Two million people in the UK are experiencing long COVID (LC), which necessitates effective and scalable interventions to manage this condition. This study provides the first results from a scalable ...rehabilitation programme for participants presenting with LC.
601 adult participants with symptoms of LC completed the Nuffield Health COVID-19 Rehabilitation Programme between February 2021 and March 2022 and provided written informed consent for the inclusion of outcomes data in external publications. The 12-week programme included three exercise sessions per week consisting of aerobic and strength-based exercises, and stability and mobility activities. The first 6 weeks of the programme were conducted remotely, whereas the second 6 weeks incorporated face-to-face rehabilitation sessions in a community setting. A weekly telephone call with a rehabilitation specialist was also provided to support queries and advise on exercise selection, symptom management and emotional wellbeing.
The 12-week rehabilitation programme significantly improved Dyspnea-12 (D-12), Duke Activity Status Index (DASI), World Health Orginaisation-5 (WHO-5) and EQ-5D-5L utility scores (all
< 0.001), with the 95% confidence intervals (CI) for the improvement in each of these outcomes exceeding the minimum clinically important difference (MCID) for each measure (mean change CI: D-12: -3.4 -3.9, -2.9; DASI: 9.2 8.2, 10.1; WHO-5: 20.3 18.6, 22.0; EQ-5D-5L utility: 0.11 0.10, 0.13). Significant improvements exceeding the MCID were also observed for sit-to-stand test results (4.1 3.5, 4.6). On completion of the rehabilitation programme, participants also reported significantly fewer GP consultations (
< 0.001), sick days (
= 0.003) and outpatient visits (
= 0.007) during the previous 3 months compared with baseline.
The blended and community design of this rehabilitation model makes it scalable and meets the urgent need for an effective intervention to support patients experiencing LC. This rehabilitation model is well placed to support the NHS (and other healthcare systems worldwide) in its aim of controlling the impacts of COVID-19 and delivering on its long-term plan.
https://www.isrctn.com/ISRCTN14707226, identifier 14707226.
Introduction:
High levels of physical, cognitive, and psychosocial impairments are anticipated for those recovering from the COVID-19. In the UK, ~50% of survivors will require additional ...rehabilitation. Despite this, there is currently no evidence-based guideline available in England and Wales that addresses the identification, timing and nature of effective interventions to manage the morbidity associated following COVID-19. It is now timely to accelerate the development and evaluation of a rehabilitation service to support patients and healthcare services. Nuffield Health have responded by configuring a scalable rehabilitation pathway addressing the immediate requirements for those recovering from COVID-19 in the community.
Methods and Analysis:
This long-term evaluation will examine the effectiveness of a 12-week community rehabilitation programme for COVID-19 patients who have been discharged following in-patient treatment. Consisting of two distinct 6-week phases; Phase 1 is an entirely remote service, delivered via digital applications. Phase 2 sees the same patients transition into a gym-based setting for supervised group-based rehabilitation. Trained rehabilitation specialists will coach patients across areas such as goal setting, exercise prescription, symptom management and emotional well-being. Outcomes will be collected at 0, 6, and 12 weeks and at 6- and 12-months. Primary outcome measures will assess changes in health-related quality of life (HR-QOL) and COVID-19 symptoms using EuroQol Five Dimension Five Level Version (EQ-5D-5L) and Dyspnea-12, respectively. Secondary outcome measures of the Duke Activity Status Questionnaire (DASI), 30 s sit to stand test, General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Patient Experience Questionnaire (PEQ) and Quality Adjusted Life Years (QALY) will allow for the evaluation of outcomes, mediators and moderators of outcome, and cost-effectiveness of treatment.
Discussion:
This evaluation will investigate the immediate and long-term impact, as well as the cost effectiveness of a blended rehabilitation programme for COVID-19 survivors. This evaluation will provide a founding contribution to the literature, evaluating one of the first programmes of this type in the UK. The evaluation has international relevance, with the potential to show how a new model of service provision can support health services in the wake of COVID-19.
Trial Registration:
Current Trials ISRCTN ISRCTN14707226
Web:
http://www.isrctn.com/ISRCTN14707226
The introduction of monoclonal antibodies (mAbs) to the treatment of inflammatory bowel disease (IBD) was an important medical milestone. MAbs have been demonstrated as safe and efficacious ...treatments of IBD. However, a large percentage of patients either fail to respond initially or lose response to therapy after a period of treatment. Although there are factors associated with poor treatment outcomes in IBD, one cause for treatment failure may be low mAb exposure. Consequently, gastroenterologists have begun using therapeutic drug monitoring (TDM) to guide dose adjustment. However, while beneficial, TDM does not provide sufficient information to effectively adjust doses. The pharmacokinetics (PK) and pharmacodynamics (PD) of mAbs are complex, with numerous factors impacting on mAb PK and PD. The concept of dashboard-guided dosing based on Bayesian PK models allows physicians to combine TDM with factors influencing mAb PK to individualize therapy more effectively. One issue with TDM has been the slow turnaround of assay results, either necessitating an additional clinic visit for a sample or reacting to TDM results at a subsequent, rather than the current, dose. New point-of-care (POC) assays for mAbs are being developed that would potentially allow physicians to determine drug concentration quickly. However, work remains to understand how to determine what target exposure is needed for an individual patient, and whether the combination of POC assays and dashboards presents a safe approach with substantial outcome benefit over the current standard of care.
Ovarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) ...to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS.
In this randomised controlled trial, postmenopausal women aged 50–74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032.
Between April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1–17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (−41·8 to –2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (−21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group.
The reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended.
National Institute for Health Research, Cancer Research UK, and The Eve Appeal.
The availability of tests for blood concentrations of anti-tumor necrosis factor (TNF) agents and antibodies against these drugs could improve dose selection for patients with inflammatory bowel ...disease (IBD). However, there is little consensus on when to test and how to interpret test results. We used the RAND/UCLA Appropriateness Method to determine when these tests are appropriate and how to clinically interpret their results.
We conducted a systematic literature search in November 2013 to identify observational or experimental studies of the measurement of anti-TNF drug and antibody concentrations in patients with IBD and interpretation of their results. We developed 35 scenarios that assessed the appropriateness of testing and 143 scenarios that addressed clinical strategies in response to test results, and presented the findings to an expert panel. The appropriateness of each scenario was rated before and after an in-person meeting with the panel. Panelists rated the appropriateness of various clinical management options including changing therapy within class, switching out of class, adjusting drug dose or interval, adding or adjusting concomitant immune modulators, and doing nothing for each of 6 permutations of high versus low drug concentrations and high, low, or undetectable antibody concentrations. Disagreement was assessed using a validated index.
Assessment of anti-TNF drug and antibody concentrations was rated appropriate at the end of induction therapy in primary nonresponders, in secondary nonresponders, at least once during the first year of maintenance therapy, and following a drug holiday. Routine assessment in responders at the end of induction was rated uncertain. In nearly all scenarios, escalation of drug dosing was rated appropriate when drug concentration was low in the absence of antibodies, and switching within class was rated appropriate when antibodies were present. Other recommendations depended on the specific clinical scenario for which the test was obtained.
Based on the RAND/UCLA Appropriateness Method of analysis, an expert panel recommends testing for drug and antibody concentrations in many clinical scenarios. The appropriate timing and best way to respond to anti-TNF drug and antibody testing for IBD depends on the specific clinical scenario. These recommendations can help guide clinicians to best optimize anti-TNF therapy.
The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that ...TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.
The Discovery of Cepheids and a Distance to NGC 5128 Ferrarese, Laura; Mould, Jeremy R; Stetson, Peter B ...
Astrophysical journal/The Astrophysical journal,
01/2007, Letnik:
654, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We discuss a new distance to NGC 5128 (Centaurus A) based on Cepheid variables observed with the Hubble Space Telescope. Twelve F555W (V) and six F814W (I) epochs of cosmic-ray-split WFPC2 ...observations were obtained. A total of 56 bona fide Cepheids were discovered, with periods ranging from 5 to 650 days; five of these are likely Population II Cepheids of the W Virginis class, associated with the bulge or halo of NGC 5128. Based on the period and V- and I-band luminosities of asubsample of 42 classical (Population I) Cepheids, and adopting an LMC distance modulus and extinction of 18.50 c 0.10 mag and E(B - V) = 0.10 mag, respectively, the true reddening-corrected distance modulus to NGC 5128 is k sub(0) = 27.67 c0.12 (random) c 0.16 (systematic) mag, corresponding to a distance of 3.42 c 0.18 (random) c 0.25 (systematic) Mpc. The random uncertainty in the distance is dominated by the error on the assumed value for the ratio of total to selective absorption, R sub(V), in NGC 5128, and by the possible metallicity dependence of the Cepheid period-luminosity relation at V and I. This represents the first determination of a Cepheid distance to an early-type galaxy.
The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment ...required for advanced endometrial cancer. We developed the WID‐EC (Women's cancer risk IDentification‐Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid‐based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID‐EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID‐EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88‐0.97) in the external set and of 0.82 (95% CI: 0.74‐0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID‐EC test can identify women with or at risk of endometrial cancer.
What's new?
The endometrial cancer incidence is rising, and imaging‐based screening is often not suitably accurate for endometrial cancers. Here, the authors show that a new DNA methylation signature (Women's cancer risk IDentification‐Endometrial Cancer, or WID‐EC) can both detect the presence and predict the risk of endometrial cancer. Together with three other recently‐reported methylation indices that detect breast, ovarian, and cervical cancers (WID‐BC, WID‐OC, and WID‐CIN), WID‐EC completes a list of signatures that can detect/predict all four women‐specific cancers using a single cervical sample and the same technology platform for methylation array‐based tests.
Pathogenic
variants account for 5.8-24.8% of ovarian cancers. The identification of such a variant can have a significant impact on the affected individual and their relatives, determining ...eligibility for targeted therapies, predicting treatment response, and granting access to disease prevention strategies. Cancer services are responding to the increased demand for genetic testing with the introduction of mainstreamed genetic testing via oncology clinics. This study aimed to evaluate patient experience of the mainstreamed genetic testing pathway at a tertiary referral center in London, UK.
Study participants were patients diagnosed with high-grade non-mucinous ovarian cancer, tested via a mainstreamed genetic testing pathway at the tertiary referral center between February 2015 and June 2017. Eligible participants were invited to complete the retrospective study questionnaire. Five quantitative measures with additional free-text items were used to evaluate the patient experience of mainstreamed genetic testing.
The tertiary referral center tested 170 ovarian cancer patients. Twenty-three pathogenic
mutations were identified (23/170, 13.5%). One-hundred and six patients (106/170, 62.4%) met the study inclusion criteria. Twenty-nine of those invited to participate (29/106, 27.4%) returned the retrospective study questionnaire. Pathogenic
variants were identified within four respondents (4/29, 13.8%). Motivations for genetic testing related to improved medical management, and the ability to provide relatives with genetic information. Participants did not appear to be adversely affected by result disclosure post-mainstreamed genetic testing. Two individuals with a pathogenic variant reported that the support provided by the tertiary referral center post-result disclosure could have been improved.
Results of the current study support further psychosocial research into the expansion of the mainstreamed genetic testing pathway. The results, although promising, have also highlighted the importance of genetic awareness within the multi-disciplinary team and the provision of timely psychological support from genetic specialists.
PDF
