Practicing health equity in involuntary discharges to overcome disparities in dialysis and kidney patient care.

PURPOSE OF REVIEW: Potential causes and consequences of involuntary discharge (IVD) of patients from dialysis facilities are widely unknown. So, also are the extent of racial disparities in IVDs and their impact on health equity. RECENT FINDINGS: Under the current End-Stage Renal Disease (ESRD) programConditions for Coverage (CFC), there are limited justifications for IVDs. The ESRD Networks oversee dialysis quality and safety including IVDs in US dialysis facilities, with support from the Agency for Healthcare Quality and Research (AHRQ) and other stakeholders. Whereas black Americans constitute a third of US dialysis patients, they are even more overrepresented in the planned and executed IVDs. Cultural gaps between patients and dialysis staff, psychosocial and regional factors, structural racism in kidney care, antiquated ESRD policies, unintended consequences of quality incentive programs, other perverse incentives, and failed patient-provider communications are among potential contributors to IVDs. SUMMARY: Practicing health equity in kidney care may be negatively impacted by IVDs. Accurate analyses of patterns and trends of involuntary discharges, along with insights from well designed AHRQ surveys and qualitative research with mixed method approaches are urgently needed. Pilot and feasibility programs should be designed and tested, to address the root causes of IVDs and related racial disparities.

Designing Interventions Addressing Structural Racism to Reduce Kidney Health Disparities: A Report from an NIDDK Workshop.

Structural racism embodies the many ways in which society fosters racial discrimination through "mutually reinforcing inequitable systems" that limit access to resources and opportunities that can promote health and well-being among marginalized communities. To achieve health equity, and kidney health equity more specifically, structural racism must be eliminated. In February 2022, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) convened the "Designing Interventions that Address Structural Racism to Reduce Kidney Health Disparities" workshop which was aimed at describing the mechanisms through which structural racism contributes to health and healthcare disparities for people along the continuum of kidney disease; and identifying actionable opportunities for interventional research focused on dismantling or addressing the effects of structural racism. Participants identified six domains as key targets for interventions and future research: 1) apply an anti-racism lens, 2) promote structural interventions, 3) target multiple levels, 4) promote effective community and stakeholder engagement, 5) improve data collection, and 6) advance health equity through new healthcare models. There exists an urgent need for research to develop, implement and evaluate interventions that address the unjust systems, policies, and laws that generate and perpetuate inequities in kidney health.

Designing Interventions Addressing Structural Racism to Reduce Kidney Health Disparities: A Report from a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

Structural racism embodies the many ways in which society fosters racial discrimination through "mutually reinforcing inequitable systems" that limit access to resources and opportunities that can promote health and well being among marginalized communities. To achieve health equity, and kidney health equity more specifically, structural racism must be eliminated. In February 2022, the National Institute of Diabetes and Digestive and Kidney Diseases convened the "Designing Interventions that Address Structural Racism to Reduce Kidney Health Disparities" workshop, which was aimed at describing the mechanisms through which structural racism contributes to health and health care disparities for people along the continuum of kidney disease and identifying actionable opportunities for interventional research focused on dismantling or addressing the effects of structural racism. Participants identified six domains as key targets for interventions and future research: (1) apply an antiracism lens, (2) promote structural interventions, (3) target multiple levels, (4) promote effective community and stakeholder engagement, (5) improve data collection, and (6) advance health equity through new health care models. There is an urgent need for research to develop, implement, and evaluate interventions that address the unjust systems, policies, and laws that generate and perpetuate inequities in kidney health.

Development, implementation and evaluation of an evidence-based paediatric early warning system improvement programme: the PUMA mixed methods study.

BACKGROUND: Paediatric mortality rates in the United Kingdom are amongst the highest in Europe. Clinically missed deterioration is a contributory factor. Evidence to support any single intervention to address this problem is limited, but a cumulative body of research highlights the need for a systems approach. METHODS: An evidence-based, theoretically informed, paediatric early warning system improvement programme (PUMA Programme) was developed and implemented in two general hospitals (no onsite Paediatric Intensive Care Unit) and two tertiary hospitals (with onsite Paediatric Intensive Care Unit) in the United Kingdom. Designed to harness local expertise to implement contextually appropriate improvement initiatives, the PUMA Programme includes a propositional model of a paediatric early warning system, system assessment tools, guidance to support improvement initiatives and structured facilitation and support. Each hospital was evaluated using interrupted time series and qualitative case studies. The primary quantitative outcome was a composite metric (adverse events), representing the number of children monthly that experienced one of the following: mortality, cardiac arrest, respiratory arrest, unplanned admission to Paediatric Intensive Care Unit, or unplanned admission to Higher Dependency Unit. System changes were assessed qualitatively through observations of clinical practice and interviews with staff and parents. A qualitative evaluation of implementation processes was undertaken. RESULTS: All sites assessed their paediatric early warning systems and identified areas for improvement. All made contextually appropriate system changes, despite implementation challenges. There was a decline in the adverse event rate trend in three sites; in one site where system wide changes were organisationally supported, the decline was significant (ß = -0.09 (95% CI: - 0.15, - 0.05); p = < 0.001). Changes in trends coincided with implementation of site-specific changes. CONCLUSIONS: System level change to improve paediatric early warning systems can bring about positive impacts on clinical outcomes, but in paediatric practice, where the patient population is smaller and clinical outcomes event rates are low, alternative outcome measures are required to support research and quality improvement beyond large specialist centres, and methodological work on rare events is indicated. With investment in the development of alternative outcome measures and methodologies, programmes like PUMA could improve mortality and morbidity in paediatrics and other patient populations.

A prospective, mixed-methods, before and after study to identify the evidence base for the core components of an effective Paediatric Early Warning System and the development of an implementation package containing those core recommendations for use in the UK: Paediatric early warning system - utilisation and mortality avoidance- the PUMA study protocol.

BACKGROUND: In hospital, staff need to routinely monitor patients to identify those who are seriously ill, so that they receive timely treatment to improve their condition. A Paediatric Early Warning System is a multi-faceted socio-technical system to detect deterioration in children, which may or may not include a track and trigger tool. It functions to monitor, detect and prompt an urgent response to signs of deterioration, with the aim of preventing morbidity and mortality. The purpose of this study is to develop an evidence-based improvement programme to optimise the effectiveness of Paediatric Early Warning Systems in different inpatient contexts, and to evaluate the feasibility and potential effectiveness of the programme in predicting deterioration and triggering timely interventions. METHODS: This study will be conducted in two district and two specialist children's hospitals. It deploys an Interrupted Time Series (ITS) design in conjunction with ethnographic cases studies with embedded process evaluation. Informed by Translational Mobilisation Theory and Normalisation Process Theory, the study is underpinned by a functions based approach to improvement. Workstream (1) will develop an evidence-based improvement programme to optimise Paediatric Early Warning System based on systematic reviews. Workstream (2) consists of observation and recording outcomes in current practice in the four sites, implementation of the improvement programme and concurrent process evaluation, and evaluation of the impact of the programme. Outcomes will be mortality and critical events, unplanned admission to Paediatric Intensive Care (PICU) or Paediatric High Dependency Unit (PHDU), cardiac arrest, respiratory arrest, medical emergencies requiring immediate assistance, reviews by PICU staff, and critical deterioration, with qualitative evidence of the impact of the intervention on Paediatric Early Warning System and learning from the implementation process. DISCUSSION: This paper presents the background, rationale and design for this mixed methods study. This will be the most comprehensive study of Paediatric Early Warning Systems and the first to deploy a functions-based approach to improvement in the UK with the aim to improve paediatric patient safety and reduce mortality. Our findings will inform recommendations about the safety processes for every hospital treating paediatric in-patients across the NHS. TRIAL REGISTRATION: Sponsor: Cardiff University, 30-36 Newport Road, Cardiff, CF24 0DE Sponsor ref.: SPON1362-14. Funder: National Institute for Health Research, Health Services & Delivery Research Programme (NIHR HS&DR) Funder reference: 12/178/17. Research Ethics Committee reference: 15/SW/0084 [13/04/2015]. PROSPERO reference: CRD42015015326 [23/01/2015]. ISRCTN: 94228292 https://doi.org/10.1186/ISRCTN94228292 [date of application 13/05/2015; date of registration: 18/08/2015]. Prospective registration prior to data collection and participant consent commencing in September 2014.

Assessment of the efficacy and safety of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler versus a multi-dose inhaler in patients with chronic obstructive pulmonary disease.

BACKGROUND: This study tested the clinical non-inferiority of the fluticasone propionate/salmeterol combination 50/250 µg (FSC) Rotacaps®/Rotahaler® system, a single unit dose inhaler, with the multi-dose FSC Diskus® inhaler in adults with chronic obstructive pulmonary disease (COPD). METHODS: This multi-centre, randomised, double-blind, double-dummy, two-way cross-over study compared 12 weeks' treatment of FSC administered twice daily using Rotacaps/Rotahaler or Diskus. The primary endpoint was change from baseline in trough morning forced expiratory volume in 1 s (FEV1) at Day 85, and the pre-defined non-inferiority criteria was: the lower limit of the confidence interval (CI) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than -45 mL. Secondary endpoints included change in breathlessness (as measured by transition dyspnoea index (TDI)) and COPD-specific health status measures. RESULTS: The LS mean increase from baseline in trough FEV1 at Day 85 was 116 mL in the Rotacaps/Rotahaler group and 91 mL in the Diskus group (difference in model-adjusted LS mean change: 25 mL (95% CI 2 mL, 47 mL)), the lower limit of the CI for the treatment difference being greater than the protocol-defined criterion for non-inferiority i.e. -45 mL. Data for breathlessness, COPD-specific health status and safety parameters were similar following FSC treatment via either inhaler. CONCLUSIONS: This study demonstrated the clinical non-inferiority of FSC 50/250 µg when administered using Rotacaps/Rotahaler compared with Diskus in patients with COPD. The risk:benefit profile for the two inhalers was comparable.

Using Bayesian Dynamic Borrowing to Maximize the Use of Existing Data: A Case-Study.

Bayesian Dynamic Borrowing (BDB) designs are being increasingly used in clinical drug development. These methods offer a mathematically rigorous and robust approach to increase efficiency and strengthen evidence by integrating existing trial data into a new clinical trial. The regulatory acceptability of BDB is evolving and varies between and within regulatory agencies. This paper describes how BDB can be used to design a new randomised clinical trial including external data to supplement the planned sample size and discusses key considerations related to data re-use and BDB in drug development programs. A case-study illustrating the planning and evaluation of a BDB approach to support registration of a new medicine with the Center for Drug Evaluation in China will be presented. Key steps and considerations for the use of BDB will be discussed and evaluated, including how to decide whether it is appropriate to borrow external data, which external data can be re-used, the weight to put on the external data and how to decide if the new study has successfully demonstrated treatment benefit.

Baseline Characteristics and ICS/LAMA/LABA Response in Asthma: Analyses From the CAPTAIN Study.

BACKGROUND: Findings from CAPTAIN (NCT02924688) suggest that treatment response to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) differs according to baseline type 2 inflammation markers in patients with moderate to severe asthma. Understanding how other patient physiologic and clinical characteristics affect response to inhaled therapies may guide physicians toward a personalized approach for asthma management. OBJECTIVE: To investigate, using CAPTAIN data, the predictive value of key demographic and baseline physiologic variables in patients with asthma (lung function, bronchodilator reversibility, age, age at asthma onset) on response to addition of the long-acting muscarinic antagonist UMEC to inhaled corticosteroid/long-acting ß2-agonist combination FF/VI, or doubling the FF dose. METHODS: Prespecified and post hoc analyses of CAPTAIN data were performed using categorical and continuous variables of key baseline characteristics to understand their influence on treatment outcomes (lung function [trough FEV1], annualized rate of moderate/severe exacerbations, and asthma control [Asthma Control Questionnaire]) following addition of UMEC to FF/VI or doubling the FF dose in FF/VI or FF/UMEC/VI. RESULTS: Adding UMEC to FF/VI led to greater improvements in trough FEV1 versus doubling the FF dose across all baseline characteristics assessed. Doubling the FF dose was generally associated with numerically greater reductions in the annualized rate of moderate/severe exacerbations compared with adding UMEC, independent of baseline characteristics. Adding UMEC and/or doubling the FF dose generally led to improvements in Asthma Control Questionnaire scores irrespective of baseline characteristics. CONCLUSIONS: Unlike previous findings with type 2 biomarkers, lung function, bronchodilator reversibility, age and age at asthma onset do not appear to predict response to inhaled therapy.

ISPD Catheter-related Infection Recommendations: 2023 Update.

Peritoneal dialysis (PD) catheter-related infections are important risk factors for catheter loss and peritonitis. The 2023 updated recommendations have revised and clarified definitions and classifications of exit site infection and tunnel infection. A new target for the overall exit site infection rate should be no more than 0.40 episodes per year at risk. The recommendation about topical antibiotic cream or ointment to catheter exit site has been downgraded. New recommendations include clarified suggestion of exit site dressing cover and updated antibiotic treatment duration with emphasis on early clinical monitoring to ascertain duration of therapy. In addition to catheter removal and reinsertion, other catheter interventions including external cuff removal or shaving, and exit site relocation are suggested.

The Impact of Phosphorus Management Today on Quality of Life: Patient Perspectives.

Patients with kidney failure and early stages of chronic kidney disease often develop hyperphosphatemia, which is associated with negative outcomes. The reduction of phosphate levels is the established clinical practice. However, achieving and maintaining target phosphate levels is challenging, and the current methods of phosphate management lead to poor quality of life (QoL) in patients receiving dialysis, particularly because patients might not receive adequate education on phosphate control. Patients receiving dialysis are advised to maintain stringent dietary restrictions and might experience anxiety and depression due to the constant burden of dietary self-management. The lack of nutritional information on food labels makes adhering to dietary restrictions even more confusing and difficult. Phosphate binders are the only pharmacologic treatment currently indicated for hyperphosphatemia. However, phosphate binders have a limited binding capacity and are difficult to incorporate into patients' daily routines. Because of the suboptimal efficacy of phosphate binders and the negative impact of dietary restrictions on patient QoL, novel therapies for more effective phosphate control are needed. New treatment options that control phosphate levels would enable patients to eat a more normal, healthy diet and potentially improve their QoL.

Living Well With Kidney Disease and Effective Symptom Management: Consensus Conference Proceedings.

Chronic kidney disease (CKD) confers a high burden of uremic symptoms that may be underrecognized, underdiagnosed, and undertreated. Unpleasant symptoms, such as CKD-associated pruritus and emotional/psychological distress, often occur within symptom clusters, and treating 1 symptom may potentially alleviate other symptoms in that cluster. The Living Well with Kidney Disease and Effective Symptom Management Consensus Conference convened health experts and leaders of kidney advocacy groups and kidney networks worldwide to discuss the effects of unpleasant symptoms related to CKD on the health and well-being of those affected, and to consider strategies for optimal symptom management. Optimizing symptom management is a cornerstone of conservative and preservative management which aim to prevent or delay dialysis initiation. In persons with kidney dysfunction requiring dialysis (KDRD), incremental transition to dialysis and home dialysis modalities offer personalized approaches. KDRD is proposed as the preferred term given the negative connotations of "failure" as a kidney descriptor, and the success stories in CKD journeys. Engaging persons with CKD to identify and prioritize their personal values and individual needs must be central to ensure their active participation in CKD management, including KDRD. Person-centered communication and care are required to ensure diversity, equity, and inclusion; education/awareness that considers the health literacy of persons with CKD; and shared decision-making among the person with CKD, care partners, and providers. By putting the needs of people with CKD, including effective symptom management, at the center of their treatment, CKD can be optimally treated in a way that aligns with their goals.

Consistent phenological shifts in the making of a biodiversity hotspot: the Cape flora.

BACKGROUND: The best documented survival responses of organisms to past climate change on short (glacial-interglacial) timescales are distributional shifts. Despite ample evidence on such timescales for local adaptations of populations at specific sites, the long-term impacts of such changes on evolutionary significant units in response to past climatic change have been little documented. Here we use phylogenies to reconstruct changes in distribution and flowering ecology of the Cape flora--South Africa's biodiversity hotspot--through a period of past (Neogene and Quaternary) changes in the seasonality of rainfall over a timescale of several million years. RESULTS: Forty-three distributional and phenological shifts consistent with past climatic change occur across the flora, and a comparable number of clades underwent adaptive changes in their flowering phenology (9 clades; half of the clades investigated) as underwent distributional shifts (12 clades; two thirds of the clades investigated). Of extant Cape angiosperm species, 14-41% have been contributed by lineages that show distributional shifts consistent with past climate change, yet a similar proportion (14-55%) arose from lineages that shifted flowering phenology. CONCLUSIONS: Adaptive changes in ecology at the scale we uncover in the Cape and consistent with past climatic change have not been documented for other floras. Shifts in climate tolerance appear to have been more important in this flora than is currently appreciated, and lineages that underwent such shifts went on to contribute a high proportion of the flora's extant species diversity. That shifts in phenology, on an evolutionary timescale and on such a scale, have not yet been detected for other floras is likely a result of the method used; shifts in flowering phenology cannot be detected in the fossil record.

Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.

BACKGROUND: Despite inhaled corticosteroid plus long-acting ß2-agonist (ICS/LABA) therapy, 30-50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI. METHODS: In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries. Participants were eligible if they were aged 18 years or older, with inadequately controlled asthma (Asthma Control Questionnaire [ACQ]-6 score of ≥1·5) despite ICS/LABA, a documented health-care contact or a documented temporary change in asthma therapy for treatment of acute asthma symptoms in the year before screening, pre-bronchodilator FEV1 between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV1 of ≥12% and ≥200 mL in the 20-60 min after four inhalations of albuterol or salbutamol) at screening. Participants were randomly assigned (1:1:1:1:1:1), via central based randomisation stratified by pre-study ICS dose at study entry, to once-daily FF/VI (100/25 µg or 200/25 µg) or FF/UMEC/VI (100/31·25/25 µg, 100/62·5/25 µg, 200/31·25/25 µg, or 200/62·5/25 µg) administered via Ellipta dry powder inhaler (Glaxo Operations UK, Hertfordshire, UK). Patients, investigators, and the funder were masked to treatment allocation. Endpoints assessed in the intention-to-treat population were change from baseline in clinic trough FEV1 at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV1 at 3 h post-dose, St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-7 total score, all at week 24. Change from baseline in Evaluating Respiratory Symptoms in Asthma total score at weeks 21-24 was also a secondary endpoint but is not reported here. Exploratory analyses of biomarkers of type 2 airway inflammation on treatment response were also done. This study is registered with ClinicalTrials.gov, NCT02924688, and is now complete. FINDINGS: Between Dec 16, 2016, and Aug 31, 2018, 5185 patients were screened and 2439 were recruited and randomly assigned to FF/VI (100/25 µg n=407; 200/25 µg n=406) or FF/UMEC/VI (100/31·25/25 µg n=405; 100/62·5/25 µg n=406; 200/31·25/25 µg n=404; 200/62·5/25 µg n=408), with three patients randomly assigned in error and not included in analyses. In the intention-to-treat population, 922 (38%) patients were men, the mean age was 53·2 years (SD 13·1) and body-mass index was 29·4 (6·6). Baseline demographics were generally similar across all treatment groups. The least squares mean improvement in FEV1 change from baseline for FF/UMEC/VI 100/62·5/25 µg versus FF/VI 100/25 µg was 110 mL (95% CI 66-153; p<0·0001) and for 200/62·5/25 µg versus 200/25 µg was 92 mL (49-135; p<0·0001). Adding UMEC 31·25 µg to FF/VI produced similar improvements (FF/UMEC/VI 100/31·25/25 µg vs FF/VI 100/25 µg: 96 mL [52-139; p<0·0001]; and 200/31·25/25 µg vs 200/25 µg: 82 mL [39-125; p=0·0002]). These results were supported by the analysis of clinic FEV1 at 3 h post-dose. Non-significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62·5 µg/VI versus FF/VI (pooled analysis), with rates lower in FF 200 µg-containing versus FF 100 µg-containing treatment groups. All pooled treatment groups demonstrated mean improvements (decreases) in SGRQ total score at week 24 compared with baseline in excess of the minimal clinically important difference of 4 points; however, there were no differences between treatment groups. For mean change from baseline to week 24 in asthma control questionnaire-7 score, improvements (decreases) exceeding the minimal clinically important difference of 0·5 points were observed in all pooled treatment groups. Adding UMEC to FF/VI resulted in small, dose-related improvements compared with FF/VI (pooled analysis: FF/UMEC 31·25 µg/VI versus FF/VI, -0·06 (95% CI -0·12 to 0·01; p=0·094) FF/UMEC 62·5 µg/VI versus FF/VI, -0·09 (-0·16 to -0·02, p=0·0084). By contrast with adding UMEC, the effects of higher dose FF on clinic trough FEV1 and annualised moderate and/or severe exacerbation rate were increased in patients with higher baseline blood eosinophil count and exhaled nitric oxide. Occurrence of adverse events was similar across treatment groups (patients with at least one event ranged from 210 [52%] to 258 [63%]), with the most commonly reported adverse events being nasopharyngitis (51 [13%]-63 [15%]), headache (19 [5%]-36 [9%]), and upper respiratory tract infection (13 [3%]-24 [6%]). The incidence of serious adverse events was similar across all groups (range 18 [4%]-25 [6%)). Three deaths occurred, of which one was considered to be related to study drug (pulmonary embolism in a patient in the FF/UMEC/VI 100/31·25/25 µg group). INTERPRETATION: In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk-benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice. FUNDING: GSK.

Observations and monitoring: routine practices on the ward.

AIM: To review routine observations on all children admitted to the Children's Hospital for Wales and the feasibility of implementing an early warning score for children developing critical illness. METHOD: Nursing staff, while performing their routine duties, recorded the physiological observations of temperature, heart rate, respiratory rate and blood pressure, as well as identifying airway threat, recording oxygen saturation levels, level of consciousness using the AVPU scale (alert, responds to voice, responds to pain, unresponsive) and identifying if they had concerns about a child on a new paediatric observation chart. The clinical care policy for each ward determined the frequency of recording observations. RESULTS: Data were collected for 1,000 patients on whom 9,075 sets of observations were performed. Of those 9,075 sets, temperature was the most frequently recorded observation at 88.4% (95% confidence interval (CI) 87.7-89), followed by heart rate at 86.8% (95% CI 86.1-87.5), respiratory rate at 79.7% (95% CI 78.9-80.5), AVPU at 36.4% (95% CI 35.4-37.4) and blood pressure at 25.1% (95% CI 24.2-26.0). A complete set of observations needed for the Cardiff and Vale Paediatric Early Warning System to trigger effectively were only recorded in 52.7% (95% CI 52.4-53.1) of patients. CONCLUSION: There were variations in the frequency, type and recording of observations. This issue needs to be addressed if scoring systems are to be implemented. The findings of this observational study suggest that the required basic observations of acutely ill children are not being carried out.

Synergistic cytotoxicity of interferonalpha-2b and interleukin-2 in combination with PBMC against ovarian cancer: development of an experimental model for cellular therapy.

OBJECTIVES: Current therapies for ovarian cancer (OC) patients have a modest impact on long-term survival justifying the need for novel treatment strategies. We developed in vitro and in vivo systems to test the effects of cytokines in combination with peripheral blood mononuclear cells (PBMC) on OC cells. METHODS: Two OC cell-lines were transfected with a plasmid encoding Red Fluorescent Protein (SKOV3-RFP and CAR3-RFP). Proliferation of these lines in the presence of cytokines alone and in combination was assayed. Cytotoxicity of SKOV3-RFP cells mediated by PBMC and cytokines was determined by lactate dehydrogenase release. Mice were injected intraperitoneally (IP) with SKOV3-RFP cells; solid tumor and ascitic fluid were collected, analyzed, and cell lines were established. Tumor-derived cell lines were re-injected to produce a more tumorigenic line. RESULTS: IFNalpha-2b showed an inhibitory effect on OC cell proliferation. The remaining cytokines, either alone or in combination, showed no significant effect. PBMC in combination with IL-2 showed clear dose-dependent cytotoxicity against SKOV3-RFP. IFNalpha-2b had a synergistic effect with IL-2 and PBMC increasing the cytotoxicity by an average of 20%. Using an animal model, SKOV3-RFP cells continue to express RFP when harvested from the peritoneum and are more tumorigenic when re-injected into mice. CONCLUSION: These observations justify the use of IL-2, IFNalpha-2b, and PBMC in a xenograph animal model of OC to determine if combination cytokine and cellular therapy has an anti-tumor effect in vivo. This approach may prove useful as an in vivo system of IP cytokines administered in combination with cellular therapy.

Validity and effectiveness of paediatric early warning systems and track and trigger tools for identifying and reducing clinical deterioration in hospitalised children: a systematic review.

OBJECTIVE: To assess (1) how well validated existing paediatric track and trigger tools (PTTT) are for predicting adverse outcomes in hospitalised children, and (2) how effective broader paediatric early warning systems are at reducing adverse outcomes in hospitalised children. DESIGN: Systematic review. DATA SOURCES: British Nursing Index, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effectiveness, EMBASE, Health Management Information Centre, Medline, Medline in Process, Scopus and Web of Knowledge searched through May 2018. ELIGIBILITY CRITERIA: We included (1) papers reporting on the development or validation of a PTTT or (2) the implementation of a broader early warning system in paediatric units (age 0-18 years), where adverse outcome metrics were reported. Several study designs were considered. DATA EXTRACTION AND SYNTHESIS: Data extraction was conducted by two independent reviewers using template forms. Studies were quality assessed using a modified Downs and Black rating scale. RESULTS: 36 validation studies and 30 effectiveness studies were included, with 27 unique PTTT identified. Validation studies were largely retrospective case-control studies or chart reviews, while effectiveness studies were predominantly uncontrolled before-after studies. Metrics of adverse outcomes varied considerably. Some PTTT demonstrated good diagnostic accuracy in retrospective case-control studies (primarily for predicting paediatric intensive care unit transfers), but positive predictive value was consistently low, suggesting potential for alarm fatigue. A small number of effectiveness studies reported significant decreases in mortality, arrests or code calls, but were limited by methodological concerns. Overall, there was limited evidence of paediatric early warning system interventions leading to reductions in deterioration. CONCLUSION: There are several fundamental methodological limitations in the PTTT literature, and the predominance of single-site studies carried out in specialist centres greatly limits generalisability. With limited evidence of effectiveness, calls to make PTTT mandatory across all paediatric units are not supported by the evidence base. PROSPERO REGISTRATION NUMBER: CRD42015015326.

Parenting stress trajectories in mothers of very preterm infants to 2 years.

OBJECTIVE: To examine levels of parenting stress in mothers of preterm and term infants when the children were 2 years old; to determine the trajectory of stress over three time periods and to examine the association of maternal and neonatal factors and developmental outcomes with parenting stress. DESIGN: It is a prospective longitudinal study to determine parenting stress in mothers of preterm and term infants with outcomes having been previously obtained at 4 and 12 months. At 2 years, 79 preterm mothers (96 babies) and 64 term mothers (77 babies) participated. The mothers completed the Parenting Stress Index-Short Form (PSI-SF), the Depression, Anxiety, Stress Scale (DASS) and the Child Behaviour Checklist (CBCL). The infants had a neurological examination and the Bayley-III scales were administered. RESULTS: The mean total PSI-SF at 2 years was significantly higher for the preterm group compared with the term group of mothers (p=0.007). There was a significant increase in the mean total PSI over time for the preterm mothers (p<0.001). For mothers at 2 years, there was an association with high levels of parenting stress and abnormal scores on the DASS (p<0.001) and high total T-scores on the CBCL (internalising p<0.001; externalising p=0.006). There was no association between parenting stress and maternal demographics, neonatal factors or Bayley-III results. CONCLUSIONS: Parenting stress in mothers of preterm infants continues to be high at 2 years having increased over time. Maternal mental health problems and infant behavioural issues contribute to the stress.

Parenting stress and psychosocial health in mothers with twin-twin transfusion syndrome managed with laser surgery: a preliminary study.

Twin-twin transfusion syndrome (TTTS) is a severe complication of twin pregnancies with high risk for perinatal mortality and long-term morbidity. This cross-sectional cohort study aimed to determine parenting stress and psychosocial health in mothers with a pregnancy complicated by TTTS that had been managed with laser ablation of communicating placental vessels. Questionnaires were sent to the mothers for completion: Parenting Stress Index (PSI), Edinburgh Postnatal Depression Scale (EPDS) and a semi-structured questionnaire related to mental health problems and support received from health professionals. Thirty-seven mothers were sent questionnaires with 32 being returned. The results showed that 47% of women had total scores equal to or greater than the 85th percentile on the PSI, which is considered abnormally high. Twenty-six per cent of mothers had evidence of depression on the EPDS. Mothers of children with prolonged medical conditions or neurological problems had significantly higher scores (p =.011). Parenting stress was not associated with high scores on the EPDS. Medical and midwifery staff were considered to provide high levels of support, with social work providing none or low levels of support. In conclusion, women whose TTTS pregnancy was managed by laser surgery have high levels of parenting stress. As the results showed that parenting stress cannot be predicted at the time of hospitalization, it is suggested that more support should be provided in hospital with further follow-up after discharge.