational medicinal product trial with 1962 patients, produced 89 tonnes CO2e, largely attributable to trial-specific in-person participant assessments. CONCLUSION: We have developed a method and guidance that trialists can use to determine the carbon footprint of clinical trials. The guidance can be used to identify carbon hotspots where alternative approaches to trial design and conduct could reduce a trial footprint, and where methodology research is required to investigate the potential impact of interventions taken to reduce carbon emissions. We will continue to refine the guidance to increase the potential application and improve usability.

Equality, diversity, and inclusion in oncology clinical trials: an audit of essential documents and data collection against INCLUDE under-served groups in a UK academic trial setting.

BACKGROUND: Clinical trials should be as inclusive as possible to facilitate equitable access to research and better reflect the population towards which any intervention is aimed. Informed by the UK's National Institute for Health and Care Research (NIHR) Innovations in Clinical Trial Design and Delivery for the Under-served (INCLUDE) guidance, we audited oncology trials conducted by the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London (ICR-CTSU) to identify whether essential documents were overtly excluding any groups and whether sufficient data were collected to assess diversity of trial participants from groups suggested by INCLUDE as under-served by research in the UK. METHODS: Thirty cancer clinical trials managed by ICR-CTSU and approved between 2011-2021 were audited. The first ethics approved version of each trial's protocol, patient information sheet, and patient completed questionnaire, together with the first case report forms (CRFs) version were reviewed. A range of items aligned with the INCLUDE under-served groups were assessed, including age, sex and gender, socio-economic and health factors. The scope did not cover trial processes in participating hospitals. RESULTS: Data relating to participants' age, ethnic group and health status were well collected and no upper age limit was specified in any trials' eligibility criteria. 23/30 (77%) information sheets used at least one gendered term to address patients. Most CRFs did not specify whether they were collecting sex or gender and only included male or female categories. The median reading age for information sheets was 15-16 years (IQR: 14-15 - 16-17). Socio-economic factors were not routinely collected and not commonly mentioned in trial protocols. CONCLUSIONS: No systemic issues were identified in protocols which would explicitly prevent any under-served group from participating. Areas for improvement include reducing use of gendered words and improving readability of patient information. The challenge of fully assessing adequate inclusion of under-served populations remains, as socio-economic factors are not routinely collected because they fall beyond the data generally required for protocol-specified trial endpoint assessments. This audit has highlighted the need to agree and standardise demographic data collection to permit adequate monitoring of the under-served groups identified by the NIHR.

Upstreamist leaders: how risk factors for unscheduled return visits (URV) to the emergency department can inform integrated healthcare.

PURPOSE: This paper aims to report on research undertaken in an National Health Service (NHS) emergency department in the north of England, UK, to identify which patients, with which clinical conditions are returning to the emergency department with an unscheduled return visit (URV) within seven days. This paper analyses the data in relation to the newly introduced Integrated Care Boards (ICBs). The continued upward increase in demand for emergency care services requires a new type of "upstreamist", health system leader from the emergency department, who can report on URV data to influence the development of integrated care services to reduce further demand on the emergency department. DESIGN/METHODOLOGY/APPROACH: Patients were identified through the emergency department symphony data base and included patients with at least one return visit to emergency department (ED) within seven days. A sample of 1,000 index visits between 1 January 2019-31 October 2019 was chosen by simple random sampling technique through Excel. Out of 1,000, only 761 entries had complete data in all variables. A statistical analysis was undertaken using Poisson regression using NCSS statistical software. A review of the literature on integrated health care and its relationship with health systems leadership was undertaken to conceptualise a new type of "upstreamist" system leadership to advance the integration of health care. FINDINGS: Out of all 83 variables regressed with statistical analysis, only 12 variables were statistically significant on multi-variable regression. The most statistically important factor were patients presenting with gynaecological disorders, whose relative rate ratio (RR) for early-URV was 43% holding the other variables constant. Eye problems were also statistically highly significant (RR = 41%) however, clinically both accounted for just 1% and 2% of the URV, respectively. The URV data combined with "upstreamist" system leadership from the ED is required as a critical mechanism to identify gaps and inform a rationale for integrated care models to lessen further demand on emergency services in the ED. RESEARCH LIMITATIONS/IMPLICATIONS: At a time of significant pressure for emergency departments, there needs to be a move towards more collaborative health system leadership with support from statistical analyses of the URV rate, which will continue to provide critical information to influence the development of integrated health and care services. This study identifies areas for further research, particularly for mixed methods studies to ascertain why patients with specific complaints return to the emergency department and if alternative pathways could be developed. The success of the Esther model in Sweden gives hope that patient-centred service development could create meaningful integrated health and care services. PRACTICAL IMPLICATIONS: This research was a large-scale quantitative study drawing upon data from one hospital in the UK to identify risk factors for URV. This quality metric can generate important data to inform the development of integrated health and care services. Further research is required to review URV data for the whole of the NHS and with the new Integrated Health and Care Boards, there is a new impetus to push for this metric to provide robust data to prioritise the need to develop integrated services where there are gaps. ORIGINALITY/VALUE: To the best of the authors' knowledge, this is the first large-scale study of its kind to generate whole hospital data on risk factors for URVs to the emergency department. The URV is an important global quality metric and will continue to generate important data on those patients with specific complaints who return back to the emergency department. This is a critical time for the NHS and at the same time an important opportunity to develop "Esther" patient-centred approaches in the design of integrated health and care services.

What is the purpose of clinical trial monitoring?

BACKGROUND: The sources of information on clinical trial monitoring do not give information in an accessible language and do not give detailed guidance. In order to enable communication and to build clinical trial monitoring tools on a strong easily communicated foundation, we identified the need to define monitoring in accessible language. METHODS: In a three-step process, the material from sources that describe clinical trial monitoring were synthesised into principles of monitoring. A poll regarding their applicability was run at a UK national academic clinical trials monitoring meeting. RESULTS: The process derived 5 key principles of monitoring: keeping participants safe and respecting their rights, having data we can trust, making sure the trial is being run as it was meant to be, improving the way the trial is run and preventing problems before they happen. CONCLUSION: From the many sources mentioning monitoring of clinical trials, the purpose of monitoring can be summarised simply as 5 principles. These principles, given in accessible language, should form a firm basis for discussion of monitoring of clinical trials.

Monitoring advances including consent: learning from COVID-19 trials and other trials running in UKCRC registered clinical trials units during the pandemic.

The COVID-19 pandemic has affected how clinical trials are managed, both within existing portfolios and for the rapidly developed COVID-19 trials. Sponsors or delegated organisations responsible for monitoring trials have needed to consider and implement alternative ways of working due to the national infection risk necessitating restricted movement of staff and public, reduced clinical staff resource as research staff moved to clinical areas, and amended working arrangements for sponsor and sponsor delegates as staff moved to working from home.Organisations have often worked in isolation to fast track mitigations required for the conduct of clinical trials during the pandemic; this paper describes many of the learnings from a group of monitoring leads based in United Kingdom Clinical Research Collaboration (UKCRC) Clinical Trials Unit (CTUs) within the UK.The UKCRC Monitoring Task and Finish Group, comprising monitoring leads from 9 CTUs, met repeatedly to identify how COVID-19 had affected clinical trial monitoring. Informed consent is included as a specific issue within this paper, as review of completed consent documentation is often required within trial monitoring plans (TMPs). Monitoring is defined as involving on-site monitoring, central monitoring or/and remote monitoring.Monitoring, required to protect the safety of the patients and the integrity of the trial and ensure the protocol is followed, is often best done by a combination of central, remote and on-site monitoring. However, if on-site monitoring is not possible, workable solutions can be found using only central or central and remote monitoring. eConsent, consent by a third person, or via remote means is plausible. Minimising datasets to the critical data reduces workload for sites and CTU staff. Home working caused by COVID-19 has made electronic trial master files (TMFs) more inviting. Allowing sites to book and attend protocol training at a time convenient to them has been successful and worth pursuing for trials with many sites in the future.The arrival of COVID-19 in the UK has forced consideration of and changes to how clinical trials are conducted in relation to monitoring. Some developed practices will be useful in other pandemics and others should be incorporated into regular use.

Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial.

Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas.

Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial.

BACKGROUND: Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS. METHODS: In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing. FINDINGS: Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34·3 months (IQR 23·7-55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8·3% (IQR -26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase. INTERPRETATION: Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. FUNDING: Cancer Research UK and AstraZeneca.

Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.

Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.

Lung ultrasound immediately after birth to describe normal neonatal transition: an observational study.

OBJECTIVE: Lung ultrasound (LUS) has shown promise as a diagnostic tool for the evaluation of the newborn with respiratory distress. No study has described LUS during 'normal' transition. Our goal was to characterise the appearance of serial LUS in healthy newborns from the first minutes after birth until airway liquid clearance is achieved. STUDY DESIGN: Prospective observational study. SETTING: Single-centre tertiary perinatal centre in Australia. PATIENTS: Of 115 infants born at ≥35 weeks gestational age, mean (SD) gestational age of 386/7 weeks±11 days, mean birth weight of 3380±555 g, 51 were delivered vaginally, 14 via caesarean section (CS) after labour and 50 infants via elective CS. INTERVENTIONS: We obtained serial LUS videos via the right and left axillae at 1-10 min, 11-20 min and 1, 2, 4 and 24 hours after birth. MAIN OUTCOME MEASURES: LUS videos were graded for aeration and liquid clearance according to a previously validated system. RESULTS: We analysed 1168 LUS video recordings. As assessed by LUS, lung aeration and airway liquid clearance occurred quickly. All infants had an established pleural line at the first examination (median=2 (1-4) min). Only 14% of infants had substantial liquid retention at 10 min after birth. 49%, 78% and 100% of infants had completed airway liquid clearance at 2, 4 and 24 hours, respectively. CONCLUSIONS: In healthy transitioning newborn infants, lung aeration and partial liquid clearance are achieved on the first minutes after birth with complete liquid clearance typically achieved within the first 4 hours of birth. TRIAL REGISTRATION NUMBER: ANZCT 12615000380594.

Conducting non-commercial international clinical trials: the ICR-CTSU experience.

BACKGROUND: Academic clinical trials play a fundamental role in the development of new treatments, the repurposing of existing treatments and in addressing areas of unmet clinical need. With cancer treatments increasingly targeted at molecular subtypes, and with priority placed on developing new treatments for rare tumour types, the need for international trial participation to access sufficient patient numbers for successful trial conduct is growing. However, lack of harmonisation of international legal, ethical and financial systems can make this challenging and the cost and effort of conducting trials internationally can be considered prohibitive, particularly where the sample size is comparatively small. METHODS: The Institute of Cancer Research - Clinical Trials and Statistics Unit (ICR-CTSU) is a UK-based academic clinical trials unit that specialises in the design, conduct and analysis of clinical trials of cancer treatments with an expanding portfolio of trials in molecular subtypes of breast and urological cancers and in other rare cancer types. Implementing appropriate mechanisms to enable international participation has therefore been imperative. In this article, we explain how we have approached the challenges involved and describe examples of successful international trial conduct, achieved through robust collaborations with academic and industry partners. CONCLUSION: Conducting academic trials internationally is challenging but can and should be achieved through appropriate governance mechanisms and strong collaborations.

Lung ultrasound during the initiation of breathing in healthy term and late preterm infants immediately after birth, a prospective, observational study.

INTRODUCTION: Lung ultrasound (LUS) has shown promise for evaluation of newborns with respiratory distress. However, no study has described the appearance of LUS during the initiation of breathing. We used LUS to describe the appearance of the lungs in healthy infants immediately after birth, starting with the infant's first breath, through the first 20min after birth. METHODS: This was a single-center observational study enrolling neonates born at ≥35 weeks. We obtained LUS video recordings with the initiation of breathing. Recordings that captured one of the 1st four breaths after birth were included. We also obtained recordings at 1-10 and 11-20min after birth. Recordings were graded using a modified version of a previously published system, with additional grades to describe the appearance of the lungs prior to establishment of the pleural line. RESULTS: We studied 63 infants, mean gestational age=391/7±2 days, mean weight=3473g±422, 33 infants were delivered vaginally and 30 via cesarean section. We captured the first breath after birth in 28 infants and within the first four breaths from the remaining 35 infants. The pleural line was established by a median of 4 breaths (3-6). At the 1-10min examination, all infants had an established pleural line and 89% demonstrated substantial liquid clearance. At the 11-20min examination, all infants had substantial liquid clearance. CONCLUSION: Establishment of the pleural line, indicating lung aeration and substantial liquid clearance is achieved with the first few breaths after birth in term and near term infants.

Cognitive Coping Style and the Effectiveness of Distraction or Sensation-Focused Instructions in Chronic Pain Patients.

AIM: This study set out to investigate whether cognitive coping strategies that match participants' preferred coping style effectively reduce pain intensity and situational anxiety in a population of people with chronic pain. METHOD: Chronic pain patients (N = 43) completed questionnaires on coping style, pain intensity, self-efficacy, and situational/trait anxiety. Participants were classified as Monitors (n = 16) or Blunters (n = 19) based on their Miller Behavioural Style Scale score. Participants were then provided with an audiotaped intervention in which they were instructed to focus on pain sensations or to engage in a distraction task and then to rate the pain intensity and their anxiety during and after the attentional focus and distraction conditions. The two interventions were each completed by all participants, having been presented in counterbalanced order. RESULTS: Findings revealed that Monitors' level of anxiety decreased following a congruent (i.e., sensation-focused) intervention. No effects were obtained in terms of perceived pain. For blunters, however, their perceived levels of anxiety and pain did not attenuate following a congruent, distraction-focused intervention. CONCLUSION: Among persons experiencing chronic pain, tailoring coping strategies to match an individual's preferred coping style--in particular, those with a high level of monitoring--may enhance the benefit of psychological approaches to management of anxiety.

Challenges of neurodevelopmental follow-up for extremely preterm infants at two years.

AIM: This study examined the rates of follow-up for a cohort of extremely preterm (EP -<28weeks gestation) and/or extremely low birthweight (ELBW -<1000g) children at two years with related perinatal and geographical factors. The secondary aim was to determine the rates of developmental delay and disability. METHODS: A retrospective review of two year follow-up data for all EP and/or ELBW infants born in a large tertiary neonatal hospital over a two year period was undertaken. Neurodevelopmental outcome was assessed using the Bayley Scales of Infant and Toddler Development Scale - 3rd edition (Bayley-III) and neurosensory disability was assessed by a paediatrician using a standard proforma. Rates of delay (composite score≥1SD below mean) were determined using the Bayley-III test norms and a local cohort normative group. Attrition rates and reasons for loss to follow-up were determined. RESULTS: Only 50% (109/219) of eligible children participated in the follow-up. The follow-up rate for children engaged in an ongoing research project was excellent at 98% (58/59), however it was only 32% (51/160) for children following the clinical pathway. The main reason for not attending the follow-up was loss of contact. Factors associated with attendance included a lower gestation, sepsis and living in the metropolitan areas. The rates of delay in this cohort were greater with reference to local cohort normative data compared to Bayley-III test norms with an overall rate of delay of 72% (95%CI, 63% to 81%) compared to 38% (95%CI, 29% to 50%). CONCLUSIONS: Follow-up of EP/ELBW infants to two years is an important part of clinical care, however the high rate of attrition in routine clinical follow-up and consequent difficulty in accurately determining rates of delay highlight challenges for centres providing ongoing care.

Notes from the Field: Tickborne Relapsing Fever Outbreak at an Outdoor Education Camp - Arizona, 2014.

Tickborne relapsing fever (TBRF) is a bacterial infection characterized by recurring episodes of fever, headache, muscle and joint aches, and nausea. In North America, TBRF primarily is caused by Borrelia hermsii spirochetes transmitted by Ornithodoros hermsii ticks. Once infected, these soft ticks are infectious for life and transmit the spirochete to sleeping humans quickly (possibly within 30 seconds) during short feeds (15-90 minutes). On August 10, 2014, the Coconino County Public Health Services District in Arizona was notified by a local hospital that five high school students who attended the same outdoor education camp had been hospitalized with fever, headache, and myalgias. Hantavirus infection initially was suspected because of reported exposure to rodent droppings, but after detecting spirochetes on peripheral blood smears from all five hospitalized students, TBRF was diagnosed. The camp was instructed to close immediately, and the health department, in collaboration with local university experts, investigated to identify additional cases, determine the cause, and prevent further infections. A total of 11 cases (six confirmed and five probable) were identified.

Evaluation of calibration curve-based approaches to predict clinical inducers and noninducers of CYP3A4 with plated human hepatocytes.

Cytochrome P450 (P450) induction is often considered a liability in drug development. Using calibration curve-based approaches, we assessed the induction parameters R3 (a term indicating the amount of P450 induction in the liver, expressed as a ratio between 0 and 1), relative induction score, Cmax/EC50, and area under the curve (AUC)/F2 (the concentration causing 2-fold increase from baseline of the dose-response curve), derived from concentration-response curves of CYP3A4 mRNA and enzyme activity data in vitro, as predictors of CYP3A4 induction potential in vivo. Plated cryopreserved human hepatocytes from three donors were treated with 20 test compounds, including several clinical inducers and noninducers of CYP3A4. After the 2-day treatment, CYP3A4 mRNA levels and testosterone 6ß-hydroxylase activity were determined by real-time reverse transcription polymerase chain reaction and liquid chromatography-tandem mass spectrometry analysis, respectively. Our results demonstrated a strong and predictive relationship between the extent of midazolam AUC change in humans and the various parameters calculated from both CYP3A4 mRNA and enzyme activity. The relationships exhibited with non-midazolam in vivo probes, in aggregate, were unsatisfactory. In general, the models yielded better fits when unbound rather than total plasma Cmax was used to calculate the induction parameters, as evidenced by higher R(2) and lower root mean square error (RMSE) and geometric mean fold error. With midazolam, the R3 cut-off value of 0.9, as suggested by US Food and Drug Administration guidance, effectively categorized strong inducers but was less effective in classifying midrange or weak inducers. This study supports the use of calibration curves generated from in vitro mRNA induction response curves to predict CYP3A4 induction potential in human. With the caveat that most compounds evaluated here were not strong inhibitors of enzyme activity, testosterone 6ß-hydroxylase activity was also demonstrated to be a strong predictor of CYP3A4 induction potential in this assay model.

The relationship between ventricular size at 1 month and outcome at 2 years in infants less than 30 weeks' gestation.

BACKGROUND: Cranial ultrasound cerebral biometric measurements have been used in preterm neonates, particularly in cases of ventriculomegaly. While cerebral biometric measures using MRI have been found to correlate with long-term outcome, the relationship between cranial ultrasound biometric measures and neurodevelopmental outcome has not been established. OBJECTIVE: To assess the relationship between ventricular size at 1 month of age using cranial ultrasound and neurodevelopmental outcome at 2 years in very preterm infants. METHOD: Digital cranial ultrasound images taken between 25 and 35 days of age of 44 infants born at less than 30 weeks' gestation were analysed independently by two observers. Infants with significant ultrasound abnormalities were excluded. A range of ultrasound linear measures were correlated with Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) motor, language and cognitive composite scores at 2 years using linear regression. RESULTS: Larger lateral ventricular sizes (anterior horn width, ventricular height, midbody ventricular height) and larger ventricular-brain biparietal ratios were related to poorer motor composite score at 2 years. A ventricular-brain ratio of less than 0.3 was reassuring with regard to motor outcome. Poorer language composite scores at 2 years were associated with larger midbody ventricular heights. There was little evidence of a relationship with the cognitive composite score. CONCLUSIONS: Larger lateral ventricles in the parietal region at a month of age were related to poorer motor development at 2 years. Larger ventricular measurements were also related to slower early language development. The role of cranial ultrasound biometric measures as biomarkers of later outcome in very preterm infants warrants further investigation.

Clinical nurse specialists leading research to improve practice in the use of ankle blood pressure readings.

PURPOSE: The purpose of this article is to describe Clinical Nurse Specialist (CNS) practice as it relates to leadership in clinical research through the presentation of a study on ankle blood pressure (BP) measurements led by the CNS. BACKGROUND: Under the direction of the CNS, staff nurses engaged in the EBP process to explore the association between arm and ankle BP measurements. This EBP project led to a research study which was directed and led by the CNS. RATIONALE: CNS practice requires leadership in the areas of evidence-based practice and research. CNS leadership was critical to the success of the research project. DESCRIPTION: A descriptive study was undertaken which examined the agreement between upper extremity BP readings and ankle BP readings by comparing a series of three simultaneous ankle and arm BP readings on 174 subjects. CONCLUSION: Leading the research project elevated the CNS's visibility and influence within the organization by clearly demonstrating the value of the CNS in the research process and the impact nursing research has on nursing practice and patient outcomes.

Outcomes of preterm infants receiving positive pressure support at term corrected gestation.

AIM: To establish the mortality rate to hospital discharge of very preterm infants who remain on positive pressure support (PPS) at term corrected gestation and describe factors that are associated with increased mortality. METHODS: Infants born <30 weeks' gestation between 1 January 2001 and 31 December 2009 who were receiving PPS at 40 weeks' postmenstrual age (PMA) were identified from our database, and their medical records reviewed. The fraction of inspired oxygen (FiO2 ), mean airway pressure and partial pressure of carbon dioxide (PaCO2 ) at 40 weeks' PMA were recorded. Receiver operating characteristic curves for mortality before discharge were generated. RESULTS: One thousand three hundred fifty-nine of 1572 infants survived to term. Forty-nine infants were receiving PPS at 40 weeks' PMA. Of these, 15 (31%) infants died before hospital discharge. All three infants who were ventilated via an endotracheal tube died. Increased oxygen requirement at term was associated with increased risk of death before discharge (area under curve (AUC) 0.75). FiO2 > 0.5 was associated with an 80% risk of death. PaCO2 was not predictive of death (AUC 0.49). CONCLUSIONS: Two thirds of very preterm infants who remained on PPS at 40 weeks' PMA survived to hospital discharge. Risk of death rises with increasing oxygen requirements. All five infants with FiO2 > 0.70 died.

Neonatal exchange transfusions in the 21st century: a single hospital study.

AIM: In the 21st century, neonatal exchange transfusions (ETs) are uncommon procedures usually performed in tertiary neonatal units. As junior clinical staff now lack familiarity with the procedure, it is important to maintain awareness of its complications in order to manage clinical risks and counsel parents appropriately. The study aims to analyse the ET rate, its indications and its associated complications, in a single tertiary centre in the 21st century. METHODS: This is a retrospective cohort study of all infants receiving ET from 1 January 2001 to 31 December 2010 at the Royal Women's Hospital, Melbourne. RESULTS: Sixty-four ETs were performed in 51 infants, an average of 6.4 ETs per year. Forty-nine (96%) infants were exchanged for hyperbilirubinaemia and two (4%) for anaemia. Thirty-six (71%) infants had Rhesus haemolytic disease of the newborn and six (12%) had ABO incompatibility. Six infants were intubated and mechanically ventilated after ET; these infants were significantly more acidotic during the ET than those who were never on respiratory support (mean pH 7.153 and 7.309 respectively, mean difference -0.156, 95% CI -0.196 to -0.116, t = 7.85, P < 0.001). Overall mortality was 8% (n = 4). CONCLUSIONS: Our current ET rate is very low compared with historical data. It is difficult to ascribe mortality and morbidity directly to ET as the procedure is now often performed on smaller, sicker or more premature infants whose risks of mortality and morbidity are high regardless of ET. Prospective multi-centre studies are needed to provide adequate data to analyse complications in greater detail.