Developing longitudinal qualitative designs: lessons learned and recommendations for health services research

published_fina

Symptom Experience in Patients with Gynecological Cancers: The Development of Symptom Clusters through Patient Narratives

The vast majority of the increasing cancer literature on physical and psychological symptom clusters is quantitative, attempting either to model clusters through statistical techniques or to test priori clusters for their strength of relationship. Narrative symptom clusters can be particularly sensitive outcomes that can generate conceptually meaningful hypotheses for symptom cluster research. We conducted a study to explore the explanation of patients about the development and coexistence of symptoms and how patients attempted to self-manage them. We collected 12-month qualitative longitudinal data over four assessment points consisting of 39 interview data sets from 10 participants with gynecological cancer. Participants' experiences highlighted the presence of physical and psychological symptom clusters, complicating the patients' symptom experience that often lasted 1 year. While some complementary and self-management approaches were used to manage symptoms, few options and interventions were discussed. The cancer care team may be able to develop strategies for a more thorough patient assessment of symptoms reported as the most bothersome and patient-centered sensitive interventions that encompass the physiological, psychological, sociocultural, and behavioral components of the symptom experience essential for effective symptom management

Adherence to ocular hypotensive therapy: Patient health education needs and views on group education

BACKGROUND: In this study the authors sought both to understand the health education needs of patients with glaucoma, with particular regard to adherence to glaucoma treatment, and to examine these patients’ views of group education. METHODS: Using a health promotion approach to health education, 27 qualitative interviews with new and established patients receiving glaucoma treatment were conducted. Health promotion is defined as a way of strengthening people’s capacities to control and optimize their own health. The interviews were transcribed and were then analyzed thematically RESULTS: Nine categories of health education needs were identified from the transcripts: (1) to understand glaucoma; (2) to understand their diagnosis or understand the difficulties in giving a diagnosis; (3) to understand the implications of eye drops, their side effects, and how to renew the eye drops; (4) to feel confident to put in eye drops; (5) to put the condition into perspective - to know how to manage their risk; (6) to be able to ask questions of clinicians; (7) to be able to navigate the health care system; (8) to understand and be able to manage own adherence behavior; and (9) to know where to access other sources of information. The majority of patients had something positive to say about group education, and about half of the patients said they would attend group education if they were offered the opportunity. CONCLUSION: A health promotion approach identified a wide range of patient-centered health education needs regarding adherence to glaucoma treatment. Group education will be attractive to some patients. Clinicians could use the health education needs identified in this study to guide the development of either individual or group-based educational intervention to improve adherence to glaucoma treatment. However, clinicians need to be aware that when developing a group intervention, attention will need to be given to making the education relevant to the circumstances of each patient

A study to assess the feasibility of undertaking a randomized controlled trial of adherence with eye drops in glaucoma patients.

BACKGROUND: Adherence with therapy could influence the progression of glaucoma and ultimately affect the onset of visual impairment in some individuals. This feasibility study evaluated the measures to be used for a future randomized controlled trial assessing the effects of group-based education on adherence with eye drops. METHODS: People diagnosed with glaucoma within the previous 12 months attending a regional ophthalmology clinic in the North West of England were recruited. A two-session education program delivered one week apart had been devised as part of a previous project. A combined adult learning and health needs approach to education was taken. Outcomes measured were knowledge of glaucoma, self-report of adherence, illness perception, beliefs about medicines, patient enablement, and general health (Short Form-12). Adherence was also measured objectively using a Medical Events Monitoring System device. RESULTS: Twenty-six participants consented to undertake the educational program and 19 produced analyzable data. Knowledge of glaucoma, illness perception, beliefs about medicine, and patient enablement all showed statistically significant improvements after education. Mean adherence with eye drops was maintained above 85% before and for 3 months after attendance at the educational program. Self-report exaggerated adherence by at least 10% when compared with the objective Medical Events Monitoring System data, and in fact the kappa agreement was zero. CONCLUSION: All questionnaires other than the Short Form-12 were considered to be valuable measures and use of a Medical Events Monitoring System device was considered to be an objective surrogate measure for adherence with eye drops. A multicenter, randomized, controlled equivalence trial of group versus individualized education using adherence as the primary outcome is the next step

Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair

Ataxia telangiectasia (ATM) mutated and Artemis, the proteins defective in ataxia telangiectasia and a class of Radiosensitive-Severe Combined Immunodeficiency (RS-SCID), respectively, function in the repair of DNA double strand breaks (DSBs), which arise in heterochromatic DNA (HC-DSBs) following exposure to ionizing radiation (IR). Here, we examine whether they have protective roles against oxidative damage induced and/or endogenously induced DSBs. We show that DSBs generated following acute exposure of G0/G1 cells to the oxidative damaging agent, tert-butyl hydroperoxide (TBH), are repaired with fast and slow components of similar magnitude to IR-induced DSBs and have a similar requirement for ATM and Artemis. Strikingly, DSBs accumulate in ATM−/− mouse embryo fibroblasts (MEFs) and in ATM or Artemis-defective human primary fibroblasts maintained for prolonged periods under confluence arrest. The accumulated DSBs localize to HC-DNA regions. Collectively, the results provide strong evidence that oxidatively induced DSBs arise in HC as well as euchromatic DNA and that Artemis and ATM function in their repair. Additionally, we show that Artemis functions downstream of ATM and is dispensable for HC-relaxation and for pKAP-1 foci formation. These findings are important for evaluating the impact of endogenously arising DNA DSBs in ATM and Artemis-deficient patients

HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication