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railty-adjusted therapy n ransplant on-ligible patient with newly diagnoed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): a study protocol for a randomised phase III trial.
No full textINTRODUCTION
Multiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population.Over the last 10 years, patient outcomes have improved. However, this is less apparent in older, less fit patients, who are ineligible for stem cell transplant. Research is required in this patient group, taking into account frailty and aiming to improve: treatment tolerability, clinical outcomes and quality of life.
METHODS AND ANALYSIS
Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma is a national, phase III, multicentre, randomised controlled trial comparing standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide to lenalidomide+ixazomib, in patients with newly diagnosed multiple myeloma not suitable for stem cell transplant. Overall, 740 participants will be registered into the trial to allow 720 and 478 to be randomised at induction and maintenance, respectively.All participants will receive IRD induction with the dosing strategy randomised (1:1) at trial entry. Patients randomised to the standard, reactive arm will commence at the full dose followed by toxicity dependent reactive modifications. Patients randomised to the adaptive arm will commence at a dose level determined by their International Myeloma Working Group frailty score. Following 12 cycles of induction treatment, participants alive and progression free will undergo a second (double-blind) randomisation on a 1:1 basis to maintenance treatment with lenalidomide+placebo versus lenalidomide+ixazomib until disease progression or intolerance.
ETHICS AND DISSEMINATION
Ethical approval has been obtained from the North East-Tyne & Wear South Research Ethics Committee (19/NE/0125) and capacity and capability confirmed by local research and development departments for each participating centre prior to opening to recruitment. Participants are required to provide written informed consent prior to trial registration. Trial results will be disseminated by conference presentations and peer-reviewed publications.
TRIAL REGISTRATION NUMBER
ISRCTN17973108, NCT03720041
Efficacy of Isatuximab With Pomalidomide and Dexamethasone in Relapsed Myeloma: Results of a UK-Wide Real-World Dataset.
No full textReal-world data on the efficacy and tolerability of isatuximab with pomalidomide and dexamethasone (IsaPomDex) in relapsed/refractory myeloma patients have not been reported. In this UK-wide retrospective study, IsaPomDex outcomes were evaluated across 24 routine care cancer centers. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response (DOR) for patients who achieved an objective response (≥partial response [PR]), and adverse events (AEs). In a total cohort 107 patients, median follow up (interquartile range [IQR]) was 12.1 months (10.1-18.6 mo), median age (IQR) was 69 years (61-77). Median (IQR) Charlson Comorbidity Index (CCI) score was 3 (2-4); 43% had eGFR <60 mL/min. Median (IQR) number of prior therapies was 3 (3-3). Median (IQR) number of IsaPomDex cycles administered was 7 (3-13). ORR was 66.4%, with responses categorized as ≥ very good partial response: 31.8%, PR: 34.6%, stable disease: 15.9%, progressive disease: 15%, and unknown 2.8%. Median PFS was 10.9 months. Median DOR was 10.3 months. There was no statistical difference in median PFS by age (<65: 10.2 versus 65-74 13.2 versus ≥75: 8.5 mo, log-rank = 0.4157), by CCI score (<4: 10.2 mo versus ≥4: 13.2, log-rank = 0.6531), but inferior PFS was observed with renal impairment (≥60: 13.2 versus <60: 7.9 mo, log-rank = 0.0408). Median OS was 18.8 months. After a median of 4 cycles, any grade AEs were experienced by 87.9% of patients. The most common ≥G3 AEs were neutropenia (45.8%), infections (18.7%), and thrombocytopenia (14%). Our UK-wide IsaPomDex study demonstrated encouraging efficacy outcomes in the real world, comparable to ICARIA-MM trial
Photobiomodulation in acute traumatic brain injury: a systematic review and meta-analysis.
No full textPhotobiomodulation (PBM) is a therapeutic modality which has gained increasing interest in neuroscience applications, including acute traumatic brain injury (TBI). Its proposed mechanisms for therapeutic effect when delivered to the injured brain include anti-apoptotic and anti-inflammatory effects. This systematic review summarises the available evidence for the value of PBM in improving outcomes in acute TBI and presents a meta-analysis of the pre-clinical evidence for neurological severity score (NSS) and lesion size in animal models of TBI. A systematic review of the literature was performed, with searches and data extraction performed independently in duplicate by two authors. Eighteen published articles were identified for inclusion: seventeen pre-clinical studies of in vivo animal models; and one clinical study in human patients. The available human study supports safety and feasibility of PBM in acute moderate TBI. For pre-clinical studies, meta-analysis for NSS and lesion size were found to favour intervention versus control. Sub-group analysis based on PBM parameter variables for these outcomes was performed. Favourable parameters were identified as: wavelengths in the region of 665 nm and 810 nm; time to first administration of PBM ≤ 4 hours; total number of daily treatments ≤3. No differences were identified between pulsed and continuous wave modes or energy delivery. Mechanistic sub-studies within included in vivo studies are presented and were found to support hypotheses of anti-apoptotic, anti-inflammatory and pro-proliferative effects, and a modulation of cellular metabolism. This systematic review provides substantial meta-analysis evidence of the benefits of PBM on functional and histological outcomes of TBI in in vivo mammalian models. Consideration of study design and PBM parameters should be closely considered for future human clinical studies
Outpatient parenteral antimicrobial therapy (OPAT) in the UK: findings from the BSAC National Outcomes Registry (2015-19).
No full textBACKGROUND
Reporting of outpatient parenteral antimicrobial therapy (OPAT) outcomes with national benchmarking is key to informing service development and supporting quality improvement.
OBJECTIVES
To analyse and report on data collected by the BSAC OPAT National Outcomes Registry from 2015 to 2019.
METHODS
Quarterly data to 2020 was extracted from the BSAC National Outcomes Registry and analysed.
RESULTS
57 organizations submitted data on 27 841 patient episodes and 442 280 OPAT treatment days. A diverse range of infections and antimicrobials were reported with a mean OPAT treatment duration of 16.7 days (adults) and 7.7 days (paediatrics). In adults, the top five conditions treated were skin and soft tissue (27.6%), bronchiectasis (11.4%), urinary tract infections (7.6%), and diabetic foot infections (5.5%). Ceftriaxone followed by teicoplanin, ertapenem and piperacillin/tazobactam were the most-used antimicrobials. A median of 1.4 vascular-device-related complications were observed per 1000 OPAT treatment days (range 0.11 to 10.4) with device infections in 0.3 per 1000 OPAT days (range 0.1 to 1.7). Other adverse events (rash, blood dyscrasias, antibiotic-associated diarrhoea) were observed in a median of 1.9 per 1000 OPAT days. OPAT infection outcome (cured/improved) was 92.4% and OPAT outcome (success/partial success) was 90.7%.
CONCLUSIONS
This report demonstrates the safety, breadth, and complexity of modern UK OPAT practice. Future analyses of OPAT data should focus on infection- and service-specific quality indicators. OPAT registries remain central to planning and assessing safe, effective, and efficient delivery of patient-centred care and should be an important focus for UK and global OPAT practice
A population cohort analysis of English transplant centers indicates major adverse cardiovascular events after kidney transplantation.
No full textMajor adverse cardiovascular event (MACE) rates immediately after kidney transplantation remain uncertain due to heterogeneous reporting in the literature. To clarify this, we retrospectively studied every eligible kidney transplant procedure performed in England between April 1, 2002 and March 31. 2018 with follow-up through August 31, 2019. The primary outcome of interest was MACE broadly defined as any hospital admission with myocardial infarction, stroke, unstable angina, heart failure, any coronary revascularisation procedure and/or any cardiovascular death. Among 30,325 kidney transplant recipients, MACE occurred in 781 within the first year after transplantation (2.6% of all kidney transplant procedures). Of these 781 events, 201 occurred during the index admission for kidney transplantation surgery representing 25.7% of all first-year MACE and 0.7% of all kidney transplant procedures. Kidney transplant recipients who suffered a non-fatal MACE within the first year had significantly decreased 1-, 3-, 5- and 10-year patient survival of 80.5%, 70.2%, 59.5% and 38.6% respectively, compared to 97.4%, 94.4%, 90.7% and 78.4% for kidney transplant recipients not developing MACE.. In an adjusted Cox proportional hazard model, non-fatal MACE within the first-year post-transplant was associated with significant long-term mortality risk (hazard ratio 2.59; 95% confidence interval 2.34-2.88). Kidney transplant recipients experiencing MACE during the index admission compared to subsequent admissions were differentiated by age, sex and previous cardiac history but had similar patient survival. These rates are significantly lower than those reported in North America. Thus, our data confirms MACE is not a benign post-transplant event and has a strong association with long-term mortality risk
High generation of reactive oxygen species from neutrophils in patients with severe COVID-19.
No full textNeutrophilia and an elevated neutrophil:lymphocyte ratio are both characteristic features of severe COVID-19 infection. However, functional neutrophil responses have been poorly investigated in this setting. We utilised a novel PMA-based stimulation assay to determine neutrophil-derived reactive oxygen species (ROS) generation in patients with severe COVID-19 infection, non-COVID related sepsis and healthy study participants. ROS production was markedly elevated in COVID-19 patients with median values ninefold higher than in healthy controls and was particularly high in patients on mechanical ventilation. ROS generation correlated strongly with neutrophil count and elevated levels were also seen in patients with non-COVID related sepsis. Relative values, adjusted for neutrophil count, were high in both groups but extreme low or high values were seen in two patients who died shortly after testing, potentially indicating a predictive value for neutrophil function. Our results show that the high levels of neutrophils observed in patients with COVID-19 and sepsis exhibit functional capacity for ROS generation. This may contribute to the clinical features of acute disease and represents a potential novel target for therapeutic intervention
Clinical standards for drug-susceptible pulmonary TB.
No full textThe aim of these clinical standards is to provide guidance on 'best practice´ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB). A panel of 54 global experts in the field of TB care, public health, microbiology, and pharmacology were identified; 46 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all 46 participants. Seven clinical standards were defined: Standard 1, all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events, and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB. These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB
Assessing spinal movement during four extrication methods: a biomechanical study using healthy volunteers.
No full textBACKGROUND
Motor vehicle collisions are a common cause of death and serious injury. Many casualties will remain in their vehicle following a collision. Trapped patients have more injuries and are more likely to die than their untrapped counterparts. Current extrication methods are time consuming and have a focus on movement minimisation and mitigation. The optimal extrication strategy and the effect this extrication method has on spinal movement is unknown. The aim of this study was to evaluate the movement at the cervical and lumbar spine for four commonly utilised extrication techniques.
METHODS
Biomechanical data was collected using inertial Measurement Units on 6 healthy volunteers. The extrication types examined were: roof removal, b-post rip, rapid removal and self-extrication. Measurements were recorded at the cervical and lumbar spine, and in the anteroposterior (AP) and lateral (LAT) planes. Total movement (travel), maximal movement, mean, standard deviation and confidence intervals are reported for each extrication type.
RESULTS
Data from a total of 230 extrications were collected for analysis. The smallest maximal and total movement (travel) were seen when the volunteer self-extricated (AP max = 2.6 mm, travel 4.9 mm). The largest maximal movement and travel were seen in rapid extrication extricated (AP max = 6.21 mm, travel 20.51 mm). The differences between self-extrication and all other methods were significant (p < 0.001), small non-significant differences existed between roof removal, b-post rip and rapid removal. Self-extrication was significantly quicker than the other extrication methods (mean 6.4 s).
CONCLUSIONS
In healthy volunteers, self-extrication is associated with the smallest spinal movement and the fastest time to complete extrication. Rapid, B-post rip and roof off extrication types are all associated with similar movements and time to extrication in prepared vehicles
Visual deterioration in patients with photoreceptor loss after retinal reattachment surgery.
No full textPURPOSE
Assess the relationship between photoreceptor degeneration and visual function after retinal reattachment surgery (RRS) in a prospective cohort.
METHODS
Patients with rhegmatogenous retinal detachment (RRD) were reviewed before and 6 months after vitreoretinal surgery. Optical coherence tomographical thickness of the outer nuclear layer (ONL), outer retinal segment (ORS), retinal pigmented epithelium to ellipsoid zone (RPE-EZ) and external limiting membrane to EZ (ELM-EZ) were recorded 6 months post-operatively. These were compared to best corrected visual acuity (BCVA) and retinal sensitivity (Humphrey visual field).
RESULTS
Thirteen macula-off and 8 macula-on RRD patients were included. The mean ONL thickness was higher after macula-on RRD compared to macula-off RRD (97.70 ± 3.62 μm vs. 73.10 ± 4.98 μm). In all RRD eyes, every 1 μm decrease in ONL thickness correlated with a 0.052 dB decrease and in retinal sensitivity and every 1 μm decrease in ORS thickness was associated with a 0.062 dB reduction in retinal sensitivity. ORS, ELM-EZ and RPE-EZ thickness did not correlate with BCVA post-RRS.
CONCLUSION
There was greater ONL and ORS thinning following macula-off compared to macula-on RRD. Correlations between ONL and ORS thinning with decreased retinal sensitivity may be explained by RRD-induced photoreceptor death